as 
 explained in more detail in our previous report , in the course of a screening campaign of new chemical entities against infectious agents , compounds 1 and 2 were found active on our whole cell measles virus replication assay 
 ( figure 1 ) .
an 
 initial structure  activity study led to confirmation of the 
 potential of this original chemotype and to greatly improved antiviral 
 compounds , including the 2-(3-isopropyloxy-1h - pyrazol-1-yl)pyrimidine 
 derivative 3 , which displayed a subnanomolar mic50 on this measles virus replication assay ( figure 1 ) .
moreover , a search for the biochemical mechanism 
 of action of this series pointed out that , as for other recently reported 
 compounds , the inhibition of the cellular dihydroorotate dehydrogenase ( dhodh ) 
 is at the origin of the antiviral effect .
from these results , in order to increase the chemical diversity 
 possible in this series , we initially replaced the pyrimidine ring 
 by a pyridine moiety because its additional carbon would provide another 
 position for structure  activity studies .
accordingly , as in 
 our first report , we are describing here 
 a succession of synthesis campaigns 
 followed by comments on the antiviral effect obtained . most of these 
 results are presented in tables in which the first result column ( % ) 
 provides the yield of the reaction depicted and the second column 
 describes the observed antiviral effect expressed as pmic50 values .
this corresponds to the negative 
 log of the minimum compound concentration required to inhibit viral 
 growth by 50% when using a recombinant measles virus strain expressing 
 a luciferase as a reporter .
we first 
 undertook the preparation of the 2-pyridyl derivatives 6a  t depicted in table 1 .
as compound 2 , these analogues were prepared from 
 the 3-ethoxypyrazole 4(10 ) and 
 commercially available 2-halogenopyridines 5a  p . from 2-halogenopyridines featuring electron - attracting 
 substituents ,
the use of cesium carbonate in dry dimethylformamide 
 or acetonitrile and heating at 150 c with a microwave oven for 
 1 h efficiently gave the n - pyridyl derivatives .
on 
 the other hand , from 2-fluoropyridines featuring electron donating 
 substituents , a temperature of 180 c ( under pressure ) was found 
 necessary and , because of its decomposition into dimethylamine , dimethylformamide 
 was replaced by acetonitrile . for the preparation of compound 6a(7 ) or 6p , we used 
 2-bromopyridine 5a or 5p and taillefer and 
 cristau copper - catalyzed arylation conditions . moreover , as for compound 1 , the regioselectivity 
 of these reactions was unambiguously checked in a couple of instances .
miyaura reaction between 
 cyclopropyl boronic acid and the 5-bromo derivatives 6j . alternatively , as described in the experimental 
 section , the 2-fluoropyridines 5q  s were prepared via suzuki 
miyaura reactions between 
 cyclopropyl boronic acid and the corresponding 5-bromo precursors . 
 from them ,
the analogues 6q  s were 
 then obtained by n - arylation of 4 .
the n - arylation of 
 compound 4 with 2-(6-fluoropyridin-3-yl)propan-2-ol ( 5 t ) gave the hydroxylated analogue 6 t , and a 
 reduction of its alcohol function led to the 5-isopropyl derivative 6u .
interestingly , the palladium - catalyzed hydrogenation at 
 room temperature of 6 t was mostly inefficient . to avoid 

the use of high hydrogen pressure , which would probably have also 
 resulted in the hydrogenation of the pyridine ring , we used triethylsilane in the presence of trifluoromethanesulfonic 
 acid and achieved its hydrogenation into 6u in an unoptimized 
 24% yield . concerning the antiviral effects , as seen in table 1 , the  methyl scan  leading to compounds 2 and 6b  d , pointed out the 
 importance of occupying the position 5 of the pyridine ring for a 
 tangible antiviral effect ( pmic50 = 6.2 for compound 2 ) .
the lack of substituents or the introduction of a small 
 fluorine atom seen in 6a , 6e , and 6f also gave almost inactive compounds although some improvement 
 can be observed when comparing the antiviral effect of compound 6a ( pmic50 < 5 ) and the 3-fluorinated derivative 6e ( pmic50 = 5.2 ) . the recourse to a trifluoromethyl 
 ( compound 6 g ) or a chlorine atom ( compound 6i ) on position 5 gave slightly more active analogues ( both pmic50 of 5.5 ) , but the bigger bromine present in compound 6j did not improve this further ( pmic50 = 5.3 ) . 
 on the other hand , the combination of the 3-fluoro and 5-bromo substituents 
 seen in compound 6k appeared to be the cause of slight 
 synergic effect ( pmic50 = 5.9 ) when considering the pmic50 of the parent monosubstituted compounds 6e and 6j ( respectively 5.2 and 5.3 ) .
in contrast to a fluorine group , 
 the 3-methyl substituent of 5-brominated derivative 6l led only to a weak antiviral effect .
a loss of effect was also seen 
 for the three derivatives 6 m , 6n , and 6o featuring respectively a cyano , an ester , or a methyl ketone 
 on position 5 . to a lesser extent ,
a similar phenomenon was observed 
 with the methoxy of compound 6p ( pmic50 = 
 5.5 ) .
it is only the introduction of the cyclopropyl group featured 
 by compound 6q that led to an improved inhibition of 
 the virus replication ( pmic50 = 7.0 nm ) .
combination of 
 this group with the fluorine of compound 6r led to an 
 unchanged antiviral effect ( pmic50 7.0 ) , whereas the nitrile 
 of compound 6s replacing this fluorine caused a loss 
 ( pmic50 = 6.6 ) .
interestingly , the branched isopropyl derivative 6u turns out to be an order of magnitude less active ( pmic50 = 5.9 ) than the cyclopropyl analogue 6q . finally , 
 the polar hydroxyl moiety of compound 6 t ( pmic50 5.3 ) led to an even bigger loss of effect in comparison with the 
 hydrogen - bearing isopropyl group of compound 6u .
< 2% . using 2-bromopyridine and a 
 copper 
 catalyst . using 2-bromo-5-methoxypyridine 
 and a copper catalyst see text and experimental section
. from 6j , 
 see text and experimental section . from 6 t , see text and experimental section . as for the pyrimidine - containing series , by arylation of the 4-aryloxypyrazoles 7a  q with the 2-fluoropyridine 5q , we prepared the 
 4-aryloxy derivatives 8a  q depicted 
 in table 2 .
later on , we also prepared the 
 corresponding pyridazine homologues 10b  q from 3-chloro-6-cyclopropylpyridazine ( 9 ) . 
 for comparison purposes , table 2
the pattern 
 of antiviral effect for analogues 8a  q featuring a 5-cyclopylpyridine is somehow mirroring the one seen 
 for the 5-ethylpyrimidyl bearing homologues . in comparison with the phenoxy - bearing compound 8a ( pmic50 = 7.0 ) , ortho - substitution with a fluorine , a chlorine of 
 a bromine atom improved the antiviral effect ( pmic50 of 
 respectively 7.7 , 7.9 , and 7.8 ) .
a trifluoromethyl group instead of 
 these halogens had a lesser effect ( compound 8e , pmic50 = 7.3 ) . shifting this trifluoromethyl group on the meta 
 position of the phenoxy ring did not alter much the antiviral effect 
 ( pmic50 = 7.1 for 8f ) , whereas placing this 
 group on the para position led to a substantial loss ( pmic50 = 5.3 for 8 g ) .
a similar trend is observed with the 
 fluorine atom of compounds 8k  m , 
 the ortho - fluoro derivative 8k being 
 the most active ( pmic50 = 7.4 ) and the para - fluorinated analogue 8 m far less effective ( pmic50 = 5.9 )
although ortho - substituted derivatives 
 are the most active but , as in the pyrimidine series , with a pmic50 of 9.0 , the 2,6-difluorophenoxy 
 derivative 8q is the best antiviral of this group of 
 analogues .
very similar comments can be made on the antiviral effects 
 of compounds 10b  q , and the differences 
 between any given pair of analogues is always less than an order of 
 magnitude .
( i ) cs2co3 , mecn , 
 microwave 180 c 6 h or 2 h. log(mic50 ) , mic50 in mol / l , standard 
 deviation < 2% . as depicted 
 in scheme 1 , we also explored 
 the preparation and use of precursors featuring a 5-cyclopropylpyridine 
 moiety to which additional chemistry would allow the introduction 
 of various group on the carbon 4 of the pyrazole ring .
the n - arylation 
 of the 4-iodopyrazole 11a(5 ) with 5-cyclopropyl-2-fluoropyridine ( 5q ) had to be 
 conducted at 180 c for up to 12 h and only led to a rather small 
 amount ( 13% ) of the 4-iodinated target compound 12a along 
 with some ( 9% ) of the reduced derivative 12b .
this is 
 quite in contrast with the 55% yield we reported for the n - arylation 
 of compound 11a with 2-fluoropyridine at the same temperature 
 for 3 h. extensive analysis of the reaction 
 mixture pointed out the presence of a large amount of 3-ethoxy-5-methylpyrazole 
 ( 11b ) resulting from the reduction of the 4-iodopyrazole 11a under this long reaction time . although an explanation 
 for this reduction is not obvious ( a carbene occurrence ? ) , we suggest 
 that the much decreased reactivity of the electron rich 5-cyclopropyl-2-fluoropyridine 
 ( 5q ) toward nucleophilic reaction in comparison with 
 2-fluoropyridine is allowing the necessary time for this side reaction 
 to proceed to a large extent .
somehow related to such behavior is 
 the quick evolution of iodine , or iodochloride , upon heating 3-ethoxy-4-iodopyrazole 
 in hydrochloric acid . in any case , the 
 iodinated target compound 12b was treated with butyllithium 
 followed by the addition of benzoyl chloride to give the 4-benzoyl 
 derivative 13 in 44% yield . in an attempt to improve 
 these results , we undertook the n - arylation of the 4-bromopyrazole 11c . under similar conditions ,
the sodium 
 borohydride reduction of ketone 13 led to the secondary 
 alcohol 14a , whereas the addition of methyl lithium to 
 ketone 13 provided an access to the tertiary alcohol 14b . from compound 12c , palladium - catalyzed reactions 
 allowed the preparation of few analogues .
miyaura 
 reaction with phenylboronic acid gave 33% of compound 15 , whereas negishi reactions with benzylzinc bromide or ( 1-phenylethyl)zinc 
 chloride gave compounds 6q and 16 in , respectively , 
 71 and 42% .
of note in this part is an optimization of the preparation 
 of 1-phenylethylzinc chloride using the lithium chloride , dibromoethane , 
 and trimethysilyl chloride - based protocol as well as 
 the use of cphos instead of xphos in an attempt to lessen the extent 
 of -elimination possible with ( 1-phenylethyl)zinc chloride . concerning the antiviral effects of these compound , 
 as for the pyrimidine - containing series , the benzoyl derivative 13 ( pmic50 = 6.9 ) 
 was slightly less effective than the corresponding methylene analogue 6q ( pmic50 = 7.0 ) .
on the other hand , the alcohol 14a retained a more sizable antiviral effect ( pmic50 = 7.4 ) but the gain is far from what we could observe in the case 
 of the pyrimidine - containing series . introducing 
 an additional methyl on this carbon led the tertiary alcohol 14b and to a much reduced antiviral activity ( pmic50 = 6.1 ) .
= 7.0 ) , leading to the much less effective 
 analogue 16 ( pmic50 = 5.2 ) . finally , the low 
 antiviral effect of the 4-phenyl derivative 15 ( pmic50 = 6.0 ) pointed out the importance of a bridge between the 
 pyrazole and the aromatic ring .
( i ) 5-cyclopropyl-2-fluoropyridine 
 ( 5q ) , mecn , microwave 180 c 12 h ; ( ii ) ( a ) buli , 
 thf , 78 c , ( b ) phcocl , 78  20 c ; 
 ( iii ) nabh4 , etoh ; ( iv ) meli , thf , 20 c ; ( v ) phb(oh)2 , pddppf , cs2co3 , proh / h2o ; ( vi ) phch2znbr , xphos , or phchmezncl , cphos , pd(oac)2 , thf , 50 c .
as depicted in 
 table 3 , we then retained 
 the 2,6-difluorophenoxy component of compound 8q and 
 prepared the 2-pyridyl derivatives 18a  s .
analogues 18a  n were obtained 
 by the n - arylation of the pyrazole 7q by the corresponding 
 2-halogenopyridines 5a , 5 g , 5j  o , and 5q  t and the 2-fluoropyridines 17l  n ( prepared as described in the experimental section ) . in the case of the methoxy - bearing analogue 18p , 
 we used again the 2-bromo-5-methoxypyridine ( 5p ) and 
 taillefer  cristau copper - catalyzed arylation conditions .
the following n - arylation of compound 7q with this 2-bromopyridine 17n had to be conducted at 
 a relatively lower temperature to avoid extensive decomposition , and 
 the pure difluoromethylene - bearing analogue 18n was thus 
 obtained in a modest 12% yield .
a rather slow catalytic hydrogenation 
 of the cyclopropyl ring of compound 18d enabled an access 
 to the propyl analogue 18o in a 30% yield .
the preparation 
 of analogues 18p  r turned out to 
 be possible as , under basic conditions , the fluorine atom on the pyridine 
 ring of 18d could be displaced by methanol , dimethylamine , 
 or benzylalcohol using high temperature and a microwave oven .
in the 
 last case , the catalytic hydrogenation of the resulting 3-benzyloxyderivative 18r led to the 3-hydroxypyridinyl derivative 18s . unexpectedly , despite few trials , the direct hydrolysis of compound 18d into 18s , using sodium hydroxide in thf , 
 was not successful .
as seen in table 3 , with 
 these compounds we could assess the effect of varying the pyridine 
 substituents while retaining a 2,6-difluorophenoxy moiety .
going from 
 the hydrogen of the n - pyridine derivative 18a ( pmic50 = 4.9 ) to the 5-methyl homologue 18b ( pmic50 = 7.6 ) , a 400-fold improvement of the antiviral effect was 
 observed . from then , the 5-cyclopropyl group of compound 8q ( pmic50 = 9 ) provided another order of magnitude . on 
 the other hand ,
the ethyl group of compound 18l ( pmic50 = 7.1 ) caused a loss of antiviral effect .
this is actually 
 reminiscent of what was observed for the 5-isopropyl bearing compound 6u ( pmic50 = 5.9 ) in comparison with the 5-cyclopropyl 
 bearing analogue 6q ( pmic50 = 7.0 ) described 
 above .
moreover , it is contrasting with what we previously reported 
 for the 5-ethyl and 5-cyclopropyl pyrimidine analogues which had mostly 
 the same antiviral effect ( pmic50 = 9.2 and 8.9 ) .
replacement of the methyl group of compound 18b ( pmic50 = 7.6 ) by the trifluoromethyl of compound 18c ( pmic50 = 6.5 ) led to more than a 10-fold loss . 

if adding a fluorine atom on carbon 3 of the pyridine ring has very 
 little effect when comparing the 5-ethyl bearing analogues 18l and 18 m ( pmic50 both of 7.1 ) , a 2-fold loss 
 was seen in comparison with the 5-cyclopropyl pair 8q and 18d ( pmic50 = 9 and 8.6 ) . on the other 
 hand , as for the pair of analogues 6j and 6k , a fluorine on the same position is improving the antiviral effect 
 when comparing the activity of the 5-bromo derivatives 18f and 18 g ( pmic50 = 6.3 and 6.9 ) .
attempts 
 to introduce various polar groups on carbon 5 of the pyridine ring 
 such as the one seen in compound 18i  k did not improve the antiviral effect , and the two fluorine atoms 
 of compound 18n ( pmic50 = 7.1 ) had no effect 
 in comparison with the 5-ethyl analogue 18l ( pmic50 = 7.1 ) . only relatively small losses were observed for the 
 bis - substitued derivatives 18p  s featuring 
 a cyclopropyl group .
interestingly , the influence of the methoxy moiety 
 of compound 18p ( pmic50 = 7.5 ) is comparable 
 to the dimethylaminated derivative 18q ( pmic50 = 7.5 ) , whereas the hydroxyl - bearing analogue 18o ( pmic50 = 8.1 ) displayed a relatively stronger activity . somehow 
 unexpectedly ,
the larger benzyloxy group of compound 18r ( pmic50 = 7 ) only caused a relatively small loss of antiviral 
 effect . in any case , none of the analogues described in table 3 displayed an antiviral effect better than the nanomolar 
 level of compound 8q .
< 2% . using 2-bromo-5-methoxypyridine 
 and a copper catalyst , see text and experimental 
 section . by catalytic 
 reduction of 18d
reduction of 18r , see 
 text and experimental section . as depicted in figure 2 and fully described 
 in the experimental section , from the 2,6-difluorophenoxy 
 pyrazole 7q , some other possible azines - bearing compounds 
 such as 3-pyridyl and 5-pyrimidyl , the 2-pyrazinyl and the 1,2,4-triazine 
 derivatives were also prepared .
the 3-pyridyl bearing compounds 19a  c were made by the taillefer  cristau copper catalyzed n - arylation of 7q with the commercially available 5-bromo-2-methyl , 5-bromo-2-ethyl , 
 and 5-bromo-2-methoxypyridines .
the 5-pyrimidyl derivative 20a was also made with the copper catalyzed reaction between 7q and 5-bromo-2-tert - butylpyrimidine .
for the preparation 
 of the 5-cyclopropyl analogue 20b , we had recourse to 
 the n - arylation of compound 7q with a small sample of 
 2-cyclopropylpyrimidin-5-ylboronic acid using lam and chan reaction 
 conditions .
the n - arylation of 2,6-difluorophenoxy 
 pyrazole 7q with 2,5-dibromopyrazine led to the 5-bromopyrazine 
 analogue 21a .
the 
 methoxy - bearing analogue 21c was then made from 21a by displacement of the bromine atom with methanol under 
 basic conditions .
as described in the experimental 
 section , the preparation of 2-bromo-5-cyclopropylpyrazine allowed 
 the synthesis of the cyclopropyl - bearing analogue 21d by n - arylation . in similar ways ,
the pyridazine - bearing analogues 10q and 22a  b were prepared 
 from the corresponding chloropyridazines .
the methoxy or ethoxy - bearing 
 analogues 22c  d were made by displacement 
 of the chlorine atom of compound 22b with the corresponding 
 alcohols because an n - arylation trials using 3-chloro-6-methoxypyridazine 
 led to extensive side reactions , including , as seen by lc / ms , a methylation 
 of compound 7q .
the 1,2,4-triazine - bearing analogue 23 was prepared in a modest 10% yield by the n - arylation of 
 compound 7q with 6-ethyl-3-(methylthio)-1,2,4-triazin-5-ol 
 ( preparation given ) at 200 c . finally ,
as fully described in 
 the experimental section , we also prepared 
 the n - ethyl imidazole - bearing analogues 24 by the copper 
 catalyzed n - arylation of compound 7q with 1-ethyl-4-iodo-1h - imidazole . in view of the antiviral effect of the azine - bearing 
 analogues 8q , 10q , 19b , and 21d
, one fact clearly stands out . as for the 2-pyrimidyl analogues 
 previously studied , an ethyl or a cyclopropyl group para to the pyrazole ring often provides a low nanomolar antiviral effect . 

however , this is not true for the 2-cyclopropylpyrimidine derivative 20b ( pmic50 = 6.8 ) or the triazine 23 ( pmic50 = 7.6 ) , which is in this case featuring an additional 
 hydroxyl group . attempt to replace such alkyl groups by side chains 
 of similar size but featuring more polar groups mostly failed , as 
 seen for the 2-methoxypyridine derivative 19c ( pmic50 = 6.0 ) , the 2-methoxypyrazine 21c ( pmic50 = 6.1 ) , or the 3-methoxypyridazine 22c ( pmic50 = 7.1 ) .
the same trend was observed for the halogen - bearing 
 analogues 21a  b ( pmic50 = 5.5 and 5.3 ) or 22b ( pmic50 = 6.8 ) .
finally , 
 the relatively low antiviral effect of the n - ethylimidazole derivative 23 may be another example of the trend which points at a detrimental 
 effect of polar atoms ( a nitrogen in this case ) in the vicinity of 
 this alkyl side chain .
the elucidation of the biochemical 
 target of our series has led us to publish a survey of all the reported 
 inhibitors of dhodh along with their uses .
this review pointed out that teriflunomide ( 25 ) depicted 
 in figure 3 is the only human dhodh inhibitor 
 used in medicine against autoimmune diseases such as rheumatoid arthritis 
 and multiple sclerosis .
interestingly , in our cellular assay , teriflunomide 
 ( 25 ) displayed an antiviral effect with an mic50 of 5 m , which is reflected in the previously reported ic50 of 1 m on recombinant human dhodh .
this relatively modest effect of teriflunomide ( 25 ) 
 on the enzyme had actually triggered the search and the discovery 
 of some off - target inhibitions in the past .
this value 
 can also be compared to the enzymatic ic50 of 10 nm reported 
 for brequinar ( 26 ) , a stronger 
 inhibitor of dhodh which underwent disappointing phase ii trials against 
 solid tumors .
structure 
 and antiviral effect of teriflunomide 
 ( 25 ) and brequinar ( 26 ) . to assess the potential of our series in comparison 
 with these 
 compounds
, we undertook an array of biological assays using compound 18d . in cellulo , as depicted in figure 4 , we could point out that compound 18d is affecting 
 pyrimidine nucleoside biosynthesis . indeed ,
while adding 18d at concentration varying from 4 to 100 nm blocked the measles virus 
 replication in cells , the addition of the pyrimidine - containing nucleoside 
 uridine at 10 g / ml ( figure 4a ) restored 
 its replication . on the other hand ,
the addition of the purine - containing 
 nucleoside guanosine at 10 g / ml did not restore this ( figure 4b ) .
moreover , a restored virus replication was seen 
 with the addition of orotic acid at 3 mm ( figure 4c ) while , as seen in figure 4d , dihydroorotic 
 acid at 3 mm had no such effect .
these last results thus narrowed 
 down the biochemical target of compound 18d to dhodh . 

accordingly , as reported , we produced 
 recombinant human dhodh and compound 18d was indeed found 
 to be an inhibitor of this enzyme with an ic50 of 25  
 5 nm .
t cells were infected with recombinant mv strain expressing 
 luciferase ( multiplicity of infection = 0.1 ) , incubated with dmso 
 alone or 18d at 4 , 20 , or 100 nm , and culture medium 
 was supplemented with uridine ( a ) , guanosine ( b ) , orotate ( c ) , or 
 dihydroorotate ( d ) .
experiment was performed in triplicate , and data represent means  
 sd . by using a metabolite analysis 
 protocol , the hek-293 t cells content 
 in adenosine triphosphate ( atp ) , guanosine 
 triphosphate ( gtp ) , cytidine triphosphate ( ctp ) , and uridine triphosphate 
 ( utp ) treated for 24 h with various concentration of compound 18d could be determined .
as seen in table 4 , intracellular concentrations of uridine and cytidine collapsed 
 in cells treated with 18d , whereas purine nucleotides 
 concentrations were slightly increased , likely as a consequence of 
 the control loops connecting purine and pyrimidine metabolic pathways . 

this strongly demonstrates in cell cultures the inhibition of de novo 
 pyrimidine biosynthesis by 18d .
we recently reported that the inhibition of pyrimidine biosynthesis 
 amplifies cellular response to pathogen - associated molecular patterns 
 such as exogenous rna molecules . when 
 transfecting cells with small synthetic rna molecules ( ssrna ) that 
 mimic viral rna genomes or transcripts , activation of the interferon - stimulated 
 response element ( isre ) that drives innate immunity genes was enhanced 
 by dhodh inhibition .
as depicted in figure 5 , we thus monitored that compound 18d increased the 
 expression of an isre - luciferase reporter gene when transfecting cells 
 with ssrna molecules .
this adds to the panel of cellular assays that 
 support the inhibition of pyrimidine biosynthesis by compound 18d .
( top ) hek-293 t cells with the isre - luciferase reporter 
 gene ( sting-37 cells ) were transfected with increasing doses of synthetic 
 5-triphosphate rna molecules ( ssrna ) and incubated in the 
 presence of compound 18d or dmso alone in 96-well cultures 
 plates . after 24 h , luciferase expression was determined .
( bottom ) 
 same experiment was performed in the presence of uridine at 30 g / ml . 
 both experiments were performed in duplicate , and the data represents 
 means  sd . aside from their antiviral 
 effect , pyrimidine biosynthesis inhibitors 
 are also well - known for blocking the proliferation of lymphocytes , 
 and this probably accounts for their immunosuppressive property in 
 vivo .
accordingly , we also determined 
 the effect of compound 18d on the growth of jurkat t 
 lymphocyte cell line , which has been demonstrated to be sensitive 
 to dhodh inhibitors .
as shown in figure 6 , compound 18d strongly inhibited jurkat cells 
 proliferation ( ic50 = 0.02 m ) and its level of inhibition 
 compared favorably with brequinar ( ic50 = 0.2 m ) 
 or teriflunomide ( ic50 close to 60 m , data not shown ) . inhibition 
 ( % ) of jurkat cells proliferation by compound 18d and 
 brequinar ( 26 ) .
jurkat cells were incubated 
 with increasing doses of 18d or brequinar . as a control , 

cells were treated with dmso alone . at t = 0 and 
 after 72 h of culture , the number of living cells was determined using 
 the celltiter - glo reagent .
the inhibition of cellular proliferation 
 is expressed as a percentage relative to dmso - treated control wells . 

also of much interest 
 is the recent demonstration that plasmodium falciparum dhodh is a valid target for 
 the treatment of malaria and that a dual inhibition of human and p. falciparum dhodh was noticed for some series .
accordingly , we screened all 
 these antiviral compounds for a potential inhibition of p. falciparum growth .
no growth inhibition was seen 
 in a cellular assay at the concentration of 8.66 g / ml ( data 
 not shown ) for all the compounds aside from a modest effect for the 
 pyridazine - bearing analogues 10q and 22a ( ic50 of 0.33 and 0.47 m ) .
of course , these values 
 led us to prepare many more pyridazine - bearing analogues , including 
 compound 10b  p , but all of them turned 
 out to be at least an order of magnitude less effective on the parasite 
 growth . just in case , compound 10q and 22a were also assayed for their eventual inhibition of recombinant p. falciparum dhodh but they turned out to be completely 
 devoid of effect on this biochemical assay .
in conclusion , along with our previous report , this study made good use of the alkoxypyrazole 
 chemistry 
 we previously reported , which somehow cleared a sort of  chemical blind spot  
 existing in pyrazole chemistry .
the ensuing screenings of the resulting 
 new chemical entities led us to extensively explore the structure 
activity 
 relationship of a new series of human dhodh inhibitors . of note is 
 a cellular antiviral assay which greatly simplified the evaluation 
 of the compounds prepared and probably filtered out analogues of low 
 cell membrane permeability . concerning the potential of this series 
 of inhibitors against immune diseases , the current success of teriflunomide 
 ( 25 ) has led to renewed interest in 
 the search for better inhibitors of human dhodh .
quite a few strong 
 acid - bearing human dhodh inhibitors have thus emerged and are currently 
 at various stage of clinical development for the treatments of autoimmune 
 diseases or graft rejection . because all these compounds , as well as brequinar ( 26 ) , are featuring a carboxylic acid function , we are currently working 
 on the selection of compounds displaying optimal preclinical properties 
 in order to secure a proof of effect on an animal model of autoimmune 
 disease .
this endeavor is based on the reasonable assumption that 
 our carboxylic acid - free series of inhibitors could display a different 
 and beneficial pharmacological profile in comparison with the inhibitors 
 currently in preclinical or clinical studies .
however , so far , our 
 best inhibitors can be only considered as tools as a too short microsomal 
 stability has been a recurrent feature for this series . indeed , low 
 half - life values were observed for compounds such as 8k ( t1/2 = 4 min ) or 8q ( t1/2 = 6 min ) on human microsomes and only modest 
 improvements were seen for the  fluorine - protected
 
 compound 18d ( t1/2 = 2741 
 min ) , the  hydroxy - protected
 compound 18s ( t1/2 = 38 min ) , or the less active 
 analogues 22c ( t1/2 = 22 
 min ) and 18 g ( t1/2 = 60 min ) . 
 related to
this aspect is a report mentioning similar difficulties 
 for another type of n - arylated pyrazoles .
accordingly , additional work will be required to improve this and 
 the x - ray based determination of the binding mode of this series of 
 inhibitors to human dhodh could be very useful in this regard . finally , 
 these results are probably an illustration of the interest of designing 
 whole cell / phenotypic assays of sufficient sensitivity ( a bioluminescent 
 virus in the present case ) .
this led 
 us to detect an unexpected biological effect and provided a simple 
 biological mean not only to undertake further structure  activity 
 study but also to find the mode of action of this series of compounds .
hek-293 t cells ( atcc ) 
 were maintained in dulbecco s modified eagle s medium 
 ( dmem ; gibco - invitrogen ) containing 10% fetal calf serum ( fcs ) , penicillin , 
 and streptomycin at 37 c and 5% co2 .
antiviral activity 
 of compounds was determined using a recombinant vaccine strain of 
 measles virus expressing firefly luciferase ( rmv2/luc ) from an additional 
 transcription unit . to determine the 
 mic50 ,
hek-293 t cells were infected with rmv2/luc ( moi 
 = 0.1 ) and incubated in 96-well culture plates at 3  10 cells / well with increasing concentrations of compounds or 
 dmso alone .
the 
 mic50 corresponds to the concentration of a compound inhibiting 
 luciferase activity by 50% .
compounds were screened against p. falciparum 3d7 strain parasites with a starting 
 parasitemia of 0.8% at 2% hematocrit 
 in 96-well plates .
parasite growth and proliferation was measured using 
 sybr green i. the 
 assay was performed as described previously .
this 
 enzyme was expressed as recombinant proteins in escherichia 
 coli and purified as previously described .
steady - state kinetic analysis was performed using the 2,5-dichloroindophenol 
 ( dcip)-based spectrophotometric method as described .
enzyme and substrate concentrations were : dhodh ( e = 510 nm ) and substrates ( 0.2 mm l - dihydroorotate 
 and 0.02 mm coqd ) .
the 100 compound stock solutions were made 
 in dmso by covering a 3-fold dilution series such that final concentrations 
 in the assay for inhibition ranged from 0.001100 m .
one day later , culture medium 
 was supplemented with increasing doses of compound 18d or dmso alone .
after an additional 24 h of culture , cells were harvested , 
 carefully counted , and monitored for viability by trypan blue exclusion . 

sting-37 
 cell line was 
 previously described and corresponds to hek-293 t cells that express 
 luciferase under control of five interferon - stimulated response elements 
 ( isre ) .
cells were transfected with increasing 
 amounts of ssrna molecules using jetprime pei reagents ( polyplus transfection ) 
 and dispensed in 96-well plates at 35000 cells / well in 100 l 
 of dulbecco s modified eagle s medium ( dmem ; gibco - invitrogen ) 
 containing 10% fetal calf serum ( fcs ) , penicillin , and streptomycin . 

dmso or compound 18d was added to culture medium , and 
 after mixing , cells were cultured for 24 h at 37 c and 5% co2 .
finally , firefly luciferase activity was determined using 
 the bright - glo reagent following manufacturer s recommendations 
 ( promega ) .
jurkat cells 
 were cultured in at 5  10 cells per well in flat - bottom 
 96-well culture dishes .
cells were maintained at 37 c and 5% 
 co2 in rpmi ( gibco - invitrogen ) containing 10% fetal calf 
 serum ( fcs ) , pyruvate sodium , nonessential amino acids , penicillin , 
 and streptomycin .
number of living cells was determined by quantification 
 of adenosine triphosphate ( atp ) in culture wells using the celltiter - glo 
 assay ( promega ) following manufacturer s recommendations .
this 
 luciferase - based assay evaluates by atp quantification the number 
 of metabolically active cells in culture wells .
the microsomal stability 
 assessments were subcontracted to oroxcell , romainville , france . a biotage initiator 2
h nmr 
 and c nmr spectra were recorded on a bruker avance 400 
 spectrometer at 400 and 100 mhz , respectively .
shifts (  ) are 
 given in ppm with respect to the tms signal , and coupling constants 
 ( j ) are given in hertz .
column chromatography were 
 performed either on merck silica gel 60 ( 0.0350.070 mm ) or 
 neutral alumina containing 1.5% of added water using a solvent pump 
 and an automated collecting system driven by a uv detector set to 
 254 nm unless required otherwise .
sample deposition was carried out 
 by adsorption of the mixture to be purified on a small amount of the 
 solid phase followed by its deposition of the top of the column .
the 
 low resolution mass spectra were obtained on an agilent 1100 series 
 lc / msd system using an atmospheric electrospray ionization system 
 and the high resolution mass spectra ( hrms ) were obtained using a 
 waters micromass q - tof with an electrospray ion source .
unless stated 
 otherwise , a purity of at least 95% was obtained for all the compounds 
 by means of chromatography , recrystallization , or distillation and 
 this level of purity was established by tlc , lc / ms and nmr spectroscopy under 
 an inert atmosphere , 5-bromo-2-fluoropyridine ( 5j ) ( 17 
 g , 0.096 mol ) and cesium carbonate ( 114 g , 0.35 mol ) were dispersed 
 in a 95/5 vv mixture of toluene and water ( 500 ml ) .
this was degassed 
 by gently bubbling argon in the reaction and cyclopropyl boronic acid 
 ( 10 g , 0.11 mol ) and [ 1,1-bis(diphenyl phosphino)ferrocene ] 
 dichloropalladium complexed with dichloromethane ( 1.45 g , 0.0018 mol ) 
 was added .
the flask was heated to reflux for 40 min ; upon cooling , 
 the suspension was diluted in ethyl acetate , and the filtered organic 
 layer was washed with water and brine , dried over magnesium sulfate , 
 and concentrated to dryness .
the residue was purified by a distillation 
 at ambient pressure ( e760  mm = 206 
 c ) to give a volatile oil ( 8.06 g , 62% ) . a lesser pure fraction 
 ( about 7% )
h nmr ( cdcl3 ) : 0.68 ( m , 2h ) , 1.02 ( m , 2h ) , 1.91 ( m , 1h ) , 6.81 ( m , 1h ) , 7.42 ( m , 
 1h ) , 8.02 ( m , 1h ) .
c nmr ( cdcl3 ) : 8.6 , 12.2 , 
 108.9 ( 38 hz ) ; 136.7 ( 4 hz ) ; 138.1 ( 7 hz ) ; 145.5 ( 14 hz ) ; 162.2 ( 236 
 hz ) . hrms
: too volatile for analysis . by using the procedure described for the 
 preparation of 5-cyclopropyl-2-fluoropyridine 
 ( 5q ) , this compound was obtained from 5-bromo-2,3-difluoropyrimidine 
 ( 5k ) in 63% yield , as a volatile oil , after a chromatography 
 over silica gel ( cyclohexane  dichloromethane 2/1 )
h nmr ( cdcl3 ) : 0.71 ( m , 2h ) , 1.06 ( m , 2h ) , 1.94 ( m , 1h ) , 
 7.18 ( m , 1h ) , 7.78 ( m , 1h ) .
c nmr ( cdcl3 ) : 
 9.0 , 12.2 , 123.5 ( 3 and 15 hz ) ; 139.3 , 139.4 ( 5 and 13 hz ) ; 145.4 
 ( 29 and 260 hz ) ; 150.4 ( 15 and 236 hz ) . hrms : too volatile for analysis . by using the procedure described for the preparation of 5-cyclopropyl-2-fluoropyridine 
 ( 5q ) ,
this compound was obtained from 5-bromo-2-chloronicotinonitrile 
 in 53% yield , as a solid , after a chromatography over silica gel ( cyclohexane  dichloromethane 
 1/1 ) .
h nmr ( cdcl3 ) : 0.79 ( m , 2h ) , 1.17 ( m , 
 2h ) , 1.97 ( m , 1h ) , 7.59 ( d , 1h , j = 2.5 ) , 8.38 ( d , 
 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 9.8 , 12.3 , 110.2 , 114.8 , 139.1 , 139.3 , 149.4 .
hrms calcd 
 for c9h7brn2 + h : 222.9871 . found : 
 222.9840 . under an inert atmosphere ,
5-bromo-2-fluoropyridine 
 ( 5j ) ( 3.12 g , 17.7 mmol ) was dissolved in dry ether ( 100 
 ml ) and the 
 solution cooled to 78 c .
butyl lithium ( 9.3 ml , 18.6 
 mmol , 2n in cyclohexane ) was added .
the resulting precipitate was 
 stirred at 78 c for 15 mn , acetone ( 0.4 ml , 90 mmol , 
 dried over 4  molecular sieves ) was added , and the reaction 
 was allowed to warm back to room temperature for 30 mn .
this was diluted 
 with a saturated solution of ammonium chloride and extracted with 
 ethyl acetate .
the organic layer was washed with a saturated solution 
 of ammonium chloride and brine , dried over magnesium sulfate , and 
 concentrated to dryness .
the residue was further purified by a chromatography 
 over silica gel ( dichloromethane  ethanol 98.5/1.5 ) to yield 
 compound 5 t as an oil ( 0.57 g , 20% ) .
h nmr 
 ( cdcl3 , slight differences with the reported one ) : 1.63 ( s , 6h ) , 1.89 ( s , 1h ) , 6.91 ( dd , 1h , j = 2.8 and 8.4 ) , 7.94 ( m , 1h ) , 8.33 ( m , 1h ) .
c nmr ( cdcl3 ) : 31.8 , 71.1 , 108.8 ( 37 hz ) ; 138.0 ( 8 hz ) ; 
 142.0 ( 4 hz ) ; 144.0 ( 14 hz ) ; 162.6 ( 238 hz ) .
hrms calcd for c8h10fno + h : 156.0825 . found : 156.0791 . under an 
 inert atmosphere , 5-bromo-2-fluoropyridine ( 5j )
( 5.35 
 g , 30.39 mmol ) and potassium carbonate ( 16.8 g , 121.59 mmol ) were 
 dissolved in dry dimethylformamide ( 75 ml , dried over 4  molecular 
 sieves ) . oxygen was removed from this solution by a slow stream of 
 argon , and [ 1,1-bis(diphenylphosphino)ferrocene ] dichloropalladium 
 complexed with dichloromethane ( 0.62 g , 1.52 mmol ) was added , followed 
 by a 1 m solution of triethylborane ( 40 ml , 40.4 mmol ) which was slowly 
 added with a syringe .
this darkening suspension was heated at 85 c 
 for 4 h using an oil bath .
the resulting black suspension was diluted 
 in diethyl ether and water , the organic layer was washed with water 
 5 times and brine , dried over magnesium sulfate , and cautiously concentrated 
 to dryness to take into account the volatility of the reaction product . 

the residue was purified by a chromatography over silica gel ( cyclohexane  dichloromethane 
 from 2/3 to 1/4 ) to yield the 5-ethyl derivative 17l as 
 a volatile oil ( 1.52 g , 40% ) .
h nmr ( cdcl3 ) : 
 1.25 ( t , 3h , j = 7.6 ) , 2.65 ( q , 2h , j = 7.6 ) , 6.84 ( dd , 1h , j = 3.0 and 8.4 ) , 7.61 ( m , 
 1h ) , 8.03 ( m , 1h ) .
c nmr ( cdcl3 ) : 15.3 , 25.1 , 
 108.9 ( 37 hz ) ; 136.7 ( 4 hz ) ; 140.5 ( 8 hz ) ; 145.6 ( 14 hz ) ; 162.2 ( 236 
 hz ) . hrms
: too volatile for analysis . by 
 using the protocol described for the synthesis of 2-fluoro-5-ethylpyridine 
 ( 17l ) ,
compound 17k was obtained in 17% 
 yield from 5-bromo-2,3-difluoropyridine ( 5q ) as a volatile 
 oil after a chromatography over silica gel ( cyclohexane  dichloromethane 
 from 1/1 to 1/4 ) .
h nmr ( cdcl3 ) : 1.27 ( t , 3h , j = 7.6 ) , 2.68 ( q , 2h , j = 7.6 ) , 7.40 ( m , 
 1h ) , 7.80 ( m , 1h ) .
c nmr ( cdcl3 ) : 15.1 , 25.0 , 
 125.9 ( 3 and 14 hz ) ; 138.9 ( 4 hz ) , 140.3 ( 5 and 12 hz ) , 145.2 ( 28 
 and 260 hz ) , 150.4 ( 14 and 235 hz ) . hrms : too volatile for analysis . 

another fraction of this chromatography led , after a recrystallization 
 in cyclohexane , to 5,5,6,6-tetrafluoro-3,3-bipyridine 
 in a 25% yield as fine needles .
h nmr ( cdcl3 ) : 7.75 ( m , 2h ) , 8.18 ( m , 2h ) .
c nmr ( cdcl3 ) : 125.2 ( 4 and 16 hz ) , 131.1 ( 5 hz ) , 139.7 ( 6 and 13 hz ) , 145.7 
 ( 29 and 264 hz ) , 152.2 ( 14 and 242 hz ) .
calcd for c10h4f4n2 : c , 
 52.64 ; h , 1.77 ; n , 12.28 . found : c , 52.44 ; h , 1.84 ; n , 12.26 . in a closed teflon flask , 1-(6-bromopyridin-3-yl)ethanone 
 ( 5o ) ( 0.95 g , 4.75 mmol ) and bis(2-methoxyethyl)aminosulfur 
 trifluoride ( 3.6 g , 11.4 mmol ) were stirred for 7 days ( as only a 
 78% conversion was monitored by h nmr , a longer reaction 
 time may lead to an even better yield ) .
this was diluted in water , 
 solid calcium chloride was added , and the solution was extracted with 
 ethyl acetate .
the organic layer was washed with water and brine , 
 dried over magnesium sulfate , and concentrated to dryness ( not for 
 too long , this compound is volatile ) .
the residue was purified by 
 a chromatography over silica gel ( cyclohexane dichloromethane 
 1/1 ) to yield the difluorinated pyridine 17n as a colorless 
 and volatile oil ( 0.57 g , 54% ) .
h nmr ( cdcl3 ) : 1.96 ( t , 3h , j = 18 ) , 7.57 ( d , 1h , j = 8.3 ) , 7.69 ( dd , 1h , j = 2.3 and 8.3 ) , 8.20 ( m , 
 1h ) .
c nmr ( cdcl3 ) : 25.7 ( 29 hz ) ; 120.5 ( 240 
 hz ) ; 128.0 , 133.2 ( 27 hz ) ; 135.0 ( 5 hz ) ; 143.7 ( 2 hz ) ; 146.9 ( 6 hz ) . 

hrms calcd for c7h6brf2n + h : 221.9730 . 
 found : 221.9667 . under 
 an inert atmosphere , 
 2,5-dibromopyrazine ( 0.21 g , 0.88 mmol ) and cesium carbonate ( 1.12 
 g , 3.43 mmol ) were dispersed in a 95/5 v / v mixture of toluene and 
 water ( 5 ml ) .
this was degassed 
 by gently bubbling argon in the reaction , and [ 1,1-bis(diphenylphosphino)ferrocene ] 
 dichloropalladium complexed with dichloromethane ( 0.018 g , 0.022 mmol ) 
 and cyclopropyl boronic acid ( 0.098 g , 1 .
the 
 flask was heated to reflux for 30 min ; upon cooling , the suspension 
 was diluted in ethyl acetate , the filtered organic layer was washed 
 with water and brine , dried over magnesium sulfate , and concentrated 
 to dryness .
this was residue was purified by a chromatography over 
 silica gel ( cyclohexane  ethyl acetate 97/3  9/1 to 
 yield the 2-bromo-5-cyclopropylpyrazine ( 0.08 g , 45% ) as a solid .
h nmr ( cdcl3 ) : 1.09 ( m , 4h ) , 2.03 ( m , 1h ) , 8.26 
 ( d , 1h , j = 1.4 ) , 8.48 ( d , 1h , j = 1.4 ) .
c nmr ( cdcl3 ) : 10.6 , 14.1 , 136.8 , 
 143.0 , 146.5 . 157.3 .
hrms calcd for c7h7brn2 + h : 198.9871 . found : 198.9784 . by 
 using the same procedure used for the preparation of 2-bromo-5-cyclopropylpyrazine , 

this compound was obtained in 40% yield as a solid ( on a much larger 
 scale ) , from 3,6-dichloropyridazine , after two consecutive chromatography 
 processes over silica gel ( dichloromethane  ethanol 99/1 ) and 
 the second using only dichloromethane to yield the 2-bromo-5-cyclopropylpyrazine .
h nmr ( cdcl3 ) : 1.20 ( m , 4h ) , 2.15 ( m , 1h ) , 7.21 
 ( d , 1h , j = 8.8 ) , 7.35 ( d , 1h , j = 8.8 ) .
c nmr ( cdcl3 ) : 10.9 , 15.4 , 127.0 , 
 127.6 , 154.2 , 164.0 .
hrms calcd for c7h7cln2 + h : 155.0376 . found : 155.0354 . first step . 

preparation of 2-(2-carbamothioylhydrazono)butanoic acid : as previously 
 described , 2-oxobutyric acid ( 3.15 g , 
 0.0308 mol ) and thiosemicarbazide ( 2.81 g , 0.0308 mol ) were stirred 
 in water ( 60 ml ) at 70 c for 10 min .
this was left to cool , 
 and the precipitate was filtered , washed with water , and dried at 
 50 c under vacuum to give the hydrazone ( 4.47 g , 82% ) as 4/17 
 mixture of isomers .
h nmr ( dmso - d6 ) : ( major isomer ) 0.93 ( t , 3h , j = 7.5 ) , 
 2.65 ( q , 2h , j = 7.5 ) , 8.59 ( s , 1h ) , 8.68 ( s , 1h ) , 
 10.85 ( s , 1h ) ; ( minor isomer ) 1.08 ( t , 3h , j = 7.4 ) , 
 2.44 ( q , 2h , j = 7.4 ) , 8.01 ( s , 1h ) , 8.65 ( s , 1h ) , 
 12.15 ( s , 1h ) .
c nmr ( dmso - d6 ) major isomer , 10.8 , 18.7 , 143.3 , 164.8 , 180.4 ; minor isomer , 11.6 , 
 26.8 , 139.0 , 164.4 , 179.1 .
preparation of 6-ethyl-3-mercapto-1,2,4-triazin-5-ol : 
 as previously described , the hydrazone 
 ( 4.24 g , 0.0269 mol ) and sodium carbonate ( 2.56 g , 0.0269 mol ) were 
 heated to reflux in water ( 300 ml ) for 3 h. the solution was made 
 acid with acetic acid and extracted with ethyl acetate . the organic 
 layer was washed with brine , dried over sodium sulfate , and concentrated 
 to dryness to yield the 1,2,4-triazin-5-ol as a white powder ( 3.09 
 g , 86% ) .
h nmr ( dmso - d6 ) : 
 1.07 ( t , 3h , j = 7.6 ) , 2.50 ( q , 2h , j = 7.6 ) , 12.99 ( s , 1h ) , 13.28 ( s , 1h ) .
c nmr ( dmso - d6 ) : 10.3 , 23.0 , 152.1 , 153.5 , 173.7 .
methylation of this compound : in water ( 30 ml ) , sodium 
 hydroxide ( 1.25 g , 0.031 mol ) was dissolved , and after cooling , the 
 1,2,4-triazin-5-ol ( 2.46 g , 0.015 mol ) was dissolved . methyl iodide 
 ( 1.07 ml , 0.017 mmol ) , diluted in tetrahydrofuran ( 2 ml ) , was then 
 slowly added .
the solution was stirred at room temperature for 4 h ; 
 this was diluted with water , made acid with acetic acid , and extracted 
 with ethyl acetate .
the organic layer was washed with brine , dried 
 over magnesium sulfate , and concentrated to dryness to yield the pure 
 thioether as a white powder ( 2.28 g , 85% ) .
h nmr ( dmso - d6 ) : 1.07 ( t , 3h , j = 7.6 ) , 
 2.50 ( q , 2h , j = 7.6 ) , 12.99 ( s , h ) , 13.28 ( s , 1h ) .
c nmr ( dmso - d6 ) : 10.5 , 12.5 , 
 23.6 , 153.6 , 160.7 , 164.4 .
step 1 : 
 under a moisture - protected atmosphere , a 50/50 mixture of 4,5-diiodo-1h - imidazole and 2,4,5-triiodo-1h - imidazole , 
 obtained when iodinating imidazole using the described procedure , and ethyl iodide ( 2.14 g , 0.0137 mol ) potassium 
 carbonate ( 3.97 g , 0.0286 mol ) were stirred in dimethylformamide ( 50 
 ml , dried over 4a molecular sieve ) for 22 h. this was diluted in water , 
 extracted with ethyl acetate , and the organic layer was washed with 
 water and brine , dried over magnesium sulfate , and concentrated to 
 dryness .
the residue was purified by a chromatography over silica 
 gel ( dichloromethane  ethanol 99/1 to 97/3 ) to give the 1-ethyl-4,5-diiodo-1h - imidazole ( 1.79 g , 37% from imidazole ) .
h 
 nmr ( cdcl3 ) : 1.43 ( t , 3h , j = 7.3 ) , 4.03 
 ( q , 2h , j = 7.3 ) , 7.64 ( s , 1h ) . c nmr 
 ( cdcl3 ) : 16.1 , 44.9 , 81.8 , 95.8 , 140.2 . note : the 1-ethyl-2,4,5-triiodo-1h - imidazole also obtained in this step ( 1.90 g , 29% from 
 imidazole ) can be selectively and completely reduced back to the 1-ethyl-4,5-diiodo-1h - imidazole by refluxing it with an excess of sodium sulfite 
 in a 1/1 mixture of water and ethanol for 30 mn .
step 2 : under argon , 
 1-ethyl-4,5-diiodo-1h - imidazole ( 1.8 g , 0.0051 mol ) 
 was dissolved in dry tetrahydrofuran ( 20 ml ) .
the solution was cooled 
 to 0 c , and ethyl magnesium ( 1.8 ml , 0.0054 mol , 3 m solution 
 in ether ) was added .
the resulting suspension was stirred for 30 min , 
 quenched with an excess of ammonium chloride in water , and extracted 
 with ethyl acetate .
the organic layer was washed with water and brine , 
 dried over magnesium sulfate , and concentrated to dryness .
the residue 
 was purified by a chromatography over silica gel ( dichloromethane  ethanol 
 98/2 ) to give the 1-ethyl-4-iodo-1h - imidazole ( 0.78 
 g , 68% ) as an oil .
h nmr ( cdcl3 ) : 1.45 ( t , 
 3h , j = 7.3 ) , 3.98 ( q , 2h , j = 7.3 ) , 
 7.01 ( d , 1h , j = 1.3 ) , 7.38 ( d , 1h , j = 1.3 ) .
c nmr ( cdcl3 ) : 16.1 , 42.2 , 81.6 , 
 124.0 , 138.1 . in a reaction vial designed for microwave heating , 
 the considered alkoxypyrazole ( 2 mmol ) , the considered halogenated 
 heteroaryl ( 2.2 mmol ) , and cesium carbonate ( 2.8 mmol ) were stirred 
 in dimethylformamide or acetonitrile ( 3 ml ) as specified
this was 
 heated using a microwave at a temperature between 120 and 180 c 
 for the specified duration .
the resulting suspension was diluted in 
 water and extracted with ethyl acetate , and the organic layer was 
 washed with brine , dried over magnesium sulfate , and concentrated 
 to dryness .
obtained in 57% yield as an oil using 2-fluoro-4-methylpyridine 
 in acetonitrile at 180 c for 2 h and a chromatography over silica 
 gel ( dichloromethane ) .
h nmr ( cdcl3 ) : 1.41 
 ( t , 3h , j = 7.0 ) , 2.41 ( s , 3h ) , 2.56 ( s , 3h ) , 3.75 
 ( s , 2h ) , 4.36 ( q , 2h , j = 7.0 ) , 6.90 ( m , 1h ) , 7.18 
 ( m , 1h ) , 7.28 ( m , 4h ) , 7.59 ( m , 1h ) , 8.22 ( m , 1h ) .
c 
 nmr ( cdcl3 ) : 13.2 , 14.9 , 21.2 , 27.8 , 64.2 , 106.7 , 115.6 , 
 121.0 , 125.7 , 128.2 , 128.3 , 139.5 , 141.0 , 147.0 , 149.3 , 154.0 , 162.3 . 

obtained in 39% yield as an oil using 2-fluoro-3-methylpyridine 
 in acetonitrile at 180 c for 2 h and a chromatography over silica 
 gel ( dichloromethane ) .
h nmr ( cdcl3 ) : 1.41 
 ( t , 3h , j = 7.0 ) , 2.52 ( s , 3h ) , 2.59 ( s , 3h ) , 3.76 
 ( s , 2h ) , 4.35 ( q , 2h , j = 7.0 ) , 6.92 ( m , 1h ) , 7.19 
 ( m , 1h ) , 7.28 ( m , 4h ) , 7.59 ( m , 2h ) .
c nmr ( cdcl3 ) : 13.3 , 14.9 , 24.1 , 27.8 , 64.2 , 106.6 , 111.8 , 118.9 , 125.7 , 
 128.2 , 128.3 , 138.2 , 139.4 , 141.1 , 153.3 , 156.4 , 162.2 .
obtained in 39% yield using 2-fluoro-6-methylpyridine 
 in acetonitrile at 180 c for 2 h and a chromatography over silica 
 gel ( dichloromethane ) as a wax .
h nmr ( cdcl3 ) : 1.38 ( t , 3h , j = 7.0 ) , 2.11 ( s , 3h ) , 2.30 ( s , 
 3h ) , 3.77 ( s , 2h ) , 4.29 ( q , 2h , j = 7.0 ) , 7.19 ( m , 
 2h ) , 7.28 ( m , 4h ) , 7.66 ( m , 1h ) , 8.38 ( m , 1h ) .
c nmr 
 ( cdcl3 ) : 10.6 , 14.9 , 17.9 , 28.0 , 64.2 , 103.9 , 123.1 , 125.7 , 
 128.2 , 128.3 , 130.7 , 138.8 , 140.3 , 141.1 , 146.1 , 151.3 , 161.9 .
obtained in 74% yield as an oil , using 
 2,3-difluoropyridine in acetonitrile at 180 c for 2 h and a 
 chromatography over silica gel ( dichloromethane  ethanol from 
 100/0 to 98/2 ) .
h nmr ( cdcl3 ) : 1.40 ( t , 3h , j = 7.1 ) , 2.20 ( s , 3h ) , 3.77 ( s , 2h ) , 4.35 ( q , 2h , j = 7.1 ) , 7.19 ( m , 1h ) , 7.28 ( m , 5h ) , 7.57 ( m , 1h ) , 8.37 
 ( m , 1h ) .
c nmr ( cdcl3 ) : 10.7 , 14.9 , 27.9 , 
 64.3 , 105.6 , 123.7 , 125.5 ( j = 18 hz ) ; 125.8 , 128.3 , 
 128.32 , 139.5 , 140.7 , 141.1 , 144.1 , 152.8 ( j = 273 
 hz ) ; 163.1 . hrms calcd for c18h18fn3o + h : 312.1512 . found : 312.1503 .
obtained in 62% yield as a solid , using 
 2,6-difluoropyridine in acetonitrile at 180 c for 2 h and a 
 chromatography over silica gel ( cyclohexane  dichloromethane 
 2/1 ) .
h nmr ( cdcl3 ) : 1.41 ( t , 3h , j = 7.0 ) , 2.62 ( s , 3h ) , 3.74 ( s , 2h ) , 4.35 ( q , 2h , j = 7.0 ) , 6.64 ( m , 1h ) , 7.20 ( m , 1h ) , 7.27 ( m , 4h ) , 7.66 ( m , 1h ) , 
 7.80 ( m , 1h ) .
c nmr ( cdcl3 ) : 13.5 , 14.8 , 27.7 , 
 64.2 , 103.4 ( j = 36 hz ) ; 107.9 , 110.6 , 125.9 , 128.2 , 
 128.3 , 104.0 , 140.6 , 142.3 , 152.3 , 161.5 ( j = 237 
 hz ) ; 162.7 .
obtained in 47% yield as a white powder , 
 using 2-chloro-5-(trifluoromethyl)pyridine in acetonitrile at 180 
 c for 2 h and a chromatography over silica gel ( cyclohexane  dichloromethane 
 4/1 to 2/1 ) .
h nmr ( cdcl3 ) : 1.43 ( t , 3h , j = 7.1 ) , 2.65 ( s , 3h ) , 3.75 ( s , 2h ) , 4.37 ( q , 2h , j = 7.1 ) , 7.22 ( m , 1h ) , 7.28 ( m , 4h ) , 7.93 ( m , 2h ) , 8.61 
 ( m , 1h ) .
c nmr ( cdcl3 ) : 13.9 , 14.8 , 27.6 , 
 64.3 , 108.7 , 113.6 , 121.7 ( j = 33 hz ) ; 123.9 ( j = 271 hz ) ; 125.9 , 128.2 , 128.4 , 135.0 , 140.4 , 140.5 , 144.6 , 
 156.2 , 163.0 . hrms calcd for c19h18f3n3o + h : 362.1480 . found : 362.1449 .
obtained in 89% yield as an oil , using 
 2-fluoro-6-(trifluoromethyl)pyridine in acetonitrile at 180 c 
 for 2 h and a chromatography over silica gel ( cyclohexane  dichloromethane 
 5/1 ) .
h nmr ( cdcl3 ) : 1.42 ( t , 3h , j = 7.1 ) , 2.65 ( s , 3h ) , 3.74 ( s , 2h ) , 4.35 ( q , 2h , j = 7.1 ) , 7.19 ( m , 5h ) , 7.39 ( d , 1h , j = 8.4 ) , 7.86 
 ( t , 1h , j = 8.4 ) , 8.03 ( d , 1h , j = 8.4 ) .
c nmr ( cdcl3 ) : 8.9 , 10.0 , 22.9 , 
 59.5 , 103.6 , 110.4 , 116.6 ( 273 hz ) ; 121.1 , 123.4 , 123.6 , 134.4 , 134.7 , 
 135.7 , 135.9 , 140.8 ( 36 hz ) ; 149.1 , 158.0 . hrms calcd for c19h18f3n3o + h : 362.1480 . found : 362.1457 .
obtained in 40% yield as a white powder 
 using 2,5-dichloropyridine in acetonitrile at 180 c for 2 h 
 and a chromatography over silica gel ( cyclohexane  dichloromethane 
 4/1 ) .
h nmr ( cdcl3 ) : 1.42 ( t , 3h , j = 7.1 ) , 2.57 ( s , 3h ) , 3.74 ( s , 2h ) , 4.34 ( q , 2h , j = 7.1 ) , 7.19 ( m , 1h ) , 7.27 ( m , 4h ) , 7.68 ( dd , 1h , j = 2.5 and 8.8 ) , 7.76 ( d , 1h , j = 8.8 ) , 8.30 ( d , 
 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 13.4 , 14.8 , 27.7 , 64.2 , 107.5 , 115.5 , 125.8 , 126.9 , 128.2 , 128.3 , 
 137.7 , 139.7 , 140.7 , 145.7 , 152.2 , 162.5 .
obtained in 44% yield as a solid using 
 5-bromo-2-fluoropyridine in dimethylformamide at 130 c for 12 
 h and a chromatography over silica gel ( cyclohexane / dichloromethane 
 2/1 ) followed by concentration under high vacuum .
h nmr 
 ( cdcl3 ) : 1.41 ( t , 3h , j = 7.0 ) , 2.57 ( s , 
 3h ) , 3.74 ( s , 2h ) , 4.34 ( q , 2h , j = 7.0 ) , 7.19 ( m , 
 1h ) , 7.28 ( m , 4h ) , 7.71 ( m , 1h ) , 7.81 ( m , 1h ) , 8.38 ( m , 1h ) .
c nmr ( cdcl3 ) : 13.4 , 14.8 , 27.7 , 64.3 , 107.6 , 
 115.0 , 116.0 , 125.8 , 128.2 , 128.3 , 139.7 , 140.5 , 140.7 , 147.9 , 152.6 , 
 162.5 .
obtained in a 33% yield as an oil using 
 5-bromo-2,3-difluoropyridine in acetonitrile at 180 c for 2 
 h and a chromatography over silica gel ( cyclohexane / ethyl acetate 
 97/3 ) .
h nmr ( cdcl3 ) : 1.40 ( t , 3h , j = 7.1 ) , 2.22 ( s , 3h ) , 3.76 ( s , 2h ) , 4.34 ( q , 2h , j = 7.1 ) , 7.20 ( m , 1h ) , 7.28 ( m , 4h ) , 7.74 ( m , 1h ) , 8.40 
 ( d , 1h , j = 2.0 ) .
c nmr ( cdcl3 ) : 10.9 , 14.8 , 27.9 , 64.3 , 106.3 , 117.1 , 125.9 , 128.3 , 128.31 , 128.5 
 ( 21 hz ) ; 139.6 , 140.0 , 140.5 , 144.8 , 151.9 ( 270 hz ) ; 163.2 . hrms calcd 
 for c18h17brn3fo + h : 
 390.0617 . found : 390.0621 .
obtained in a 62% yield as solid using 
 5-bromo-2-fluoro-3-methylpyridine in acetonitrile at 180 c for 
 3 h and a chromatography over silica gel ( cyclohexane / ethyl acetate 
 from 98/2 to 97/3 ) .
h nmr ( cdcl3 ) : 1.39 ( t , 
 3h , j = 7.3 ) , 2.15 ( s , 3h ) , 2.33 ( s , 3h ) , 3.76 ( s , 
 2h ) , 4.29 ( q , 2h , j = 7.3 ) , 7.20 ( m , 1h ) , 7.27 ( m , 
 4h ) , 7.80 ( d , 1h , j = 2.4 ) , 8.41 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 10.8 , 14.9 , 
 18.1 , 27.9 , 64.2 , 104.6 , 119.0 , 125.8 , 128.2 , 128.3 , 132.3 , 139.0 , 
 140.9 , 142.6 , 146.8 , 150.0 , 162.1 .
obtained in 47% yield as a solid using 
 6-chloronicotinonitrile in dimethylformamide at 150 c for 30 
 min and a chromatography over silica gel ( cyclohexane / dichloromethane 
 1/2 ) .
h nmr ( cdcl3 ) : 1.44 ( t , 3h , j = 7.0 ) , 2.64 ( s , 3h ) , 3.74 ( s , 2h ) , 4.35 ( q , 2h , j = 7.0 ) , 7.25 ( m , 5h ) , 7.93 ( m , 2h ) , 8.60 ( m , 1h ) . c 
 nmr ( cdcl3 ) : 14.1 , 14.7 , 27.6 , 64.4 , 103.9 , 109.7 , 113.6 , 
 117.3 , 126.0 , 128.2 , 128.4 , 140.2 , 140.6 , 140.8 , 151.1 , 155.7 , 163.4 . 

obtained in 19% yield as a solid using 
 methyl 6-chloronicotinate in dimethylformamide at 150 c for 
 30 min and a chromatography over silica gel ( cyclohexane / ethyl acetate 
 from 95/5 to 85/15 ) .
h nmr ( cdcl3 ) : 1.43 ( t , 
 3h , j = 7.0 ) , 2.65 ( s , 3h ) , 3.74 ( s , 2h ) , 3.95 ( s , 
 3h ) , 4.36 ( q , 2h , j = 7.0 ) , 7.18 ( m , 1h ) , 7.27 ( m , 
 4h ) , 7.88 ( m , 1h ) , 8.30 ( m , 1h ) , 8.97 ( m , 1h ) .
c nmr 
 ( cdcl3 ) : 14.0 , 14.8 , 27.6 , 52.2 , 64.3 , 108.7 , 113.2 , 121.2 , 
 125.9 , 128.2 , 128.3 , 139.0 , 140.5 , 140.6 , 149.5 , 156.5 , 163.0 , 165.8 . 

obtained in 15% yield as a solid using 
 methyl 1-(6-bromopyridin-3-yl)ethanone at 150 c for 30 min in 
 dimethylformamide and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 9/1 ) .
h nmr ( cdcl3 ) : 1.42 ( t , 3h , j = 7.1 ) , 2.63 ( s , 3h ) , 2.66 ( s , 3h ) , 3.75 ( s , 2h ) , 4.37 
 ( q , 2h , j = 7.1 ) , 7.19 ( m , 1h ) , 7.27 ( m , 4h ) , 7.89 
 ( m , 1h ) , 8.26 ( m , 1h ) , 8.93 ( m , 1h ) .
c nmr ( cdcl3 ) : 14.0 , 14.8 , 26.5 , 27.7 , 64.3 , 109.0 , 113.5 , 125.9 , 128.0 , 
 128.2 , 128.3 , 137.5 , 140.5 , 140.6 , 148.8 , 156.5 , 163.1 , 195.7 .
obtained in 17% yield as an oil using 5-cyclopropyl-2,3-difluoropyridine 
 at 140 c for 4 h in acetonitrile after a chromatography over 
 silica gel ( cyclohexane / ethyl acetate from 97/3 to 4/1 ) followed by 
 concentration under high vacuum .
h nmr ( cdcl3 ) : 0.76 ( m , 2h ) , 1.11 ( m , 2h ) , 1.38 ( t , 3h , j = 
 7.2 ) , 1.98 ( m , 1h ) , 2.14 ( s , 3h ) , 3.76 ( s , 2h ) , 4.33 ( q , 2h , j = 7.2 ) , 7.18 ( m , 2h ) , 7.29 ( m , 4h ) , 8.18 ( d , 1h , j = 1.7 ) .
c nmr ( cdcl3 ) : 9.6 , 10.5 
 ( 2 hz ) ; 12.6 , 14.9 , 27.9 , 64.9 , 105.0 , 121.8 ( 19 hz ) ; 125.7 , 128.2 , 
 128.3 , 138.3 ( 11 hz ) ; 139.4 , 140.8 , 141.6 ( 6 hz ) ; 142.4 ( 5 hz ) ; 153.0 
 ( 260 hz ) ; 162.9 .
obtained in 18% yield as a solid using 
 2-chloro-5-cyclopropylnicotinonitrile at 160 c for 4 h in acetonitrile 
 after a chromatography over silica gel ( cyclohexane / dichloromethane 
 from 2/1 to 0/1 ) .
h nmr ( cdcl3 ) : 0.76 ( m , 2h ) , 
 1.11 ( m , 2h ) , 1.43 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 
 2.47 ( s , 3h ) , 3.74 ( s , 2h ) , 4.41 ( q , 2h , j = 7.2 ) , 
 7.18 ( m , 1h ) , 7.27 ( m , 4h ) , 7.67 ( d , 1h , j = 2.5 ) , 
 8.34 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 9.1 , 12.2 , 12.6 , 14.8 , 27.7 , 64.9 , 101.3 , 108.1 , 116.8 , 
 125.9 , 128.2 , 128.3 , 135.7 , 139.5 , 140.4 , 140.9 , 149.3 , 150.7 , 162.4 . 

obtained in 67% yield as an oil , using 
 2-(6-fluoropyridin-3-yl)propan-2-ol ( 5 t ) at 180 c 
 for 6 h in acetonitrile and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 4/1 ) .
h nmr ( cdcl3 ) : 1.41 ( t , 3h , j = 7.1 ) , 1.60 ( s , 6h ) , 2.12 ( s , 1h ) , 2.57 ( s , 3h ) , 3.76 
 ( s , 2h ) , 4.36 ( q , 2h , j = 7.1 ) , 7.25 ( m , 1h ) , 7.28 
 ( m , 4h ) , 7.71 ( dd , 1h , j = 0.8 and 8.7 ) , 7.85 ( dd , 
 1h , j = 2.5 and 8.7 ) , 8.47 ( dd , 1h , j = 0.8 and 2.5 ) .
c nmr ( cdcl3 ) : 13.1 , 14.9 , 
 27.7 , 31.6 , 64.2 , 71.2 , 106.7 , 114.6 , 125.8 , 128.2 , 128.3 , 134.8 , 
 139.4 , 140.2 , 140.9 , 143.7 , 152.6 , 163.2 .
obtained in 17% 
 yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.73 ( m , 2h ) , 1.04 ( m , 2h ) , 1.38 ( t , 3h , j = 7.2 ) , 1.93 ( m , 1h ) , 2.54 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 7.04 ( m , 3h ) , 7.30 ( m , 2h ) , 7.42 ( dd , 1h , j = 2.4 and 8.5 ) , 7.69 ( d , 1h , j = 8.5 ) , 
 8.19 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 8.6 , 11.9 , 12.5 , 14.8 , 64.8 , 114.1 , 115.1 , 121.9 , 124.8 , 
 129.4 , 133.3 , 135.2 , 135.6 , 145.4 , 151.8 , 155.4 , 158.6 .
obtained 
 in 41% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.73 ( m , 2h ) , 1.03 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.55 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 6.97 ( m , 3h ) , 7.12 ( m , 1h ) , 7.41 ( dd , 1h , j = 2.5 and 8.6 ) , 7.68 ( d , 1h , j = 8.6 ) , 
 8.19 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 12.5 , 14.8 , 64.8 , 114.1 , 116.1 , 116.4 ( 18 hz ) ; 
 123.3 ( 6 hz ) ; 124.0 ( 3 hz ) ; 124.4 , 133.3 , 135.2 , 135.7 , 145.5 , 146.4 
 ( 11 hz ) ; 151.8 , 152.1 ( 248 hz ) ; 155.1 .
obtained 
 in 70% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.54 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 6.89 ( m , 1h ) , 6.96 ( m , 2h ) , 7.15 ( m , 1h ) , 7.42 
 ( m , 2h ) , 7.69 ( d , 1h , j = 8.5 ) , 8.19 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 
 12.6 , 14.8 , 64.8 , 114.1 , 115.0 , 122.3 , 122.7 , 124.5 , 127.5 , 130.4 , 
 133.3 , 135.2 , 135.8 , 145.5 , 151.8 , 154.1 , 155.1 .
obtained 
 in 50% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.53 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 6.89 ( m , 2h ) , 7.19 ( m , 1h ) , 7.41 ( dd , 1h , j = 2.5 and 8.5 ) , 7.59 ( dd , 1h , j = 1.6 
 and 7.8 ) , 7.68 ( d , 1h , j = 8.5 ) , 8.19 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 8.7 , 11.9 , 
 12.6 , 14.8 , 64.8 , 111.2 , 114.1 , 114.9 , 123.2 , 124.6 , 128.3 , 133.3 , 
 133.4 , 135.2 , 135.8 , 145.5 , 151.8 , 155.1 , 155.2 .
obtained 
 in 44% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.74 ( m , 2h ) , 1.04 ( m , 2h ) , 1.36 ( t , 3h , j = 7.2 ) , 1.91 ( m , 1h ) , 2.51 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 6.96 ( m , 1h ) , 7.08 ( m , 1h ) , 7.43 ( m , 2h ) , 7.65 
 ( m , 2h ) , 8.20 ( d , 1h , j = 2.5 ) .
c nmr 
 ( cdcl3 ) : 8.7 , 11.6 , 12.5 , 14.8 , 64.9 , 114.2 , 114.6 , 118.6 
 ( 31 hz ) ; 121.4 , 123.6 ( 272 hz ) ; 123.9 , 127.0 ( 5 hz ) ; 133.1 , 133.4 , 
 135.2 , 135.9 , 145.5 , 151.7 , 155.1 , 153.3 ( 2 hz ) .
obtained 
 in 55% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.73 ( m , 2h ) , 1.03 ( m , 2h ) , 1.36 ( t , 3h , j = 7.2 ) , 1.93 ( m , 1h ) , 2.54 ( s , 3h ) , 4.36 ( q , 2h , j = 7.2 ) , 7.18 ( m , 1h ) , 7.20 ( m , 2h ) , 7.40 ( m , 2h ) , 7.70 
 ( d , 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 12.5 , 
 14.7 , 64.8 , 112.2 ( 4 hz ) ; 114.1 , 118.4 , 118.7 ( 4 hz ) ; 123.9 ( 273 hz ) ; 
 124.0 , 130.0 , 131.9 ( 33 hz ) ; 133.3 , 135.2 , 135.8 , 145.5 , 151.8 , 155.0 , 
 158.6 .
obtained 
 in 53% yield as a solid using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.73 ( m , 2h ) , 1.04 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 1.94 ( m , 1h ) , 2.52 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 6.9 ( d , 2h , j = 8.6 ) , 7.42 ( dd , 
 1h , j = 2.5 and 8.5 ) , 7.57 ( d , 2h , j = 8.6 ) , 7.69 ( d , 2h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 
 12.5 , 14.7 , 64.8 , 114.1 , 115.2 , 123.9 124.3 , ( 38 hz ) ; 124.4 ( 272 hz ) ; 
 126.9 ( 4 hz ) ; 131.3 , 135.2 , 135.9 , 145.5 , 151.7 , 155.0 , 161.0 .
obtained 
 in 50% yield as a solid using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 1.93 ( m , 1h ) , 2.52 ( s , 3h ) , 4.34 ( q , 2h , j = 7.2 ) , 6.82 ( dd , 1h , j = 1.5 and 8.1 ) , 
 7.08 ( t , 1h , j = 8.1 ) , 7.15 ( dd , 1h , j = 1.5 and 8.1 ) , 7.40 ( dd , 1h , j = 2.5 and 8.5 ) , 
 7.68 ( d , 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 12.5 , 
 14.8 , 64.9 , 112.9 , 114.2 , 121.5 , 123.6 , 124.3 , 127.1 , 133.3 , 133.9 , 
 135.2 , 135.9 , 145.5 , 151.7 , 154.9 , 155.5 .
obtained 
 in 43% yield as a solid using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.73 ( m , 2h ) , 1.04 ( m , 2h ) , 1.37 ( t , 3h , j = 7.1 ) , 1.93 ( m , 1h ) , 2.54 ( s , 3h ) , 4.34 ( q , 2h , j = 7.1 ) , 6.89 ( d , 1h , j = 2.3 ) , 6.96 ( dd , 
 1h , j = 2.3 and 8.5 ) , 7.33 ( d , 1h , j = 8.5 ) , 7.42 ( dd , 1h , j = 2.5 and 8.5 ) , 7.69 ( d , 
 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 12.6 , 14.8 , 64.9 , 114.1 , 
 115.6 , 120.8 , 122.8 , 124.0 , 130.9 , 133.1 , 133.3 , 135.2 , 135.9 , 145.5 , 
 151.7 , 154.5 , 154.7 .
obtained 
 in 48% yield as an oil using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.74 ( m , 2h ) , 1.05 ( m , 2h ) , 1.38 ( t , 3h , j = 7.4 ) , 1.93 ( m , 1h ) , 2.52 ( s , 3h ) , 4.34 ( q , 2h , j = 7.4 ) , 6.92 ( d , 1h , j = 1.8 ) , 7.03 ( t , 
 1h , j = 1.8 ) , 7.42 ( dd , 1h , j = 
 2.3 and 8.5 ) , 7.69 ( d , 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 
 12.6 , 14.7 , 64.8 , 114.1 , 114.3 , 122.4 , 123.7 , 133.3 , 135.2 , 135.4 , 
 135.9 , 145.5 , 151.7 , 154.7 , 159.5 .
obtained 
 in 58% yield as a solid using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.75 ( m , 2h ) , 1.03 ( m , 2h ) , 1.33 ( d , 6h , j = 6.0 ) , 1.92 ( m , 1h ) , 2.54 ( s , 3h ) , 4.98 ( sept , 1h , j = 6.0 ) , 6.98 ( m , 3h ) , 7.12 ( m , 1h ) , 7.40 ( m , 1h ) , 7.68 
 ( m , 1h ) , 8.18 ( d , 1h , j = 2.4 ) .
c nmr 
 ( cdcl3 ) : 8.6 , 11.8 , 12.5 , 22.1 , 72.1 , 114.2 , 116.3 , 116.4 
 ( 18 hz ) ; 122.3 , 124.0 , 125.1 , 133.0 , 135.1 , 135.6 , 145.4 , 146.4 ( 10 
 hz ) ; 151.9 , 152.3 ( 248 hz ) ; 154.5 .
obtained 
 in 57% yield as an oil , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.35 ( d , 6h , j = 6.2 ) , 1.92 ( m , 1h ) , 2.52 ( s , 3h ) , 5.00 ( sept , 1h , j = 6.2 ) , 6.73 ( m , 2h ) , 6.82 ( m , 1h ) , 7.22 ( m , 1h ) , 7.41 
 ( dd , 1h , j 2.4 and 8.5 ) , 7.70 ( d , 1h , j = 8.5 ) , 8.19 ( d , 1h , j = 2.4 ) .
c nmr 
 ( cdcl3 ) : 8.7 , 11.9 , 12.5 , 21.1 , 72.1 , 103.1 ( 25 hz ) ; 108.8 
 ( 21 hz ) ; 111.0 ( 3 hz ) ; 114.1 , 124.9 , 130.1 ( 10 hz ) ; 133.1 , 135.1 , 
 135.7 , 145.4 , 151.9 , 154.5 , 160.0 ( 10 hz ) ; 163.6 ( 245 hz ) .
obtained 
 in 50% yield as a solid , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.34 ( d , 6h , j = 6.2 ) , 1.93 ( m , 1h ) , 2.52 ( s , 3h ) , 4.98 ( sept , 1h , j = 6.2 ) , 6.97 ( m , 4h ) , 7.40 ( dd , 1h , j = 2.3 and 8.5 ) , 7.68 ( d , 1h , j = 8.5 ) , 8.19 ( d , 
 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.6 , 11.9 , 12.5 , 21.1 , 72.0 , 114.1 , 115.6 ( 23 hz ) ; 116.2 ( 8 hz ) ; 
 125.6 , 133.0 , 135.1 , 135.6 , 145.4 , 151.9 , 154.7 ( 3 hz ) ; 158.0 ( 239 
 hz ) . hrms calcd for c21h22fn3o2 + h : 368.1774 . found : 368.1759 .
obtained 
 in 55% yield as an oil , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.34 ( d , 6h , j = 6.2 ) , 1.92 ( m , 1h ) , 2.55 ( s , 3h ) , 4.99 ( sept , 1h , j = 6.2 ) , 6.71 ( m , 1h ) , 6.84 ( m , 1h ) , 6.91 ( m , 1h ) , 7.41 
 ( dd , 1h , j 2.3 and 8.5 ) , 7.68 ( d , 1h , j = 8.5 ) , 8.19 ( d , 1h , j = 2.3 ) .
c nmr 
 ( cdcl3 ) : 8.7 , 11.8 , 12.5 , 21.1 , 72.2 , 110.2 ( 18 hz ) ; 111.2 
 ( 3 hz ) ; 114.2 , 122.8 ( 5 and 9 hz ) ; 124.9 , 133.0 , 135.2 , 135.8 , 141.1 
 ( 15 and 249 hz ) ; 145.5 , 148.0 ( 3 and 8 hz ) ; 151.5 ( 10 and 247 hz ) ; 
 151.8 , 154.2 .
obtained 
 in 54% yield as an oil , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.33 ( d , 6h , j = 6.2 ) , 1.93 ( m , 1h ) , 2.55 ( s , 3h ) , 4.98 ( sept , 1h , j = 6.2 ) , 6.74 ( m , 1h ) , 6.91 ( m , 2h ) , 7.42 ( dd , 1h , j 2.3 and 8.5 ) , 7.67 ( d , 1h , j = 8.5 ) , 
 8.19 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 11.7 , 12.5 , 22.1 , 72.1 , 104.8 ( 22 and 28 hz ) ; 110.3 
 ( 4 and 22 hz ) ; 114.2 , 116.9 ( 2 and 10 hz ) ; 125.4 , 132.9 , 135.2 , 135.7 , 
 143.0 ( 4 and 11 hz ) ; 145.4 , 151.8 , 151.9 ( 12 and 242 hz ) ; 154.3 , 157.2 
 ( 10 and 242 hz ) . hrms calcd for c21h21f2n3o2 + h : 386.1680 . found : 386.1667 .
obtained 
 in 55% yield as an oil , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) followed by concentration under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.04 ( m , 2h ) , 1.35 ( d , 6h , j = 6.2 ) , 1.93 ( m , 1h ) , 2.55 ( s , 3h ) , 5.00 ( sept , 1h , j = 6.2 ) , 6.67 ( m , 2h ) , 7.08 ( m , 1h ) , 7.42 ( dd , 1h , j 2.3 and 8.5 ) , 7.68 ( d , 1h , j = 8.5 ) , 
 8.19 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 11.8 , 12.5 , 22.1 , 72.2 , 104.8 ( 28 hz ) ; 108.2 ( 6 and 
 24 hz ) ; 114.2 , 116.9 ( 10 and 20 hz ) ; 124.5 , 133.1 , 135.2 , 135.8 , 145.4 , 
 147.1 ( 22 hz ) ; 148.5 ( 4 and 243 hz ) ; 151.8 , 154.2 , 158.6 ( 3 and 242 
 hz ) .
obtained 
 in 53% yield as an oil , using 5-cyclopropyl-2-fluoropyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 98/2 to 97/3 ) followed by extensive drying under high vacuum .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.01 ( m , 2h ) , 1.25 
 ( d , 6h , j = 6.2 ) , 1.91 ( m , 1h ) , 2.63 ( s , 3h ) , 4.89 
 ( sept , 1h , j = 6.2 ) , 6.88 ( m , 2h ) , 7.01 ( m , 1h ) , 
 7.37 ( m , 1h ) , 7.62 ( d , 1h , j = 8.5 ) , 8.18 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.6 , 11.6 , 
 12.5 , 21.9 , 71.9 , 111.9 ( 6 and 16 hz ) ; 114.2 , 123.4 ( 9 hz ) ; 129.1 , 
 131.0 , 134.7 ( 13 hz ) ; 135.0 , 135.4 , 145.4 , 152.0 , 153.4 , 155.7 ( 4 
 and 250 hz ) .
obtained 
 in 57% yield as a solid using 3-chloro-6-cyclopropylpyridazine ( 9 ) in acetonitrile at 180 c for 2 h after a chromatography 
 over silica gel ( cyclohexane / ethyl acetate 6/1 ) .
h nmr 
 ( cdcl3 ) : 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.36 ( t , 3h , j = 7.0 ) , 2.17 ( m , 1h ) , 2.66 ( s , 3h ) , 4.34 ( q , 2h , j = 7.0 ) , 6.93 ( m , 1h ) , 7.00 ( m , 2h ) , 7.16 ( m , 1h ) , 7.34 
 ( d , 1h , j = 9.2 ) , 7.95 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.4 , 14.7 , 
 15.4 , 64.9 , 116.1 , 116.6 ( 17 hz ) ; 118.9 , 122.6 ( 7 hz ) ; 124.1 ( 4 hz ) ; 
 125.5 , 127.1 , 134.1 , 146.1 ( 11 hz ) ; 152.2 ( 246 hz ) ; 155.5 , 156.1 , 
 161.6 .
obtained in 62% yield as a solid using the procedure described 
 for 
 the preparation of compound 10b .
h nmr ( cdcl3 ) : 1.14 ( m , 2h ) , 1.22 ( m , 2h ) , 1.36 ( t , 3h , j = 7.2 ) , 2.15 ( m , 1h ) , 2.65 ( s , 3h ) , 4.34 ( q , 2h , j = 7.2 ) , 6.87 ( m , 1h ) , 6.97 ( m , 1h ) , 7.15 ( ddd , 1h , j = 1.8 , 7.4 and 8.6 ) , 7.32 ( d , 1h , j = 9.2 ) , 7.41 
 ( dd , 1h , j = 1.6 and 7.9 ) , 7.94 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.4 , 14.7 , 
 15.4 , 64.9 , 114.9 , 118.8 , 122.4 , 122.9 , 125.5 , 127.1 , 127.6 , 130.5 , 
 134.2 , 153.9 , 155.5 , 156.1 , 161.6 .
obtained in 62% yield as a solid using 
 the procedure described for the preparation of compound 10b .
h nmr ( cdcl3 ) : 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 
 1.36 ( t , 3h , j = 7.2 ) , 2.17 ( m , 1h ) , 2.64 ( s , 3h ) , 
 4.34 ( q , 2h , j = 7.2 ) , 6.81 ( dd , 2h , j = 1.4 and 8.3 ) , 6.91 ( m , 1h ) , 7.20 ( m , 1h ) , 7.34 ( d , 1h , j = 9.2 ) , 7.59 ( dd , 1h , j = 1.5 and 7.9 ) , 
 7.94 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.4 , 14.7 , 15.4 , 65.0 , 111.2 , 114.8 , 118.8 , 123.4 , 
 125.6 , 127.1 , 128.3 , 133.5 , 134.2 , 154.8 , 155.5 , 156.1 , 161.6 .
obtained 
 in 65% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.35 ( t , 3h , j = 7.2 ) , 
 2.16 ( m , 1h ) , 2.63 ( s , 3h ) , 4.33 ( q , 2h , j = 7.2 ) , 
 6.94 ( d , 1h , j = 8.3 ) , 7.10 ( m , 1h ) , 7.34 ( d , 1h , j = 9.2 ) , 7.43 ( m , h ) , 7.64 ( m , 1h ) , 7.94 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.2 , 
 14.6 , 15.4 , 65.0 , 114.5 , 118.7 ( 31 hz ) ; 118.8 , 121.6 , 127.9 , 126.1 
 ( 274 hz ) ; 127.0 ( 3 hz ) ; 127.1 , 133.1 , 134.3 , 155.5 , 156.0 ( 20 hz ) ; 
 156.1 , 161.7 .
obtained 
 in 64% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.36 ( t , 3h , j = 7.0 ) , 
 2.17 ( m , 1h ) , 2.62 ( s , 3h ) , 4.35 ( q , 2h , j = 7.0 ) , 
 7.19 ( m , 1h ) , 7.25 ( m , 1h ) , 7.30 ( m , 1h ) , 7.35 ( d , 1h , j = 9.2 ) , 7.41 ( m , 1h ) , 7.96 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.4 , 14.6 , 15.4 , 64.9 , 112.2 
 ( 4 hz ) ; 118.5 , 118.8 ( 4 hz ) ; 123.8 ( 272 hz ) ; 125.0 , 127.1 , 130.1 , 
 132.0 ( 33 hz ) ; 134.2 , 155.5 , 155.9 , 158.4 , 161.7 .
obtained 
 in 57% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.37 ( t , 3h , j = 7.0 ) , 
 2.17 ( m , 1h ) , 2.64 ( s , 3h ) , 4.35 ( q , 2h , j = 7.0 ) , 
 7.8 ( m , 2h ) , 7.35 ( d , 1h , j = 9.2 ) , 7.57 ( m , 2h ) , 
 7.96 ( d , 2h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.4 , 12.4 , 14.6 , 15.4 , 64.9 , 115.2 , 118.8 , 124.3 , ( 270 
 hz ) ; 124.5 ( 33 hz ) ; 124.9 , 127.0 ( 4 hz ) ; 127.1 , 134.2 , 155.5 , 155.9 , 
 160.7 , 161.7 .
obtained 
 in 65% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.35 ( t , 3h , j = 7.2 ) , 
 2.16 ( m , 1h ) , 2.64 ( s , 3h ) , 4.33 ( q , 2h , j = 7.2 ) , 
 6.78 ( dd , 1h , j = 1.5 and 8.2 ) , 7.08 ( t , 1h , j = 8.2 ) , 7.14 ( dd , 1h , j = 1.6 and 8.2 ) , 
 7.34 ( d , 1h , j = 9.2 ) , 7.93 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.4 , 12.4 , 14.7 , 
 15.4 , 65.0 , 112.8 , 118.8 , 121.6 , 123.8 , 125.3 , 127.1 , 127.2 , 134.0 , 
 134.2 , 155.2 , 155.5 , 155.8 , 161.8 .
obtained 
 in 50% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.37 ( t , 3h , j = 7.2 ) , 
 2.16 ( m , 1h ) , 2.66 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 
 6.85 ( d , 1h , j = 2.2 ) , 6.96 ( dd , 1h , j = 2.2 and 8.4 ) , 7.33 ( d , 1h , j = 8.4 ) , 7.35 ( d , 
 1h , j = 9.2 ) , 7.95 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.4 , 12.4 , 14.7 , 15.4 , 65.0 , 115.4 , 
 118.8 , 120.9 , 123.1 , 124.9 , 127.2 , 131.0 , 133.1 , 134.2 , 154.3 , 155.6 , 
 155.65 , 161.8 .
obtained 
 in 55% yield as a solid the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.23 ( m , 2h ) , 1.38 ( t , 3h , j = 7.2 ) , 
 2.17 ( m , 1h ) , 2.63 ( s , 3h ) , 4.35 ( q , 2h , j = 7.2 ) , 
 6.90 ( d , 1h , j = 1.8 ) , 7.04 ( t , 1h , j = 1.8 ) , 7.35 ( d , 1h , j = 9.2 ) , 7.94 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.4 , 12.4 , 
 14.7 , 15.4 , 65.0 , 114.3 , 118.8 , 122.6 , 124.7 , 127.1 , 134.2 , 135.5 , 
 155.5 , 155.7 , 159.2 , 161.8 .
obtained 
 in 67% yield as a solid the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.33 ( d , 6h , j = 6.2 ) , 
 2.16 ( m , 1h ) , 2.66 ( s , 3h ) , 4.97 ( sept , 1h , j = 6.2 ) , 
 6.92 ( m , 1h ) , 6.99 ( m , 2h ) , 7.14 ( m , 1h ) , 7.68 ( d , 1h , j = 9.2 ) , 7.94 ( d , 1h , j = 9.2 ) .
c nmr 
 ( cdcl3 ) : 10.3 , 12.3 , 15.4 , 22.0 , 72.3 , 116.3 , 116.5 ( 18 
 hz ) ; 118.8 , 119.1 , 122.6 ( 7 hz ) ; 124.1 ( 4 hz ) ; 126.1 , 127.1 , 133.9 , 
 146.2 ( 11 hz ) ; 152.2 ( 247 hz ) ; 155.5 , 155.6 , 161.5 .
obtained 
 in 67% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.35 ( d , 6h , j = 6.2 ) , 
 2.19 ( m , 1h ) , 2.63 ( s , 3h ) , 4.99 ( sept , 1h , j = 6.2 ) , 
 6.73 ( m , 2h ) , 6.80 ( m , 1h ) , 7.23 ( m , 2h ) , 7.34 ( d , 1h , j = 9.2 ) , 7.95 ( d , 1h , j = 9.2 ) .
c nmr 
 ( cdcl3 ) : 10.3 , 12.4 , 15.4 , 22.0 , 72.3 , 103.1 ( 26 hz ) ; 109.0 
 ( 21 hz ) ; 111.0 ( 3 hz ) ; 118.9 , 125.8 , 130.2 ( 9 hz ) ; 134.0 , 155.5 , 155.6 , 
 159.6 ( 10 hz ) ; 161.6 , 163.6 ( 246 hz ) ( one signal missing ) . hrms calcd 
 for c20h21fn3o2 + h : 369.1727 . 
 found : 369.1769 .
obtained 
 in 67% yield as an oil using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.33 ( d , 6h , j = 6.2 ) , 
 2.17 ( m , 1h ) , 2.63 ( s , 3h ) , 4.97 ( sept , 1h , j = 6.2 ) , 
 6.96 ( m , 4h ) , 7.33 ( d , 1h , j = 9.2 ) , 7.94 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.4 , 
 15.4 , 22.0 , 72.3 , 115.8 ( 23 hz ) ; 116.3 ( 8 hz ) ; 118.8 , 126.5 , 127.1 , 
 133.9 , 154.4 ( 2 hz ) ; 155.5 , 155.6 , 158.1 ( 240 hz ) ; 161.5 . hrms calcd 
 for c20h21fn4o2 + h : 369.1727 . 
 found : 369.1712 .
obtained 
 in 52% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.15 ( m , 2h ) , 1.22 ( m , 2h ) , 1.33 ( d , 6h , j = 6.2 ) , 
 2.18 ( m , 1h ) , 2.63 ( s , 3h ) , 4.89 ( sept , 1h , j = 6.2 ) , 
 6.70 ( m , 1h ) , 6.85 ( m , 1h ) , 6.92 ( m , 1h ) , 7.33 ( d , 1h , j = 9.2 ) , 7.93 ( d , 1h , j = 9.2 ) .
c nmr 
 ( cdcl3 ) : 10.3 , 12.3 , 15.4 , 22.0 , 72.4 , 110.5 ( 17 hz ) ; 111.2 
 ( 3 hz ) ; 118.8 , 122.9 ( 5 and 8 hz ) ; 125.9 , 127.1 , 133.9 , 141.1 ( 14 
 and 249 hz ) ; 147.7 ( 2 and 7 hz ) ; 151.5 ( 10 and 247 hz ) ; 155.2 , 155.5 , 
 161.7 .
obtained 
 in 69% yield as an oil using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.13 ( m , 2h ) , 1.18 ( m , 2h ) , 1.33 ( d , 6h , j = 6.2 ) , 
 2.16 ( m , 1h ) , 2.66 ( s , 3h ) , 4.96 ( sept , 1h , j = 6.2 ) , 
 6.72 ( m , 1h ) , 6.80 ( m , 3h ) , 7.33 ( d , 1h , j = 9.2 ) , 
 7.92 ( d , 1h , j = 9.2 ) .
c nmr ( cdcl3 ) : 10.3 , 12.3 , 15.4 , 22.0 , 72.3 , 104.9 ( 22 and 27 hz ) ; 110.3 
 ( 4 and 23 hz ) ; 117.0 ( 2 and 9 hz ) ; 118.8 , 126.5 , 133.7 , 142.6 ( 3 and 
 10 hz ) ; 151.9 ( 12 and 250 hz ) ; 155.3 , 155.5 , 157.4 ( 9 and 244 hz ) ; 
 161.6 ( one signal missing ) .
obtained 
 in 77% yield as a solid using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.16 ( m , 2h ) , 1.23 ( m , 2h ) , 1.36 ( d , 6h , j = 6.2 ) , 
 2.16 ( m , 1h ) , 2.67 ( s , 3h ) , 5.00 ( sept , 1h , j = 6.2 ) , 
 6.68 ( m , 2h ) , 7.07 ( m , 2h ) , 7.34 ( d , 1h , j = 9.3 ) , 
 7.95 ( d , 1h , j = 9.3 ) .
c nmr ( cdcl3 ) : 10.4 , 12.3 , 15.4 , 22.0 , 72.4 , 104.1 ( 28 hz ) ; 108.5 ( 7 and 
 24 hz ) ; 116.7 ( 10 and 20 hz ) ; 118.9 , 125.6 , 127.1 , 134.0 , 146.7 ( 10 
 and 12 hz ) ; 148.5 ( 3 and 242 hz ) ; 155.1 , 155.5 , 158.5 ( 2 and 243 hz ) ; 
 161.7 .
obtained 
 in 22% yield as an oil , using the procedure described for the preparation 
 of compound 10b .
h nmr ( cdcl3 ) : 
 1.11 ( m , 2h ) , 1.21 ( m , 2h ) , 1.26 ( d , 6h , j = 6.2 ) , 
 2.15 ( m 1h ) , 2.75 ( s , 3h ) , 4.88 ( sept , 1h , j = 6.2 ) , 
 6.91 ( m , 2h ) , 7.02 ( m , 1h ) , 7.29 ( d , 1h , j = 9.1 ) , 
 7.88 ( d , 1h , j = 9.1 ) .
c nmr ( cdcl3 ) : 10.2 , 12.1 , 15.4 , 21.9 , 72.1 , 111.9 ( 6 and 17 hz ) ; 118.8 , 
 123.6 ( 9 hz ) ; 126.9 , 129.8 , 131.8 , 134.5 ( 14 hz ) ; 154.4 , 155.5 ( 4 
 and 250 hz ) ; 155.7 , 161.3 .
obtained in 66% 
 yield as an oil , using 2-fluoropyridine in acetonitrile at 180 c 
 for 6 h , and a chromatography over silica gel ( cyclohexane / ethyl acetate 
 95/5 ) .
h nmr ( cdcl3 ) : 1.26 ( d , 6h , j = 6.2 ) , 2.68 ( s , 3h ) , 4.91 ( sept , 1h , j = 6.2 ) , 7.01 ( m , 2h ) , 7.06 ( m , 2h ) , 7.72 ( m , 2h ) , 8.36 ( m , 1h ) .
c nmr ( cdcl3 ) : 11.9 , 21.9 , 72.0 , 111.9 ( 6 and 
 17 hz ) ; 114.3 , 119.6 , 123.4 ( 9 hz ) ; 129.4 , 131.3 , 134.7 ( 14 hz ) ; 137.9 , 
 147.2 , 153.7 , 154.1 , 155.6 ( 5 and 250 hz ) . hrms calcd for c18h17f2n3o2 + h : 346.1367 . 
 found : 346.1409 .
obtained 
 in 34% yield as an oil , using 2-fluoro-5-methylpyridine in acetonitrile 
 at 180 c for 6 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 97/3 ) .
h nmr ( cdcl3 ) : 1.26 ( d , 6h , j = 6.2 ) , 2.33 ( s , 3h ) , 2.64 ( s , 3h ) , 4.90 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.01 ( m , 1h ) , 7.54 ( m , 1h ) , 7.64 
 ( d , 1h , j = 8.4 ) , 8.18 ( m , 1h ) .
c nmr 
 ( cdcl3 ) : 11.6 , 17.7 , 21.9 , 71.9 , 111.9 ( 6 and 17 hz ) ; 114.2 , 
 123.4 ( 9 hz ) ; 129.1 , 129.2 , 131.0 , 134.7 ( 14 hz ) ; 138.7 , 147.1 , 152.0 , 
 153.4 , 155.7 ( 5 and 250 hz ) .
obtained in 64% yield as a solid , using 2-chloro-5-(trifluoromethyl)pyridine 
 in acetonitrile at 180 c for 4 h after a chromatography over 
 silica gel ( cyclohexane / dichloromethane 8/1 ) .
h nmr ( cdcl3 ) : 1.27 ( d , 6h , j = 6.1 ) , 2.72 ( s , 3h ) , 4.93 
 ( sept , 1h , j = 6.1 ) , 6.92 ( m , 2h ) , 7.05 ( m , 1h ) , 
 7.91 ( m , 2h ) , 8.61 ( m , 1h ) .
c nmr ( cdcl3 ) : 
 12.3 , 21.8 , 72.0 , 111.9 ( 6 and 17 hz ) ; 113.0 , 121.9 ( 33 hz ) ; 121.6 
 ( 9 hz ) ; 123.9 ( 272 hz ) ; 130.3 , 132.0 , 134.4 ( 13 hz ) ; 134.9 ( 3 hz ) , 
 144.7 ( 4 hz ) ; 154.6 , 155.6 ( 5 and 250 hz ) ; 156.4 . hrms calcd for c19h16f5n3o2 + h : 
 414.1241 . found : 414.1207 .
obtained in 46% yield as an oil , using 5-cyclopropyl-2,3-difluoropyridine 
 ( 5r ) in acetonitrile at 180 c for 3 h and a first 
 chromatography over silica gel ( cyclohexane / ethyl acetate 7/1 ) and 
 a second one over silica gel ( dichloromethane ) .
h nmr 
 ( cdcl3 ) : 0.76 ( m , 2h ) , 1.11 ( m , 2h ) , 1.22 ( d , 6h , j = 6.1 ) , 1.97 ( m , 1h ) , 2.27 ( s , 3h ) , 4.87 ( sept , 1h , j = 6.1 ) , 6.82 ( m , 3h ) , 7.16 ( m , 1h ) , 8.16 ( d , 1h , j = 2.0 ) .
c nmr ( cdcl3 ) : 9.2 , 9.6 , 
 12.6 , 21.9 , 71.9 , 111.9 ( 6 and 16 hz ) ; 121.9 ( 18 hz ) ; 123.5 ( 9 hz ) ; 
 128.3 , 131.0 , 134.7 ( 14 hz ) ; 138.1 ( 10 hz ) ; 141.6 , 142.3 , 152.9 ( 263 
 hz ) ; 154.1 , 155.8 ( 5 and 250 hz ) . hrms calcd for c21h20f3n3o2 + h : 404.1586 . found : 
 404.1527 .
obtained in 96% yield as a solid , using 2-chloro-5-cyclopropylnicotinonitrile 
 in acetonitrile ( 5s ) at 150 c for 40 min and a 
 chromatography over silica gel ( cyclohexane / ethyl acetate 97/3 ) .
h nmr ( cdcl3 ) : 0.76 ( m , 2h ) , 1.12 ( m , 2h ) , 1.28 
 ( d , 6h , j = 6.2 ) , 1.94 ( m , 1h ) , 2.58 ( s , 3h ) , 4.94 
 ( sept , 1h , j = 6.2 ) , 6.94 ( m , 2h ) , 7.05 ( m , 1h ) , 
 7.67 ( d , 1h , j = 2.4 ) , 8.34 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 9.0 , 11.4 , 12.2 , 
 21.8 , 72.8 , 100.6 , 111.9 ( 6 and 16 hz ) ; 116.7 , 123.7 ( 9 hz ) ; 130.0 , 
 131.1 , 134.3 ( 14 hz ) ; 135.7 , 141.1 , 149.3 , 152.7 , 153.9 , 155.7 ( 4 
 and 249 hz ) .
obtained 
 in 79% yield as a solid , using 2-fluoro-5-bromopyridine in acetonitrile 
 at 160 c for 3 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 98/2 to 9/1 ) .
h nmr ( cdcl3 ) : 1.25 ( d , 
 6h , j = 6.2 ) , 2.65 ( s , 3h ) , 4.89 ( sept , 1h , j = 6.2 ) , 6.94 ( m , 2h ) , 7.02 ( m , 1h ) , 7.69 ( d , 1h , j = 8.8 ) , 7.80 ( dd , 1h , j = 2.6 and 8.8 ) , 
 8.39 ( d , 1h , j = 2.6 ) .
c nmr ( cdcl3 ) : 12.0 , 21.9 , 72.1 , 111.9 ( 6 and 16 hz ) ; 115.1 , 115.4 , 123.5 
 ( 9 hz ) ; 129.7 , 131.5 , 134.5 ( 13 hz ) ; 140.4 , 147.9 , 152.8 , 154.0 , 155.6 
 ( 5 and 250 hz ) .
obtained in 73% yield as a solid , using 5-bromo-2,3-difluoropyridine 
 in acetonitrile at 180 c for 3 h and a chromatography over silica 
 gel ( cyclohexane / ethyl acetate 98/2 ) .
h nmr ( cdcl3 ) : 1.23 ( d , 6h , j = 6.2 ) , 2.35 ( s , 3h ) , 4.86 
 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 7.02 ( m , 1h ) , 
 7.75 ( d , 1h , j = 2.1 and 9.1 ) , 8.38 ( d , 1h , j = 2.1 ) .
c nmr ( cdcl3 ) : 9.6 , 21.8 , 
 72.1 , 111.9 ( 6 and 17 hz ) ; 117.6 ( 2 hz ) ; 123.7 ( 9 hz ) ; 128.6 ( 21 hz ) ; 
 129.0 , 131.2 , 134.5 ( 14 hz ) ; 139.9 ( 9 hz ) ; 144.7 ( 5 hz ) ; 151.7 ( 270 
 hz ) ; 154.5 , 155.7 ( 4 and 250 hz ) . hrms calcd for c18h15brf3n3o2 + h : 442.0378 . 
 found : 442.0346 .
obtained in 84% yield as an oil , using 5-bromo-2-fluoro-3-methylpyridine 
 in acetonitrile at 180 c for 3 h and a chromatography over silica 
 gel ( cyclohexane / ethyl acetate 98/2 ) .
h nmr ( cdcl3 ) : 1.23 ( d , 6h , j = 6.2 ) , 2.25 ( s , 3h ) , 2.32 
 ( s , 3h ) , 4.79 ( sept , 1h , j = 6.2 ) , 6.90 ( m , 2h ) , 
 7.01 ( m , 1h ) , 7.78 ( d , 1h , j = 2.3 ) , 8.39 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 9.5 , 18.2 , 
 21.9 , 72.0 , 111.9 ( 6 and 17 hz ) ; 119.0 , 123.5 ( 9 hz ) ; 128.0 , 130.7 , 
 132.1 , 134.7 ( 14 hz ) ; 142.7 , 146.7 , 149.7 , 153.3 , 155.7 ( 4 and 250 
 hz ) .
obtained in 52% yield as a solid , using 1-(6-bromopyridin-3-yl)ethanone 
 in acetonitrile at 130 c for 3 h and a chromatography over silica 
 gel ( cyclohexane / ethyl acetate 95/5 to 9/1 ) .
h nmr ( cdcl3 ) : 1.27 ( d , 6h , j = 6.1 ) , 2.63 ( s , 3h ) , 2.74 
 ( s , 3h ) , 4.93 ( sept , 1h , j = 6.1 ) , 6.92 ( m , 2h ) , 
 7.03 ( m , 1h ) , 7.87 ( d , 1h , j = 8.7 ) , 8.25 ( dd , 1h , j = 2.5 and 8.7 ) , 8.92 ( m , 1h ) .
c nmr ( cdcl3 ) : 12.5 , 21.8 , 26.5 , 72.2 , 112.0 ( 6 and 16 hz ) ; 113.0 , 123.7 
 ( 10 hz ) ; 128.2 , 130.4 , 132.1 , 134.3 ( 13 hz ) ; 137.4 , 148.8 , 154.7 , 
 155.6 ( 4 and 250 hz ) ; 156.7 , 195.7 .
obtained in 68% yield as an oil , using 2-(6-fluoropyridin-3-yl)propan-2-ol 
 ( 5 t ) in acetonitrile at 180 c for 6 h and a chromatography 
 over silica gel ( cyclohexane / ethyl acetate 4/1 ) .
h nmr 
 ( cdcl3 ) : 1.25 ( d , 6h , j = 6.2 ) , 1.63 ( s , 
 6h ) , 1.86 ( s , 1h ) , 2.65 ( s , 3h ) , 4.90 ( sept , 1h , j = 6.2 ) , 6.90 ( m , 2h ) , 6.99 ( m , 1h ) , 7.70 ( dd , 1h , j = 0.7 and 8.6 ) , 8.25 ( dd , 1h , j = 2.5 and 8.6 ) , 
 8.48 ( dd , 1h , j = 0.7 and 2.5 ) .
c nmr 
 ( cdcl3 ) : 11.8 , 21.9 , 31.7 , 71.3 , 72.0 , 111.9 ( 6 and 17 
 hz ) ; 113.8 , 123.4 ( 9 hz ) ; 129.3 , 131.2 , 134.7 ( 14 hz ) ; 134.8 , 140.2 , 
 143.7 , 152.9 , 153.6 , 155.6 ( 4 and 250 hz ) .
obtained 
 in 49% yield as an oil , using 5-ethyl-2-fluoropyridine ( 17l ) in acetonitrile at 180 c for 6 h and a chromatography over 
 silica gel ( cyclohexane / ethyl acetate 97/3 ) followed by drying under 
 high vacuum .
h nmr ( cdcl3 ) : 1.26 ( d , 6h , j = 6.2 ) , 1.27 ( t , 3h , j = 7.6 ) , 2.64 ( s , 
 3h ) , 2.65 ( q , 2h , j = 7.6 ) , 4.90 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.00 ( m , 1h ) , 7.56 ( dd , 1h , j = 1.9 and 8.5 ) , 7.66 ( d , 1h , j = 8.5 ) , 
 8.20 ( d , 1h , j = 1.9 ) .
c nmr ( cdcl3 ) : 11.6 , 15.4 , 21.9 , 25.5 , 71.9 , 111.9 ( 6 and 17 hz ) ; 114.3 , 
 123.4 ( 9 hz ) ; 129.1 , 131.0 , 134.7 ( 14 hz ) ; 135.4 , 137.6 , 146.4 , 152.2 , 
 153.5 , 155.6 ( 4 and 250 hz ) .
obtained in 34% yield as an oil , using 2,3-difluoro-5-ethylpyridine 
 ( 17 m ) in acetonitrile at 140 c for 4 h and a chromatography 
 over silica gel ( cyclohexane / ethyl acetate 97/3 ) followed by drying 
 under high vacuum .
h nmr ( cdcl3 ) : 1.23 ( d , 
 6h , j = 6.2 ) , 1.31 ( t , 3h , j = 7.6 ) , 
 2.28 ( s , 3h ) , 2.74 ( q , 2h , j = 7.6 ) , 4.88 ( sept , 
 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 7.01 ( m , 1h ) , 7.41 ( m , 
 1h ) , 8.20 ( m , 1h ) .
c nmr ( cdcl3 ) : 9.3 , 15.0 , 
 21.9 , 25.3 , 71.9 , 111.9 ( 6 and 17 hz ) ; 123.5 ( 9 hz ) ; 124.8 ( 17 hz ) ; 
 128.3 , 131.1 , 134.7 ( 14 hz ) ; 138.5 ( 11 hz ) ; 141.0 ( 3 hz ) ; 143.5 ( 5 
 hz ) ; 152.8 ( 260 hz ) ; 154.1 , 155.8 ( 4 and 250 hz ) . hrms calcd for c20h20f3n3o2 + h : 
 392.1586 . found : 392.1572 .
obtained 
 in 12% yield as an oil , using 2-bromo-5-(1,1-difluoroethyl)pyridine 
 ( 17n ) in acetonitrile at 140 c for 6 h and a chromatography 
 over silica gel ( cyclohexane / ethyl acetate from 98.5/1.5 to 9/1 ) .
h nmr ( cdcl3 ) : 1.26 ( d , 6h , j = 
 6.2 ) , 1.98 ( t , 3h , j = 18 ) , 2.70 ( s , 3h ) , 4.92 ( sept , 
 1h , j = 6.2 ) , 6.93 ( m , 2h ) , 7.02 ( m , 1h ) , 7.84 ( m , 
 2h ) , 8.50 ( s , 1h ) .
c nmr ( cdcl3 ) : 12.1 , 21.9 , 
 25.7 ( 30 hz ) ; 72.1 , 111.9 ( 6 and 16 hz ) ; 113.3 , 121.0 ( 239 hz ) ; 123.5 
 ( 9 hz ) ; 129.3 ( 27 hz ) ; 129.8 , 131.6 , 134.5 ( 14 hz ) ; 134.6 ( 5 hz ) ; 
 144.0 ( 6 hz ) ; 154.2 , 155.1 , 155.6 ( 4 and 250 hz ) .
obtained 
 in 59% yield as a white powder , using 2,5-dibromopyrazine in acetonitrile 
 at 120 c for 5 h and a chromatography over silica gel ( cyclohexane / dichloromethane 
 from 2/1 to 1/1 ) .
h nmr ( cdcl3 ) : 1.26 ( d , 6h , j = 6.2 ) , 2.64 ( s , 3h ) , 4.91 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 7.05 ( m , 1h ) , 8.35 ( d , 1h , j = 1.3 ) , 8.87 ( d , 1h , j = 1.3 ) .
c nmr 
 ( cdcl3 ) : 11.8 , 21.8 , 72.4 , 111.9 ( 6 and 17 hz ) ; 123.8 ( 9 
 hz ) ; 130.4 , 131.8 , 133.4 , 134.2 ( 13 hz ) ; 134.6 , 143.1 , 149.1 , 154.9 , 
 155.6 ( 4 and 250 hz ) . hrms calcd for c17h15brf2n4o2 + h : 425.0425 . found : 425.0418 .
obtained in 32% yield as a solid using from 2-chloro-5-(trifluoromethyl)pyrazine 
 in acetonitrile at 180 c for 4 h after a chromatography over 
 silica gel ( cyclohexane / dichloromethane 2/1 ) .
h nmr ( cdcl3 ) : 1.27 ( d , 6h , j = 6.2 ) , 2.70 ( s , 3h ) , 4.97 
 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.07 ( m , 2h ) , 
 8.60 ( s , 1h ) , 9.21 ( s , 1h ) .
c nmr ( cdcl3 ) : 
 12.1 , 21.7 , 72.6 , 112.0 ( 6 and 16 hz ) ; 121.5 ( 273 hz ) ; 123.9 ( 9 hz ) ; 
 131.0 , 132.3 , 134.0 ( 13 hz ) ; 136.1 , 137.7 ( 36 hz ) ; 138.3 ( 3 hz ) ; 151.5 , 
 155.5 ( 4 and 250 hz ) , 155.6 .
obtained 
 in 45% yield as an oil , using 2-bromo-5-cyclopropylpyrazine in acetonitrile 
 at 160 c for 2 h and a chromatography over silica gel ( cyclohexane / dichloromethane 
 from 3/2 to 1/2 ) .
h nmr ( cdcl3 ) : 1.04 ( m , 4h ) , 
 1.25 ( d , 6h , j = 6.2 ) , 2.07 ( m , 1h ) , 2.61 ( s , 3h ) , 
 4.88 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 7.02 ( m , 
 1h ) , 8.17 ( d , 1h , j = 1.4 ) , 8.90 ( d , 1h , j = 1.4 ) .
c nmr ( cdcl3 ) : 9.6 , 11.4 , 
 14.1 , 28.1 , 72.1 , 111.9 ( 6 and 17 hz ) ; 123.5 ( 9 hz ) ; 129.5 , 131.2 , 
 134.5 ( 14 hz ) ; 136.4 , 138.7 , 147.8 , 153.2 , 154.1 , 155.6 ( 4 and 250 
 hz ) .
obtained 
 in 29% yield as a solid , using 3-chloro-6-methylpyridazine in acetonitrile 
 at 140 c for 2 h and two consecutive chromatography processes , 
 the first one over silica gel ( cyclohexane / ethyl acetate 3/1 ) , the 
 second one over alumina containing 1.5% of water ( cyclohexane / dichloromethane 
 from 1/1 to 1/2 ) .
h nmr ( cdcl3 ) : 1.25 ( d , 6h , j = 6.2 ) , 2.69 ( s , 3h ) , 2.75 ( s , 3h ) , 4.88 ( sept , 1h , j = 6.2 ) , 6.89 ( m , 2h ) , 7.00 ( m , 1h ) , 7.35 ( d , 1h , j = 9.1 ) , 7.90 ( d , 1h , j = 9.1 ) .
c nmr ( cdcl3 ) : 12.1 , 21.6 , 21.8 , 72.1 , 112.0 ( 6 and 17 
 hz ) ; 118.9 , 123.6 ( 9 hz ) ; 128.8 , 129.9 , 131.9 , 134.4 ( 13 hz ) ; 154.5 , 
 155.6 ( 4 and 250 hz ) ; 155.8 , 156.7 .
obtained 
 in 58% yield as a solid , using 3,6-dichloropyridazine in acetonitrile 
 at 140 c for 1 h and a chromatography over silica gel ( cyclohexane / ethyl 
 acetate from 97/3 to 95/5 ) .
h nmr ( cdcl3 ) : 
 1.25 ( d , 6h , j = 6.2 ) , 2.75 ( s , 3h ) , 4.88 ( sept , 
 1h , j = 6.2 ) , 6.89 ( m , 2h ) , 7.01 ( m , 1h ) , 7.50 ( d , 
 1h , j = 9.3 ) , 8.01 ( d , 1h , j = 9.3 ) .
c nmr ( cdcl3 ) : 12.3 , 21.8 , 72.3 , 112.0 ( 6 and 
 17 hz ) ; 121.2 , 123.8 ( 9 hz ) ; 129.8 , 130.5 , 132.2 , 134.2 ( 14 hz ) ; 152.6 , 
 155.1 , 155.6 ( 4 and 250 hz ) ; 156.4 .
hrms calcd for c17h15clf2n4o2 + h : 381.0930 . 
 found : 381.0927 . in a 
 20 ml biotage 
 tube , 3-ethoxy-4-iodo-5-methyl-1h - pyrazole
( 1.53 
 g , 6.07 mmol ) , cesium carbonate ( 2.2 g , 6.98 mmol ) , and 5-cyclopropyl-2-fluoropyridine 
 ( 0.87 g , 6.37 mmol ) were dispersed in acetonitrile ( 14 ml , dried over 
 4  molecular sieves ) .
the resulting suspension was adsorbed over 
 silica gel and purified by a chromatography over silica gel ( cyclohexane / dichloromethane 
 from 97.5/2.5 to 96.5/3.5 ) to yield in this order , compound 12a ( 0.3 g , 13% ) as a solid , unreacted ( and volatile ) 5-cyclopropyl-2-fluoropyridine 
 ( 0.3 g , 34% ) and compound 12b , which was further purified 
 under a high vacuum as an oil ( 0.14 g , 9% ) . washing the column with 
 ethyl acetate led then to the isolation of the reduced and uv / tlc - invisible 
 3-ethoxy-5-methyl-1h - pyrazole .
5-cyclopropyl-2-(3-ethoxy-4-iodo-5-methyl-1h - pyrazol-1-yl)pyridine ( 12a ) : h nmr ( cdcl3 ) 0.73 ( m , 2h ) , 1.03 ( m , 2h ) , 1.45 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.66 ( s , 3h ) , 4.36 ( q , 2h , j = 7.2 ) , 7.39 ( dd , 1h , j = 2.4 and 8.5 ) , 
 7.62 ( d , 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 8.8 , 12.6 , 14.7 , 
 15.2 , 52.8 , 65.0 , 114.7 , 135.1 , 136.3 , 143.0 , 145.5 , 151.3 , 162.4 . 

5-cyclopropyl-2-(3-ethoxy-5-methyl-1h - pyrazol-1-yl)pyridine ( 12b ) : h nmr ( cdcl3 ) 0.71 ( m , 2h ) , 1.02 ( m , 2h ) , 1.42 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.62 ( s , 3h ) , 4.26 ( q , 2h , j = 7.2 ) , 5.66 ( s , 1h ) , 7.38 ( dd , 1h , j = 2.4 and 
 8.5 ) , 7.66 ( d , 1h , j = 8.5 ) , 8.19 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 8.6 , 12.5 , 
 14.8 ( two signals ) ; 64.4 , 94.9 , 114.8 , 135.0 , 135.6 , 142.2 , 140.4 , 
 151.6 , 162.3 . from 3-ethoxy-4-bromo-5-methyl-1h - pyrazole ( preparation provided below ) , using the protocol 
 described for the preparation of compound 12a , compound 12c was obtained in a 48% yield as an oil .
h nmr 
 ( cdcl3 ) : 0.72 ( m , 2h ) , 1.04 ( m , 2h ) , 1.46 ( t , 3h , j = 7.2 ) , 1.93 ( m , 1h ) , 2.63 ( s , 3h ) , 4.38 ( q , 2h , j = 7.2 ) , 7.40 ( dd , 1h , j = 2.3 and 8.5 ) , 
 7.62 ( d , 1h , j = 8.5 ) , 8.21 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 12.6 , 13.5 , 
 14.7 , 65.0 , 84.4 , 114.6 , 135.2 , 136.2 , 140.0 , 145.5 , 151.4 , 159.7 . 

3-ethoxy-4-bromo-5-methyl-1h - pyrazole : 
 3-ethoxy-5-methyl-1h - pyrazole ( 6.64 g , 52.63 mmol ) 
 was dissolved in dry acetonitrile ( 200 ml ) , n - bromosuccinimide 
 ( 9.83 g , 55.26 mmol ) was added , and the solution was stirred at room 
 temperature overnight .
the acetonitrile was then removed under vacuum , 
 this was dissolved in water and ethyl acetate , and the organic layer 
 was washed six times with water once with brine and dried over magnesium 
 sulfate .
removal of the solvent under vacuum allowed the isolation 
 of pure 4-bromopyrazole as a white powder ( 9.83 g , 91% ) .
h nmr ( cdcl3 ) : 1.42 ( t , 3h , j = 7.0 ) , 
 2.21 ( s , 3h ) , 4.28 ( q , 2h , j = 7.0 ) , 9.40 ( s(l ) , 
 1h ) .
c nmr ( cdcl3 ) : 10.6 , 14.8 , 65.1 , 79.7 , 
 139.2 , 160.2 . in a 10 ml biotage tube ,
compound 4 ( 0.14 g , 0.633 mmol ) , 5-methoxy-2-bromopyrimidine ( 0.12 
 g , 0.665 mmol ) , cesium carbonate ( 0.22 g , 0.696 mmol ) , 4  molecular 
 sieves ( 0.1 g , 3.2 mm pellets ) , and [ n , n-bis((2-pyridine)-methylene)]-1,2-diaminocyclohexane ( 0.018 g , 0.063 mmol ) were dispersed in acetonitrile 
 ( 4.5 ml , dried over 4  molecular sieves ) .
copper oxide 
 ( 0.004 g , 0.031 mmol ) was then added , and the tube was sealed .
this 
 was shaken thoroughly , heated for 30 s in the microwave oven at 100 
 c , and shaken again . at this stage ,
the pink copper oxide is 
 well dissolved in the reaction mixture , if not , another 30 s heating 
 at 100 c is required .
the heating was then resumed at 180 c 
 for 6 h. the resulting suspension was directly adsorbed over a small 
 amount of silica gel , and this was subjected to a chromatography over 
 silica gel ( cyclohexane / ethyl acetate 9/1 ) to give the 5-methoxypyridine 
 derivative ( 0.11 g , 53% ) as a white solid .
h nmr ( cdcl3 ) : 1.42 ( t , 3h , j = 7.2 ) , 2.51 ( s , 3h ) , 3.76 
 ( s , 2h ) , 3.88 ( s , 3h ) , 4.36 ( q , 2h , j = 7.2 ) , 7.19 
 ( m , 1h ) , 7.30 ( m , 5h ) , 7.67 ( d , 1h , j = 8.5 ) , 8.09 
 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 12.6 , 14.9 , 27.8 , 55.9 , 64.4 , 105.9 , 116.4 , 123.9 , 125.7 , 128.2 
 ( two signals ) ; 133.4 , 138.8 , 141.1 , 147.6 , 153.2 , 162.0 .
hrms calcd 
 for c19h21n3o2 + h : 324.1712 . 
 found : 324.1678 . by using 
 the same procedure described above for the preparation of 2-(4-benzyl-3-ethoxy-5-methyl-1h - pyrazol-1-yl)-5-methoxypyridine ( 6p ) ,
this 
 compound was obtained as a solid in 64% yield after a chromatography 
 over silica gel ( cyclohexane / ethyl acetate from 97/3 to 95/5 ) .
h nmr ( cdcl3 ) : 1.25 ( d , 6h , j = 
 6.2 ) , 2.60 ( s , 3h ) , 3.87 ( s , 3h ) , 4.88 ( sept , 1h , j = 6.2 ) , 6.90 ( m , 2h ) , 6.98 ( m , 1h ) , 7.30 ( dd , 1h , j = 2.4 and 8.5 ) , 7.65 ( d , 1h , j = 8.5 ) , 8.06 ( d , 
 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 11.3 , 21.9 , 55.9 , 71.9 , 112.0 ( 6 and 17 hz ) ; 115.7 , 123.4 ( 9 hz ) ; 
 124.0 , 128.8 , 133.2 , 134.8 ( 13 hz ) ; 147.7 , 153.3 , 155.7 ( 4 and 250 
 hz ) .
compound 6 t ( 0.17 g , 0.48 
 mmol ) was dissolved in dichloromethane ( 10 ml ) and trifluoroacetic 
 acid ( 2 ml ) .
triethylsilane ( 0.28 ml , 1.75 mmol ) was added , and the 
 reaction was stirred at room temperature for 4 h. an lc / ms pointed 
 out a very slow reaction .
trifluoromethanesulfonic acid ( 0.2 ml , 2.26 
 mmol ) was added , followed by some more triethylsilane ( 0.2 ml , 1.25 
 mmol ) .
a hydrogen evolution was observed , and lc / ms monitoring pointed 
 out the occurrence of compound 6u .
more triethylsilane 
 ( 0.2 ml , 1.25 mmol ) was added , and this was stirred 24 h. the resulting 
 solution was diluted in ethyl acetate , washed until neutrality with 
 saturated sodium hydrogenocarbonate and brine , dried over magnesium 
 sulfate , and concentrated to dryness .
the residue was purified by 
 two consecutive chromatography processes , the first one over silica 
 gel ( cyclohexane / ethyl acetate from 97/3 ) , the second one over silica 
 gel ( toluene ) , to yield compound 6u ( 0.04 g , 24% ) as 
 an oil .
h nmr ( cdcl3 ) : 1.30 ( t , 6h , j = 6.8 ) , 1.41 ( t , 3h , j = 7.1 ) , 2.55 ( s , 
 3h ) , 2.96 ( sept , 1h , j = 6.8 ) , 3.75 ( s , 2h ) , 4.35 
 ( q , 2h , j = 7.1 ) , 7.18 ( m , 1h ) , 7.28 ( m , 4h ) , 7.61 
 ( dd , 1h , j = 2.4 and 8.6 ) , 7.67 ( d , 1h , j = 8.6 ) , 8.25 ( d , 1h , j = 2.4 ) . c nmr 
 ( cdcl3 ) : 11.9 , 13.9 , 22.7 , 26.7 , 30.2 , 63.1 , 105.2 , 114.1 , 
 124.7 , 127.2 ( two signals ) ; 135.0 , 138.1 , 138.8 , 140.0 , 144.5 , 151.1 , 
 161.1 .
hrms calcd for c21h25n3o + 
 h : 336.2076 . found : 336.2051 . in a tube adapted for microwave oven , 2-(4-benzyl-3-ethoxy-5-methyl-1h - pyrazol-1-yl)-5-bromopyridine ( 0.16 g , 0.43 mmol ) , cesium 
 carbonate ( 0.7 g , 2.14 mmol ) , and cyclopropyl boronic acid ( 0.11 g , 
 1.28 mmol ) in dimethylformamide ( 4 ml , dried over 4  molecular 
 sieves ) were mixed .
this suspension was degassed by a gentle stream 
 of argon , [ 1,1-bis(diphenylphosphino)ferrocene ] dichloropalladium 
 complexed with dichloromethane ( 0.017 g , 0.021 mmol ) was added , the 
 tube was sealed , and heated in a microwave oven at 110 c for 
 1 h. the resulting suspension was diluted in water and extracted with 
 ethyl acetate .
the organic layer was washed with brine , dried over 
 sodium sulfate , and concentrated to dryness .
the residue was purified 
 first by a chromatography over silica gel ( cyclohexane / ethyl acetate 
 from 2/1 to 3/2 ) to yield the 5-cyclopropyl derivative as a white 
 powder ( 0.07 g , 48% ) .
h nmr ( cdcl3 ) : 0.78 ( m , 
 2h ) , 1.03 ( m , 2h ) , 1.41 ( t , 3h , j = 7.0 ) , 1.91 ( m , 
 1h ) , 2.54 ( s , 3h ) , 3.76 ( s , 2h ) , 4.35 ( q , 2h , j = 
 7.0 ) , 7.18 ( m , 1h ) , 7.28 ( m , 4h ) , 7.38 ( m , 1h ) , 7.65 ( m , 1h ) , 8.20 
 ( m , 1h ) .
c nmr ( cdcl3 ) : 8.7 , 12.5 , 12.9 , 14.9 , 
 27.8 , 64.2 , 106.3 , 115.0 , 125.7 , 128.2 , 128.3 , 135.1 , 135.3 , 139.1 , 
 141.0 , 145.4 , 151.8 , 162.2 .
hrms calcd for c21h23n3o + h : 334.1919 . found : 334.1931 . under 
 an atmosphere of argon ,
compound 12a ( 0.31 g , 0.83 mmol ) 
 was dissolved in dry thf ( 10 ml ) .
this was cooled to 78 c , 
 and 2 m butyl lithium in cyclohexane ( 0.63 ml , 1.25 mmol ) was added . 

this was stirred at 78 c for 5 min before adding benzoyl 
 chloride ( 0.14 ml , 1.25 mmol ) .
the resulting solution was allowed 
 to warm to room temperature , water was added , and this was extracted 
 with ethyl acetate .
the organic layer was washed with water and brine , 
 dried over magnesium sulfate , and concentrated to dryness .
the residue 
 was purified by a chromatography over silica gel ( cyclohexane / ethyl 
 acetate from 97/3 to 95/5 ) to yield the benzoyl derivative 13 as a glass ( 0.13 g , 44% ) .
h nmr ( cdcl3 ) : 
 0.78 ( m , 2h ) , 1.09 ( m , 2h ) , 1.23 ( t , 3h , j = 7.2 ) , 
 1.92 ( m , 1h ) , 2.75 ( s , 3h ) , 4.28 ( q , 2h , j = 7.2 ) , 
 7.47 ( m , 4h ) , 7.53 ( m , 1h ) , 7.64 ( d , 1h , j = 8.5 ) , 
 7.84 ( dd , 1h , j = 8.5 and 2.3 ) , 8.29 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 9.1 , 12.7 , 
 13.8 , 14.4 , 64.6 , 108.8 , 116.9 , 127.7 , 129.4 , 132.0 , 135.1 , 137.7 , 
 139.4 , 145.9 , 146.2 , 150.5 , 161.3 , 190.7 .
compound 13 ( 0.07 g , 0.2 mmol ) and sodium borohydride ( 0.074 g , 2.01 
 mmol ) were stirred overnight in methanol ( 15 ml ) at room temperature . 

this was neutralized with acetic acid , concentrated to dryness , and 
 diluted in ethyl acetate .
the organic layer was washed with water 
 and brine , dried over magnesium sulfate , and concentrated to dryness . 

the residue was purified by a chromatography over silica gel ( dichloromethane  ethanol 
 from 99.5/0.5 to 98/2 ) to yield the alcohol as a glass ( 0.05 g , 71% ) .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.03 ( m , 2h ) , 1.38 
 ( t , 3h , j = 7.2 ) , 1.92 ( m , 1h ) , 2.51 ( s , 3h ) , 4.35 
 ( q , 2h , j = 7.2 ) , 5.82 ( s , 1h ) , 7.25 ( m , 1h ) , 7.37 
 ( m , 3h ) , 7.47 ( m , 2h ) , 7.60 ( d , 1h , j = 8.5 ) , 8.20 
 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 12.6 , 12.9 , 14.8 , 64.5 , 67.8 , 109.2 , 115.6 , 126.0 , 127.0 , 
 128.2 , 129.8 , 135.1 , 138.9 , 143.6 , 145.6 , 151.4 , 160.9 .
hrms calcd 
 for c21h23n3o2 + h : 350.1869 . 
 found : 350.1829 . under an argon atmosphere ,
compound 13 ( 0.05 g , 0.14 
 mmol ) was dissolved in dry tetrahydrofuran ( 5 ml ) at room temperature . 

a 1.6 m solution of methyllithium in ether ( 0.5 ml , 0.84 mmol ) was 
 added and the solution stirred for 5 min .
this was diluted in water , 
 extracted with ethyl acetate , the organic layer was washed with water 
 and brine , dried over magnesium sulfate , and concentrated to dryness . 

the residue was further purified by a chromatography over silica gel 
 ( dichloromethane / ethanol from 98/2 ) to yield the tertiary alcohol 
 as a glass ( 0.04 g , 76% ) .
h nmr ( cdcl3 ) : 0.72 
 ( m , 2h ) , 1.04 ( m , 2h ) , 1.38 ( t , 3h , j = 7.2 ) , 1.91 
 ( m , 1h ) , 1.95 ( s , 3h ) , 2.31 ( s , 3h ) , 3.52 ( s , 1h ) , 4.32 ( m , 2h ) , 7.257.55 
 ( m , 7h ) , 8.21 ( d , 1h , j = 2.3 ) .
c nmr 
 ( cdcl3 ) : 8.8 , 12.6 , 13.3 , 14.8 , 31.2 , 64.6 , 73.3 , 112.6 , 
 116.9 , 125.5 , 126.7 , 126.9 , 127.9 , 135.0 , 136.6 , 138.5 , 145.7 , 151.2 , 
 161.6 .
hrms calcd for c22h25n3o2 + h : 364.2025 . found : 364.1948 . in a 
 vial adapted 
 for microwave heating , compound 12c ( 0.21 g , 0.65 mmol ) , 
 phenylboronic acid ( 0.087 g , 0.71 mmol ) , and cesium carbonate ( 0.53 
 g , 1.69 mmol ) were dissolved in a 2/3 mixture of propanol and water 
 ( 5 ml ) .
this was degassed by a gentle steam of argon , [ 1,1-bis(diphenylphosphino)ferrocene ] 
 dichloropalladium complexed with dichloromethane ( 0.026 g , 0.032 mmol ) 
 was added , and the sealed tube heated at 120 c for 30 min .
the organic layer was washed with brine , dried over sodium sulfate , 
 and concentrated to dryness .
the residue was purified first by a chromatography 
 over alumina containing 1.5% water ( cyclohexane / dichloromethane from 
 1/0 to 1/1 ) to yield the 4-phenyl derivative as a solid ( 0.07 g , 33% ) .
h nmr ( cdcl3 ) : 0.74 ( m , 2h ) , 1.05 ( m , 2h ) , 1.44 
 ( t , 3h , j = 7.2 ) , 1.93 ( m , 1h ) , 2.68 ( s , 3h ) , 4.40 
 ( q , 2h , j = 7.2 ) , 7.27 ( m , 1h ) , 7.43 ( m , 3h ) , 7.51 
 ( m , 2h ) , 7.68 ( d , 1h , j = 8.4 ) , 8.24 ( d , 1h , j = 2.3 ) .
c nmr ( cdcl3 ) : 8.7 , 12.6 , 
 13.7 , 14.9 , 64.4 , 109.3 , 115.6 , 126.2 , 128.3 , 129.2 , 131.9 , 135.1 , 
 135.9 , 138.9 , 145.6 , 151.6 , 160.9 .
preparation of 
 benzylzinc bromide : a 100 ml round - bottom flask was charged with lithium 
 chloride ( 3.9 g , 92.6 mmol ) .
this was thoroughly dried with an open 
 flame for two min under vacuum and then allowed to cool under an argon 
 atmosphere .
still under an inert atmosphere , zinc dust ( 5.5 g , 84.2 
 mmol ; vwr technical 6% oxide ) was added .
anhydrous tetrahydrofuran 
 ( 50 ml ) was injected , and the flask cooled using an ice bath .
benzyl 
 bromide ( 5 ml , 42.1 mmol . ) was added via the septum ; the mixture was 
 sonicated for 45 s and allowed to stir at 4 c overnight ( 17 
 h ) .
this solution was stocked for 3 month at 4 c , leading to 
 a 0.68 molar ( 80% ) transparent solution of benzylzinc bromide as measured 
 by the titration method previously reported .
second step : compound 12c ( 0.23 g , 0.71 mmol ) , palladium 
 acetate ( 0.008 g , 0.036 mmol ) , and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl 
 ( xphos ) ( 0.084 g , 0.071 mmol ) were added in a flask flushed with argon . 

anhydrous tetrahydrofuran ( 5 ml ) was injected , and the resulting solution 
 was allowed to stir a few minutes .
a fraction of the solution of benzylzinc 
 bromide described above ( 3.2 ml , 2.14 mmol ) was injected , and the 
 mixture heated for 16 h at 50 c .
the aqueous layer was extracted 
 once with ethyl acetate , the organic layer was washed with brine , 
 dried over magnesium sulfate , and concentrated to dryness .
the residue 
 was purified by a chromatography over silica gel ( dichloromethane / ethanol 
 99.5:0.5 ) followed by drying under high vacuum to yield compound 6q as a yellowish oil ( 0.17 g , 71% ) with analytical data identical 
 with the one described above .
preparation of ( 1-phenylethyl)zinc chloride : a 20 ml tube adapted 
 for microwave heating was charged with lithium chloride ( 0.48 g , 11.3 
 mmol ) .
this was thoroughly dried with an open flame for two min and 
 then allowed to cool under an argon atmosphere .
still under an inert 
 atmosphere , zinc dust ( 0.74 g , 11.3 mmol ; size < 10 m ) was 
 added and the tube was sealed .
anhydrous tetrahydrofuran ( 10 ml ) was 
 injected , followed by 0.2 m dibromoethane solution in tetrahydrofuran 
 ( 1.9 ml , 0.38 mmol ) .
this was allowed to cool , a 0.06 m trimethylsilychloride 
 solution in tetrahydrofuran ( 1.25 ml , 0.075 mmol ) was added , and the 
 tube was heated again with microwave irradiation for 5 min at 85 c . 
 after cooling , ( 1-chloroethyl)benzene ( 1 ml , 7.5 mmol ) was added via 
 the septum , and the mixture was heated using microwave irradiation 
 for 1 h at 80 c. this led to a 0.47 molar ( 88% ) yellow solution of 
 ( 1-phenylethyl)zinc chloride as measured by the titration method previously 
 reported .
second step : compound 12c ( 0.31 g , 0.96 mmol ) , palladium acetate ( 0.011 g , 0.048 
 mmol ) , and 2-dicyclohexylphosphino-2,6-bis(n , n - dimethylamino)biphenyl ( cphos ) ( 0.042 
 g , 0.096 mmol ) were added in a flask flushed with argon
. the decanted 
 solution of ( 1-phenylethyl)zinc chloride described above ( 6.1 ml , 
 2.89 mmol ) was injected , and the mixture heated for 16 h at 50 c . 
 the resulting suspension
the 
 aqueous layer was extracted once with ethyl acetate , and the organic 
 layer was washed with brine , dried over magnesium sulfate , and concentrated 
 to dryness .
the residue was purified by a chromatography over silica 
 gel ( dichloromethane ) , followed by drying under high vacuum to yield 
 compound 16 as a colorless oil ( 0.14 g , 42% ) .
h nmr ( cdcl3 ) : 0.72 ( m , 2h ) , 1.04 ( m , 2h ) , 1.42 ( t , 3h , j = 7.1 ) , 1.71 ( d , 3h , j = 7.4 ) , 1.92 ( m , 
 1h ) , 2.51 ( s , 3h ) , 4.08 ( q , 1h , j = 7.3 ) , 4.30 ( m , 
 2h ) , 7.20 ( m , 1h ) , 7.30 ( m , 2h ) , 7.40 ( m , 3h ) , 7.61 ( d , 1h , j = 8.5 ) , 8.20 ( d , 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 8.6 , 12.6 , 12.8 , 14.9 , 20.0 , 34.2 , 64.1 , 
 111.0 , 115.4 , 125.7 , 127.3 , 128.1 , 135.0 , 135.4 , 138.0 , 145.5 , 146.1 , 
 151.8 , 161.9 .
compound 18d ( 0.17 g , 0.42 mmol ) and 10% 
 palladium over 
 charcoal ( 0.066 g , 0.062 mmol ) were dispersed in ethanol ( 20 ml ) . 

this was charged with hydrogen at 1 atm and stirred at room temperature 
 for 5 days .
the suspension was filtered , the filtrate concentrated 
 to dryness , and the residue purified by a chromatography over silica 
 gel ( cyclohexane / ethyl acetate 97/3 ) followed by drying under high 
 vacuum to give compound 18o as an oil ( 0.05 g , 30% ) .
h nmr ( cdcl3 ) : 1.00 ( t , 3h , j = 
 7.3 ) , 1.23 ( d , 6h , j = 6.2 ) , 1.69 ( m , 2h ) , 2.28 ( s , 
 3h ) , 2.66 ( t , 2h , j = 7.4 ) , 4.88 ( sept , 1h , j = 6.2 ) , 6.89 ( m , 2h ) , 7.01 ( m , 1h ) , 7.39 ( m , 1h ) , 8.18 
 ( m , 1h ) .
c nmr ( cdcl3 ) : 9.3 , 13.5 , 21.9 , 24.0 , 
 34.2 , 71.9 , 111.9 ( 6 and 17 hz ) ; 123.5 ( 9 hz ) ; 125.2 ( 17 hz ) ; 128.3 , 
 131.1 , 134.7 ( 14 hz ) ; 138.5 ( 11 hz ) ; 139.5 ( 3 hz ) ; 144.0 ( 5 hz ) ; 152.7 
 ( 260 hz ) ; 154.1 , 155.7 ( 4 and 250 hz ) . hrms calcd for c21h22f3n3o2 + h : 406.1742 . 
 found : 406.1713 .
compound 18d ( 0.11 g , 0.272 mmol ) and cesium carbonate 
 ( 0.13 g , 0.409 mmol ) dissolved in methanol ( 2 ml ) were heated in a 
 microwave oven at 150 c for 90 min .
this was concentrated to 
 dryness and the residue purified by a chromatography over silica gel 
 ( cyclohexane / ethyl acetate 4/1 ) to yield the methoxy ether 18p ( 0.08 g , 70% ) as an oil .
h nmr ( cdcl3 ) : 0.77 
 ( m , 2h ) , 1.08 ( m , 2h ) , 1.21 ( d , 6h , j = 6.2 ) , 1.96 
 ( m , 1h ) , 2.11 ( s , 3h ) , 3.79 ( s , 3h ) , 4.87 ( sept , 1h , j = 6.2 ) , 6.87 ( m , 2h ) , 7.00 ( m , 2h ) , 7.97 ( d , 1h , j = 2.0 ) .
c nmr ( cdcl3 ) : 9.0 , 9.3 , 13.0 , 22.0 , 
 56.0 , 71.7 , 111.9 ( 6 and 16 hz ) ; 118.2 , 123.4 ( 9 hz ) ; 127.4 , 131.2 , 
 134.9 ( 14 hz ) ; 138.7 , 139.2 , 141.4 , 150.7 , 153.5 , 155.8 ( 4 and 249 
 hz ) .
compound 18d ( 0.06 g , 0.148 
 mmol ) , cesium , and a 2n solution of dimethylamine in tetrahydrofuran 
 ( 0.5 ml ) in tetrahydrofuran ( 2 ml ) were heated in a microwave oven 
 at 180 c for 9 h. this was concentrated to dryness and the residue 
 purified by a chromatography over silica gel ( cyclohexane / ethyl acetate 
 9/1 ) to yield the n - dimethylamine 18q ( 0.04 g , 62% ) as an oil .
h nmr ( cdcl3 ) : 0.75 
 ( m , 2h ) , 1.03 ( m , 2h ) , 1.20 ( d , 6h , j = 6.2 ) , 1.91 
 ( m , 1h ) , 2.09 ( s , 3h ) , 2.56 ( s , 6h ) , 4.89 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 3h ) , 5.98 ( m , 1h ) , 7.86 ( d , 1h , j = 2 ) .
c nmr ( cdcl3 ) : ( one signal missing ) 
 8.8 , 9.0 , 13.0 , 21.9 , 41.3 , 71.8 , 111.9 ( 6 and 16 hz ) ; 122.8 , 123.3 
 ( 9 hz ) ; 127.5 , 130.9 , 135.0 ( 13 hz ) ; 139.7 , 140.4 , 144.3 , 153.4 , 155.7 
 ( 4 and 249 hz ) . hrms calcd for c23h26f2n4o3 + h : 429.2102 . found : 429.2023 .
compound 18d ( 0.38 g , 0.94 mmol ) and cesium carbonate ( 0.34 g , 1.03 
 mmol ) dissolved in benzylalcohol ( 2 ml ) were heated in a microwave 
 oven at 150 c for 90 min .
this was concentrated to dryness and 
 the residue purified by two consecutive chromatography processes , 
 the first one over silica gel ( cyclohexane / ethyl acetate 4/1 ) and 
 the second one over alumina containing 1.5% of water ( cyclohexane / dichloromethane 
 1/1 ) to yield the benzyl ether 18r ( 0.14 g , 29% ) as an 
 oil .
h nmr ( cdcl3 ) : 0.74 ( m , 2h ) , 1.08 ( m , 
 2h ) , 1.22 ( d , 6h , j = 6.1 ) , 1.92 ( m , 1h ) , 2.13 ( s , 
 3h ) , 4.89 ( sept , 1h , j = 6.1 ) , 5.02 ( s , 2h ) , 6.97 
 ( m , 2h ) , 7.02 ( m , 2h ) , 7.31 ( m , 5h ) , 8.01 ( d , 1h , j = 2.0 ) .
c nmr ( cdcl3 ) : 9.1 , 9.4 , 12.9 , 22.0 , 
 71.1 , 71.8 , 111.9 ( 6 and 17 hz ) ; 123.4 ( 9 hz ) ; 127.1 , 127.5 , 128.0 , 
 128.5 , 131.2 , 134.9 ( 14 hz ) ; 135.9 , 139.3 , 139.9 , 141.4 , 149.8 , 153.6 , 
 155.8 ( 4 and 249 hz ) . hrms calcd for c29h27f2n3o3 + h : 492.2099 . found : 492.2076 .
compound 18r ( 0.22 g , 0.44 mmol ) , ammonium formate ( 0.11 
 g , 1.79 mmol ) , and 10% palladium over charcoal ( 0.023 g , 0.021 mmol ) 
 were heated to reflux in ethanol ( 50 ml ) for 45 min .
this was adsorbed 
 over silica gel and purified by a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 95/5 ) to yield the hydroxyl derivative 18s ( 0.13 
 g , 72% ) as an oil .
h hmr ( cdcl3 ) : 0.71 ( m , 
 2h ) , 1.01 ( m , 2h ) , 1.25 ( d , 6h , j = 6.1 ) , 1.89 ( m , 
 1h ) , 2.69 ( s , 3h ) , 4.75 ( sept , 1h , j = 6.1 ) , 6.92 
 ( m , 3h ) , 7.04 ( m , 1h ) , 7.75 ( d , 1h , j = 2.0 ) , 10.98 
 ( s , 1h ) .
c nmr ( cdcl3 ) : 8.9 , 11.8 , 12.4 , 21.9 , 
 72.9 , 112.0 ( 6 and 17 hz ) ; 121.9 , 123.7 ( 9 hz ) ; 128.0 , 132.6 , 134.5 
 ( 14 hz ) ; 135.8 , 137.5 , 138.1 , 144.9 , 151.2 , 155.6 ( 5 and 250 hz ) . 
 hrms calcd for c21h21f2n3o3 + h : 402.1629 . found : 402.1642 . by using 
 the procedure described above for the preparation of compound 6p ,
this compound was obtained from 5-bromo-2-methylpyridine 
 as a solid in 34% yield after two consecutive chromatography processes , 
 the first one over silica gel ( cyclohexane / ethyl acetate 3/1 ) , the 
 second one over alumina containing 1.5% of water ( cyclohexane / dichloromethane 
 from 2/3 to 1/1 ) .
h nmr ( cdcl3 ) : 1.23 ( d , 6h , j = 6.2 ) , 2.32 ( s , 3h ) , 2.59 ( s , 3h ) , 4.83 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.02 ( m , 1h ) , 7.22 ( d , 1h , j = 8.4 ) , 7.66 ( dd , 1h , j = 2.5 and 8.4 ) , 
 8.58 ( d , 1h , j = 2.5 ) .
c nmr ( cdcl3 ) : 10.0 , 21.9 , 23.9 , 72.1 , 112.0 ( 6 and 17 hz ) ; 123.2 , 123.6 
 ( 9 hz ) ; 128.4 , 129.6 , 131.5 , 134.4 , 134.6 ( 14 hz ) ; 144.0 , 153.8 , 155.7 
 ( 4 and 250 hz ) ; 156.4 . hrms calcd for c19h19f2n3o2 + h : 360.1524 . found : 360.1515 . by using 
 the procedure described above for the preparation of compound 6p ,
this compound was obtained from 5-bromo-2-ethylpyridine 
 as an oil in 42% yield after two consecutive chromatography processes , 
 the first one over silica gel ( cyclohexane / ethyl acetate 5/1 ) , the 
 second one over alumina containing 1.5% of water ( cyclohexane / dichloromethane 
 3/2 ) .
h nmr ( cdcl3 ) : 1.23 ( d , 6h , j = 6.2 ) , 1.33 ( t , 3h , j = 7.6 ) , 2.33 ( s , 3h ) , 2.87 
 ( q , 2h , j = 7.6 ) , 4.83 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 7.02 ( m , 1h ) , 7.23 ( d , 1h , j = 8.5 ) , 7.68 ( dd , 1h , j = 2.4 and 8.5 ) , 8.58 ( d , 
 1h , j = 2.4 ) .
c nmr ( cdcl3 ) : 10.0 , 13.8 , 21.9 , 30.9 , 72.1 , 112.0 ( 6 and 17 hz ) ; 122.0 , 123.6 
 ( 10 hz ) ; 128.4 , 129.6 , 131.6 , 134.5 , 134.6 ( 14 hz ) ; 144.1 , 153.8 , 
 155.7 ( 4 and 250 hz ) ; 161.5 .
hrms calcd for c20h21f2n3o2 + h : 374.1680 . found : 374.1667 . by using 
 the procedure described above for the preparation of compound 6p ,
this compound was obtained from 5-bromo-2-methoxypyridine 
 as a solid in 16% yield after a chromatography over silica gel ( cyclohexane / ethyl 
 acetate 9/1 ) .
h nmr ( cdcl3 ) : 1.23 ( d , 6h , j = 6.2 ) , 2.27 ( s , 3h ) , 3.97 ( s , 3h ) , 4.81 ( sept , 1h , j = 6.2 ) , 6.82 ( d , 1h , j = 8.7 ) , 6.91 ( m , 
 2h ) , 7.02 ( m , 1h ) , 7.65 ( dd , 1h , j = 2.7 and 8.7 ) , 
 8.20 ( d , 1h , j = 2.7 ) .
c nmr ( cdcl3 ) : 9.7 , 21.9 , 53.8 , 72.0 , 111.9 , 112.9 ( 6 and 17 hz ) ; 123.6 
 ( 9 hz ) ; 127.9 , 129.8 , 130.9 , 134.7 ( 14 hz ) ; 135.4 , 142.3 , 153.5 , 155.8 
 ( 4 and 250 hz ) ; 162.6 .
hrms calcd for c19h19f2n3o3 + h : 376.1473 . found : 376.1446 . by 
 using the procedure described above for the preparation of compound 6p ,
this compound was obtained from 5-bromo-2-tert - butylpyrimidine as a solid in 24% yield after two consecutive chromatography 
 processes , the first one over silica gel ( cyclohexane / ethyl acetate 
 95/5 ) , the second one over alumina containing 1.5% of water ( cyclohexane / dichloromethane 
 4/1 ) .
h nmr ( cdcl3 ) : 1.24 ( d , 6h , j = 6.2 ) , 1.46 ( s , 9h ) , 2.36 ( s , 3h ) , 4.82 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.03 ( m , 1h ) , 8.82 ( s , 2h ) .
c 
 nmr ( cdcl3 ) : 10.0 , 21.9 , 29.6 , 39.3 , 72.2 , 112.0 ( 6 and 
 16 hz ) ; 123.8 , ( 10 hz ) ; 128.9 , 129.6 , 132.5 , 134.4 ( 14 hz ) ; 150.4 , 
 155.6 ( 4 and 250 hz ) ; 174.6 .
hrms calcd for c21h24f2n4o2 + h : 403.1946 . found : 403.1900 . in 
 an open flask ,
compound 7q ( 0.37 g , 1.38 mmol ) , a very 
 aged sample of commercially available 2-cyclopropylpyrimidin-5-ylboronic 
 acid ( 0.25 g , 1.51 mmol ) , pyridine ( 0.23 ml , 2.75 mmol , dried over 
 4  molecular sieves ) , 4  molecular sieves ( 0.5 g ) , and 
 copper(ii ) acetate hydrate ( 0.41 g , 2.06 mmol ) were dispersed in dichloromethane 
 ( 50 ml ) .
the reaction was stirred in open air for 48 h. the suspension 
 was absorbed on a small amount of silica gel and purified by two consecutive 
 chromatography processes , the first one over silica gel ( cyclohexane / ethyl 
 acetate 4/1 ) , the second one over alumina containing 1.5% of water 
 ( cyclohexane / dichloromethane 1/1 ) to give the n - arylated compound 20b ( 0.01 g , 1.8% ) as an oil .
h nmr ( cdcl3 ) : 1.11 ( m , 2h ) , 1.15 ( m , 2h ) , 1.24 ( d , 6h , j = 6.1 ) , 2.30 ( m , 1h ) , 2.35 ( s , 3h ) , 4.82 ( sept , 1h , j = 6.1 ) , 6.93 ( m , 2h ) , 7.05 ( m , 1h ) , 8.68 ( s , 2h ) .
c 
 nmr ( cdcl3 ) : 9.9 , 11.0 , 17.9 , 21.9 , 72.2 , 112.0 ( 6 and 
 16 hz ) ; 123.8 , ( 9 hz ) ; 128.8 , 129.6 , 132.5 , 134.4 ( 14 hz ) ; 151.1 , 
 155.4 , 155.7 ( 4 and 250 hz ) .
compound 21a ( 0.076 g , 0.17 mmol ) and cesium carbonate ( 0.087 g , 0.26 
 mmol ) dissolved in methanol ( 4 ml ) were heated in a microwave oven 
 at 140 c for 60 min .
this was concentrated to dryness and the 
 residue purified by a chromatography over silica gel ( cyclohexane / dichloromethane 
 from 3/2 to 2/1 ) to yield the methoxy ether 21c ( 0.04 
 g , 59% ) as a white powder .
h nmr ( cdcl3 ) : 1.25 
 ( d , 6h , j = 6.2 ) , 2.55 ( s , 3h ) , 3.99 ( s , 3h ) , 4.88 
 ( sept , 1h , j = 6.2 ) , 6.89 ( m , 2h ) , 7.00 ( m , 1h ) , 
 7.98 ( d , 1h , j = 1.3 ) , 8.54 ( d , 1h , j = 1.3 ) .
c nmr ( cdcl3 ) : 11.0 , 21.9 , 53.9 , 
 72.1 , 112.0 ( 6 and 17 hz ) ; 123.5 ( 9 hz ) ; 129.0 , 130.8 , 130.9 , 133.1 , 
 134.5 ( 14 hz ) ; 144.4 , 153.8 , 155.6 ( 4 and 249 hz ) ; 157.8 .
hrms calcd 
 for c18h18f2n4o3 + h : 377.1425 . found : 377.1372 . by 
 using the procedure described for the preparation of compound 21a , compound 22c
was obtained from compound 22b as a white powder in 80% after a chromatography over silica 
 gel ( cyclohexane / dichloromethane from 9/1 ) .
h nmr ( cdcl3 ) : 1.24 ( d , 6h , j = 6.2 ) , 2.72 ( s , 3h ) , 4.14 
 ( s , 3h ) , 4.86 ( sept , 1h , j = 6.2 ) , 6.91 ( m , 2h ) , 
 7.03 ( m , 2h ) , 7.96 ( d , 1h , j = 9.4 ) .
c nmr ( cdcl3 ) : 12.0 , 21.9 , 54.9 , 72.1 , 111.9 ( 6 and 17 
 hz ) ; 119.8 , 123.2 , 123.6 ( 9 hz ) ; 129.6 , 131.5 , 134.5 ( 14 hz ) ; 153.8 , 
 154.2 , 155.6 ( 4 and 249 hz ) ; 163.0 . hrms calcd for c18h18f2n4o3 + h : 377.1425 . found : 
 377.1364 . by 
 using the procedure described for the preparation of compound 21a , compound 22d
was obtained from 22b and ethanol as a solid in 71% after a chromatography over silica 
 gel ( cyclohexane / dichloromethane from 9/1 ) .
h nmr ( cdcl3 ) : 1.24 ( d , 6h , j = 6.2 ) , 1.47 ( d , 6h , j = 7.1 ) , 2.72 ( s , 3h ) , 4.58 ( q , 2h , j = 
 7.1 ) , 4.86 ( sept , 1h , j = 6.2 ) , 6.92 ( m , 2h ) , 7.03 
 ( m , 2h ) , 7.96 ( d , 1h , j = 9.5 ) .
c nmr 
 ( cdcl3 ) : 11.9 , 14.5 , 21.9 , 63.4 , 72.1 , 120.0 ( 6 and 17 
 hz ) ; 119.8 , 123.2 , 123.5 ( 9 hz ) ; 129.6 , 131.5 , 134.5 ( 14 hz ) ; 153.6 , 
 154.1 , 155.6 ( 4 and 249 hz ) ; 162.8 .
6-ethyl-3-(methylthio)-1,2,4-triazin-5-ol ( 0.17 g , 1.01 
 mmol ) and 
 4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1h - pyrazole 
 ( 0.272 g , 1.01 mmol ) were heated in a sealed tube at 200 c four 
 12 h. the resulting tarry solid was dispersed in ethanol , adsorbed 
 over silica , and purified by two consecutive chromatography processes 
 over silica gel ( dichloromethane / ethanol 98/2 ) and ( cyclohexane / ethyl 
 acetate from 2/1 to 1/1 ) to give the n - arylated derivative as a glass 
 ( 0.04 g , 10% ) .
h nmr ( cdcl3 ) : 1.23 ( t , 3h , j = 7.5 ) , 1.25 ( d , 6h , j = 6.2 ) , 2.71 ( s , 
 3h ) , 2.76 ( q , 2h , j = 7.5 ) , 4.86 ( sept , 1h , j = 6.2 ) , 6.90 ( m , 2h ) , 7.04 ( m , 1h ) , 10.89 ( s(l ) , 1h ) .
c nmr ( cdcl3 ) : 10.0 , 12.1 , 21.6 , 24.0 , 73.2 , 111.9 
 ( 6 and 17 hz ) ; 124.2 ( 9 hz ) ; 131.4 , 133.7 ( 14 hz ) ; 133.8 , 150.4 , 154.4 , 
 155.4 ( 4 and 250 hz ) ; 156.1 , 162.7 .
hrms calcd for c18h19f2n5o3 + h : 392.1534 . found : 
 392.1538 . in a 10 ml biotage 

tube , compound 7q ( 0.2 g , 0.74 mmol ) , 1-ethyl-4-iodo-1h - imidazole ( 0.17 g , 0.78 mmol ) , cesium carbonate ( 0.27 
 g , 0.83 mmol ) , 4  molecular sieves ( 0.1 g , 3.2 mm pellets ) and 
 [ n , n-bis((2-pyridine)-methylene)]-1,2-diaminocyclohexane were dispersed in acetonitrile ( 4.5 ml , dried 
 over 4  molecular sieves ) .
this was degassed using a slow stream 
 of argon bubbling in the suspension . copper oxide ( 0.005 g , 0.034 
 mmol ) was then added , and the tube was sealed .
this was shaken thoroughly , 
 heated for 30 s in the microwave oven at 100 c , and shaken again . 
 at this stage the pink copper oxide
is well dissolved in the reaction 
 mixture ; if not , another 30 s heating at 100 c is required . 

the resulting 
 suspension was directly adsorbed over a small amount of silica gel , 
 and this was subjected to a chromatography over silica gel ( dichloromethane / ethanol 
 99/1  98/2 ) to give compound 24 as an oil ( 0.13 
 g , 48% ) .
h nmr ( cdcl3 ) : 1.22 ( d , 6h , j = 5.2 ) , 1.51 ( t , 3h , j = 7.3 ) , 2.39 ( s , 
 3h ) , 4.00 ( q , 2h , j = 7.3 ) , 4.85 ( m , 1h ) , 6.90 ( m , 
 2h ) , 6.98 ( m , 1h ) , 7.06 ( s(br ) ) , 7.44 ( s(br ) , 1h ) . c 
 nmr ( cdcl3 ) : 9.8 , 16.0 , 22.0 , 42.6 ( br ) ; 71.8 , 111.9 ( 6 
 and 17 hz ) ; 123.4 ( 9 hz ) ; 130.5 ( br ) ; 134.8 ( 14 hz ) ; 140.2 ( br ) ; 153.7 
 ( 4 and 250 hz ) .
 following 
 our discovery of human dihydroorotate dehydrogenase ( dhodh ) 
 inhibition by 2-(3-alkoxy-1h - pyrazol-1-yl)pyrimidine 
 derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1h - pyrazol-1-yl)-5-methylpyridine , we describe here the syntheses and 
 evaluation of an array of azine - bearing analogues . as in our previous 
 report , the structure  
 activity study of this series of human 
 dhodh inhibitors was based on a phenotypic assay measuring measles 
 virus replication . among other inhibitors , 
 this round of syntheses 
 and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1h - pyrazol-1-yl)-3-fluoropyridine . 
 inhibition of dhodh by 
 this compound was confirmed in an array of in vitro assays , including 
 enzymatic tests and cell - based assays for viral replication and cellular 
 growth . 
 this molecule was found to be more active than the known inhibitors 
 of dhodh , brequinar and teriflunomide , thus opening perspectives for 
 its use as a tool or for the design of an original series of immunosuppressive 
 agent . moreover , because other series of inhibitors of human dhodh 
 have been found to also affect plasmodium falciparum dhodh , all the compounds were assayed for their effect on p. falciparum growth . however , the modest in vitro 
 inhibition solely observed for two compounds did not correlate with 
 their inhibition of p. falciparum dhodh . 
Introduction
Results and Discussion
Conclusion
Experimental Section