two classes of agents , 
 those targeting the m2 ion - channel and those 
 targeting neuramindase , are available to treat or prevent influenza 
 infection . the emergence of resistance to the m2 ion - channel inhibiting 
 drugs , amantadine and rimantadine ,
has limited their clinical utility . resistance to neuraminidase inhibitors , including oseltamivir , has 
 also been observed in several seasonal influenza a strains .
drug resistance mutations can emerge in almost all influenza a subtypes / strains , 
 including the pandemic 2009 h1n1 virus , limiting the clinical efficacy of the currently approved drugs .
the three largest genomic rna segments encode the viral rna - dependent 
 rna polymerase ( rdrp ) consisting of the polymerase acidic protein 
 ( pa ) and polymerase basic proteins 1 ( pb1 ) and 2 ( pb2 ) . the pa subunit : 
 ( i ) has endonuclease activity , ( ii ) is involved in viral rna ( vrna)/complementary 
 rna ( crna ) promoter binding , and ( iii ) interacts with the pb1 subunit .
pa has two domains , pan ( a 25 
 kda n - terminal domain ; residues 1197 ) and pac ( 55 
 kda c - terminal domain ; residues 239716 ) .
crystal structures 
 of pac have been determined in complexes with n - terminal 
 fragments of pb1 .
the structure of pan has been solved in several crystal forms both unliganded 
 and with various ligands .
influenza rdrp is responsible for the replication and transcription 
 of the segmented viral rna genes .
viral mrna transcription involves 
 a cap - snatching mechanism in which the polymerase binds to the host 
 cellular mrna via the 5-cap and cleaves the mrna 1213 
 nucleotides downstream .
this cleaved rna fragment , which contains 
 the 5 cap , acts as a primer for viral mrna synthesis .
cap - snatching is an important event in the life 
 cycle of all members of the orthomyxoviridae family of viruses , including 
 influenza a , b , and c viruses .
because the host cell has no analogous 
 activity , inhibitors of cap - snatching may be selective against all 
 influenza subtypes and strains , including oseltamivir - resistant influenza 
 a viruses , without interfering with the host cell .
these include 2,4-dioxobutanoic acid derivatives , 5-hydroxy-1,6-dihydropyrimidine-4-carboxylic acid derivatives , and flutimide and its derivatives , 2-hydroxyphenyl amide derivatives , as well as tetramic acid derivatives .
recently , in silico screening with in vitro 
 and ex vivo follow up studies identified hexanetetrones and trihydroxyphenyls 
 as endonuclease inhibitors with anti - influenza activity .
as correctly hypothesized , the endonuclease 
 activity of influenza polymerase belongs to the two metal ion group 
 of phosphate - processing enzymes . from 
 an x - ray crystallographic screening campaign of a fragment library 
 targeting the influenza a endonuclease enzyme
, we identified the 5-chloro-3-hydroxypyridin-2(1h)-one as a bimetal chelating ligand at the active site 
 of the enzyme . using this information , 

we have reported the structure  activity relationships for two 
 new series of compounds , 3-hydroxypyridin-2(1h)-ones 
 and 3-hydroxyquinolin-2(1h)-ones , as endonuclease 
 inhibitors ( figure 1 ) .
structures 
 and of 5-(p - fluorophenyl-3-hydroxypyridin-2(1h)-one ( 5-fphp ) , 6-(p - fluorophenyl)-3-hydroxypyridin-2(1h)-one ( 6-fphp ) , 6-(p - fluorophenyl)-3-hydroxyquinolin-2(1h)-one ( 6-fphq ) , and 7-(p - fluorophenyl)-3-hydroxyquinolin-2(1h)-one 
 ( 7-fphq ) .
phenyl substituted derivatives of 3-hydroxypyridin-2(1h)-ones are among the more potent inhibitors of influenza 
 a endonuclease . 
 while 4-(4-fluorophenyl)-3-hydroxypyridin-2(1h)one 
 did not exhibit significant activity , both 5-(4-fluorophenyl)-3-hydroxypyridin-2(1h)one and 6-(4-fluorophenyl)-3-hydroxypyridin-2(1h)one had ic50 values <
1.0 m . the present 
 study was undertaken to determine the relative effects of aza substitution 
 at various positions of phenyl substituted 3-hydroxypyridin-2(1h)-ones on their potential to inhibit influenza a endonuclease .
this dione 
 can tautomerize to either 5- or 6-(4-fluorophenyl)-3-hydroxypyrazin-2(1h)-one ( 1b , 1c ) .
the 2,3-dichloropyrazine 
 was treated with excess sodium methoxide to form 2,3-dimethoxypyrazine 
 as previously described .
bromination 
 of 2,3-dimethoxypyrazine with n - bromosuccimide in 
 dmf provided the 5-bromo derivative , which 
 under suzuki coupling conditions with 4-fluorophenylboronic acid gave 
 5-(4-fluorophenyl)-2,3-dimethoxypyrazine .
treatment of this dimethoxypyrazine 
 with a ( 1:1 ) mixture of dioxane and 2 n hcl provided 1 .
suzuki 
 coupling of this intermediate with 4-fluorophenylboronic acid provided 
 6-(p - fluorophenyl)-4,5-dimethoxypyrimidine , which 
 in a 1:1 mixture of dioxane and 2 n hcl produced 5-methoxy-6-(4-fluorophenyl)pyrimidin-4(3h)-one .
the synthetic approach employed 
 for the preparation of various 
 substituted 2-phenyl 5-hydroxypyrimidin-4(3h)-ones 
 is outlined in scheme 3 .
2-chloro-4,5-dimethoxypyrimidine , 
 prepared from 2,4-dichloro-5-methoxypyrimidine , was a common intermediate for these 2-phenyl 5-hydroxypyrimidin-4(3h)-ones .
suzuki coupling with the appropriate phenylboronic 
 acid provided the desired 2-phenyl 4,5-dimethoxypyrimidine derivative , 
 which was initially hydrolyzed with 1:1 dioxane and 2 n hcl to provide 
 the requisite 2-phenyl 5-methoxypyrimidin-4(3h)-one . 

further treatment of these 5-methoxypyrimidin-4(3h)-ones with bbr3 in ch2cl2 provided 
 the 2-(fluorophenyl ) derivatives 35 as well as the various 2-biphenyl derivatives 68 . in a similar manner , the 2-(4-cyanophenyl ) and
2-(3-cyanophenyl ) 
 5-methoxypyrimidin-4(3h)-ones were prepared and treated 
 with and bbr3 in ch2cl2 to form the 
 5-hydroxypyrimidin-4(3h)-ones 9 and 10 .
treatment of 9 or 10 with sodium 
 azide in dmf in the presence of a catalytic amount of acetic acid 
 gave the 5-tetrazoyl derivatives 11 and 12 , respectively .
formation of the 2-methoxymethyl derivative of 4,5-dichloropyridazin-3(2h)-one , followed by selective replacement of the 4-chloro 
 substituent with a methoxyl group , provided 2-methoxymethyl-5-chloro-4-methoxypyridazin-3(2h)-one .
this mom - protected 
 chloropyridazin-3(2h)-one was reacted with 4-fluorophenylboronic 
 acid under suzuki coupling conditions to provide 2-methoxymethyl-5-(4-fluorophenyl)-4-methoxypyridazin-3(2h)-one .
the synthesis of various 6-phenyl substituted pyridazin-3(2h)-ones was accomplished as outlined in scheme 5 . commercially available 3,4,6-trichloropyridazine 

was converted to 6-chloro-3,4-dimethoxypyridazine , which was subsequently used with either 4-fluorophenylboronic 
 acid or 4-cyanophenylboronic acid under suzuki coupling conditions 
 to form the 6-phenyl-3,4-dimethoxypyridazine intermediates .
treatment 
 of these dimethoxypyridazines with a 1:1 mixture of dioxane and 2 
 n hcl provided the 4-methoxypyridazine-3(2h)-ones , 
 which were subsequently treated with bbr3 in ch2cl2 to provide 14 and 15 .
treatment 
 of 15 with sodium azide in dmf in the presence of a catalytic 
 amount of acetic acid provided the 6-(4-(tetrazol-5-yl)phenyl ) derivative , 16 ( table 1 ) .
the tautomeric forms of 5-(4-fluorophenyl)-1,4-dihydropyrazine-2,3-dione , 1b and 1c ( 5- and 6-(4-fluorophenyl)-3-hydroxypyrazin-2(1h)-one ) , represent the 4-aza derivatives of both 5- and 
 6-(4-fluorophenyl)-3-hydroxypyridin-2(1h)-one , respectively . 
 upon the basis of its nmr spectra
, however , the most dominant tautomeric 
 form of 1 is the 1,4-dihydropyrazine-2,3-dione , 1a , with only minor amounts of tautomers 1b and 1c .
alternatively , should 1b or 1c form to an appreciable extent under 
 the enzyme assay conditions , the presence of a 4-aza substituent adjacent 
 to the 3-hydroxyl group of either tautomer 1b or 1c may be associated with reduced intrinsic activity as an 
 inhibitor .
the 
 lack of activity observed for 2 is consistent with previous 
 structure  activity relationships 
 observed with various 4-substituted 3-hydroxypyridin-2-ones . the presence 
 of a phenyl group or other relatively large substituents at the 4-position 
 of various 3-hydroxypyridin-2-ones is associated with a dramatic loss 
 in potency as an inhibitor .
it is noteworthy that when the 4-fluorophenyl 
 substituent is at the 2-postion of 5-hydroxypyrimidin-4(3h)-ones , which is comparable to the 6-position of 3-hydroxypyridin-2-ones , 
 significant activity in terms of endonuclease inhibition is observed 
 ( ic50 = 0.58 m ) .
this 4-fluorophenyl 
 derivative is more than twice as potent as either of the 3- or 2-fluorophenyl 
 isomers , 4 and 5 .
steric factors may be responsible for 
 the decreased activity observed for the 4- and 2-biphenyl derivatives 6 and 8 , relative to 7 .
the 
 structure  activity studies performed with 3-hydroxypyridin-2-ones 
 indicated 6-[(4-tetrazoyl)phenyl]-3-hydroxypyridin-2-one had pronounced 
 activity as an endonuclease inhibitor ( ic50 = 0.085 m ) . on the basis of this observation , 2-[(tetrazoyl)phenyl ] 
 derivatives of 5-hydroxypyrimidin-4(3h)-one and their 
 2-(cyanophenyl ) precursors were targeted for synthesis and evaluation 
 as endonuclease inhibitors .
the 3-cyanophenyl derivative 10 is approximately twice as potent compared to the 4-cyanophenyl isomer 9 .
however , the 4-(tetrazoly)phenyl derivative 11 is the most potent of 5-hydroxypyrimidin-4(3h)-ones 
 evaluated ( ic50 = 0.15 m ) with 3-fold greater potency 
 than the 3-(tetrazoly)phenyl derivative 12 .
previously 
 formed crystals of apo pandemic 2009 influenza endonuclease 
 were soaked in a solution containing 11 as described 
 previously ( supporting information , table 1s ) .
the crystal structure revealed that 11 chelates to the two active site metal ions in a mode similar 
 to the 3-hydroxypyridin-2(1h)-one containing compounds 
 ( figure 2 ) .
the n1 atom of the pyrimidine ring 
 forms hydrogen bond interactions with a network of water molecules 
 present near the active site . n3 interacts with tyr130 through two 
 bridging waters .
similar to the 5-[4-(tetrazoly)phenyl ] containing 
 pyridinone compounds , the 2-[4-(tetrazoly)phenyl ] makes bidentate 
 hydrogen bond interactions with arg124 .
the 2-phenyl ring is rotated 90 relative to the 5-phenyl 
 seen previously and is coplanar with the pyrimidine ring due to the 
 lack of steric restraint from additional ring substitutions as seen 
 previously .
stereoview image of a 
 crystal structure of 11 ( yellow ) 
 bound to pan(cyan ) superposed with a previously published 
 structure ( pdb i d : 4m5u ) of 5-(4-(1h - tetrazol-5-yl)phenyl)-6-(4-fluorophenyl)-3-hydroxypyridin-2(1h)-one ( green ) .
metal - coordinating bonds are depicted as 
 black dashed lines whereas hydrogen or electrostatic bonds are depicted 
 in blue .
electron density calculated from an omit map is contoured 
 at 4.0 ( blue mesh ) .
consistent with the structure  activity relationships 
 observed with 4-phenyl substituted 3-hydroxy - pyridin-2(1h)-ones , 13 did not exhibit significant activity as an 
 endonuclease inhibitor .
these 
 6-phenylpyridazin-3(2h)-ones 1416 are more active than the 4-fluorophenylpyrazine derivative 1 but are at least an order of magnitude less active than 
 analogous 2-phenyl-5-hydroxypyrimidin-4(3h)-ones . 
 the most active derivative was the 6-(4-tetrazoyl)phenyl-4-hydroxypyridazin-3(2h)-one 16 ( ic50 = 3.0 m ) . 
 interestingly , 5-substituted 3-hydroxypyridin-2(1h)-ones and 6-substituted 4-hydroxypyridazin-3(2h)ones as well as variously substituted 3-hydroxyquinolin-2(1h)ones have been previously established as d - amino 
 acid oxidase ( daao ) inhibitors . however
, none of these 
 similarly structured aza - analogues of 3-hydroxypyridin-2(1h)-ones that were synthesized in the present study were 
 evaluated for their relative activity as daao inhibitors .
data 
 on the relative activity of these aza 3-hydroxypyridin-2(1h)-one derivatives indicate that 2-phenyl-5-hydroxypyrimidin-4(3h)-ones , which are the 5-aza analogues of 6-phenyl-3-hydroxypyridin-2(1h)-ones , can exhibit comparable activity as inhibitors of 
 endonuclease .
however , 6-phenyl-4-hydroxypyridazin-3(2h)-ones , which are the 6-aza analogues of 5-phenyl-3-hydroxypyridin-2(1h)-ones , are 2.38.2-fold less active .
although the 
 tautomers of 5-(4-fluorophenyl)-1,4-dihydropyrazine-2,3-dione can 
 be viewed as 4-aza - analogues either 5- or 6-(4-fluorophenyl)-3-hydroxypyridin-2(1h)-one , they were more than 80 times less potent than either 
 of these 3-hydroxypyridin-2(1h)-ones .
the relative 
 ranking of comparable phenyl substituted pyridin-2(1h)-ones and their aza derivatives in terms of endonuclease inhibition 
 is 3-hydroxypyridin-2(1h)-one  5-hydroxypyrimidin-4(3h)-ones > 4-hydroxypyridazin-3(2h)-ones 
 1,4-dihydropyrazine-2,3-dione .
reaction monitoring and 
 follow - up were done using aluminum backed silica g tlc plates with 
 uv254 ( sorbent technologies ) , visualizing with ultraviolet light . 

flash column chromatography was done on a combi flash rf teledyne 
 isco using hexane , ethyl acetate , dichloromethane , and methanol .
the h ( 400 mhz ) and c ( 100 mhz ) nmr spectra were 
 done in cdcl3 , methanol - d4 , 
 and dmso - d6 and recorded on a bruker avance 
 iii ( 400 mhz ) multinuclear nmr spectrometer .
data is expressed in 
 parts per million relative to the residual nondeuterated solvent signals , 
 spin multiplicities are given as s ( singlet ) , d ( doublet ) , dd ( doublet 
 of doublets ) , t ( triplet ) , dt ( doublet of triplets ) , q ( quartet ) , 
 m ( multiplet ) , and bs ( broad singlet ) , and coupling constants ( j ) are reported in hertz .
analytical hplc was 
 performed on a shimadzu lc-20at prominence liquid chromatograph using 
 a 150 mm  4.6 mm princeton spher-100 rp c18 1000a 5  
 column using 0% water for 2 min and a 0100% water / methanol 
 gradient over a 5 min period and 5 min at 100% methanol at a 2.0 ml / min 
 flow rate monitoring uv absorbance at 254 and 296 nm . using this method 
 of analysis
, the purity of all compounds used in bioassays was determined 
 to be 95% .
hrms experiments were conducted by washington university 
 resource for biomedical and bioorganic mass spectrometry department 
 of chemistry .
5-(4-fluorophenyl)-2,3-dimethoxypyrazine 
 ( 100 mg , 0.43 mmol ) was dissolved in a mixture of dioxane ( 5 ml ) and 
 2 n hcl ( 5 ml ) .
the reaction mixture was then refluxed for 21 h. after 
 the reaction was completed , it was cooled to room temperature . then 
 solvent was removed under reduced pressure .
the white suspension was 
 filtered and solid was collected and dried to give 5-(4-fluorophenyl)pyrazine-2,3(1h,4h)-dione as a white solid ( 75 mg , 85% ) ; 
 mp 285287 c .
h nmr ( 400 mhz , dmso - d6 )  11.55 ( s , 1h ) , 11.46 ( s , 1h ) , 7.57 , 
 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.237.19 
 ( m , 2h ) , 6.59 ( d , j = 3 hz , 1h ) .
c nmr 
 ( 100 mhz , dmso - d6 )  161.8 ( jc , fjc , f = 243 hz ) , 
 156.9 , 155.7 , 128.1 , 127.6 ( jc , f = 9 hz ) , 
 121.0 , 115.5 ( jc , f = 21 hz ) , 107.1 .
f nmr ( 376 mhz , dmso - d6 )  
 114.0 . hrms ( esi ) calculated for c10h7fn2o2na ( m + na ) 229.0384 , found 
 229.0382 .
5-bromo-2,3-dimethoxypyrazine 
 ( 150 mg , 0.69 mmol ) , ( 4-fluorophenyl)boronic acid ( 144 mg , 1.03 mmol ) , 
 pd(pph3)4 ( 80 mg , 0.069 mmol ) , and na2co3 ( 218 mg , 2.06 mmol ) were dissolved in a mixture of 
 dioxane ( 6 ml ) and water ( 2 ml ) .
then , the reaction mixture was refluxed for 5 
 h. because the reaction was not completed , additional ( 4-fluorophenyl)boronic 
 acid ( 48 mg , 0.34 mmol ) was added .
it was then again refluxed for 
 16 h. it was cooled to room temperature , and it was diluted with etoac 
 and washed with satd nh4cl , followed by brine .
the organic 
 layer was dried over na2so4 and concentrated 
 under reduced pressure , and the resulting residue was purified by 
 flash chromatography on silica gel , eluting with 010% etoac / hexane . 

this afforded 5-(4-fluorophenyl)-2,3-dimethoxypyrazine as a white 
 solid ( 123 mg , 77% ) ; mp 108110 c .
h nmr 
 ( 400 mhz , cdcl3 )  8.03 ( s , 1h ) , 7.90 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.157.10 
 ( m , 2h ) .
c nmr ( 100 mhz , cdcl3 )  163.06 
 ( jc , f = 247 hz ) , 149.43 , 149.41 , 140.29 , 
 132.66 ( jc , f = 3 hz ) , 127.77 , 127.73 , 
 127.69 ( jc , f = 8 hz ) , 115 .
f nmr 
 ( 376 mhz , cdcl3 )  113.7 . hrms ( esi ) calculated 
 for c12h12fn2o2 ( m + h ) 235.0877 , found 235.0880 .
2,3-dimethoxypyrazine 
 ( 565 mg , 4.03 mmol ) and nbs ( 754 mg , 4.23 mmol ) were dissolved in 
 dmf ( 5 ml ) .
then , the resulting residue was diluted with dcm , and the organic 
 layer was washed with satd nahco3 , followed by brine .
the 
 organic layer was dried over na2so4 and concentrated 
 under reduced pressure to provide 5-bromo-2,3-dimethoxypyrazine as 
 a white solid ( 384 mg , 43% ) ; mp 5456 c .
h nmr ( 400 mhz , cdcl3 )  7.86 ( s , 1h ) , 4.03 ( s , 
 3h ) , 3.88 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 ) 
  161.2 , 150.0 , 141.7 , 138.1 , 56.6 , 55.1 .
2,3-dichloropyrazine ( 1.04 ml , 
 10 mmol ) was added to meoh ( 10 ml ) .
it was treated with naome ( 5.4 g , 100 mmol ) and 
 allowed to warm to room temperature .
the resulting white suspension was filtered , 
 and the filtrate was concentrated under reduced pressure .
the residue 
 was diluted with dcm and washed with water , followed by brine .
the 
 organic layer was dried over na2so4 and concentrated 
 under reduced pressure to reveal a colorless liquid .
2,3-dimethoxypyrazine 
 was crystallized as a white solid ( 1.13 g , 81% ) ; mp 2123 c .
h nmr ( 400 mhz , cdcl3 )  7.47 ( s , 2h ) , 3.88 
 ( s , 6h ) .
c nmr ( 100 mhz , cdcl3 )  150.3 , 
 131.7 , 53.4 .
6-(4-fluorophenyl)-5-methoxypyrimidin-4(3h)-one ( 107 mg , 0.49 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and the 1 m 
 in dcm bbr3 ( 5 ml , 5 mmol ) was added .
it was then allowed 
 to warm to room temperature and stirred for 24 h. then the solvent 
 was removed under reduced pressure .
the resulting residue was diluted 
 with etoac , which was washed with satd nahco3 , followed 
 by brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to provide 6-(4-fluorophenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 50 mg , 50% ) ; mp 285287 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.67 ( bs , 1h ) , 9.83 ( bs , 1h ) , 8.20 ( dd , j = 9 hz , j = 6 hz , 2h ) , 7.87 ( s , 1h ) , 7.297.25 
 ( m , 2h ) .
c nmr ( 100 mhz , dmso - d6 )  161.9 ( jc , f = 245 hz ) , 
 158.7 , 141.1 , 138.5 , 136.0 , 132.3 , 130.7 ( jc , f = 8 hz ) , 114.8 ( jc , f = 21 hz ) .
hrms ( esi ) calculated for c10h8fn2o2 ( m + h ) 207.0564 , found 207.0568 .
4-(4-fluorophenyl)-5,6-dimethoxypyrimidine ( 134 mg 0.57 mmol ) was 
 dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the reaction 
 mixture was then refluxed for 12 h. it was then cooled to room temperature . 

the reaction mixture was put under the vacuum to remove the solvent , 
 which gave white residue .
the solid was collected and gave 6-(4-fluorophenyl)-5-methoxypyrimidin-4(3h)-one as a white solid ( 109 mg , 87% ) ; mp 204206 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.76 ( s , 1h ) , 8.07 ( s , 1h ) , 8.04 ( dd , j = 9 hz , j = 6 hz , 2h ) , 7.337.28 ( m , 2h ) , 
 3.34 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  162.5 ( jc , f = 246 
 hz ) , 158.8 , 147.4 , 143.7 , 142.9 , 131.7 , 131.2 ( jc , f = 8 hz ) , 115.0 ( jc , f = 21 hz ) , 
 58.8 .
hrms ( esi ) calculated for c11h10fn2o2 ( m + h ) 221.0721 , 
 found 221.0721 .
4-chloro-4,5-dimethoxypyrimidine 
 ( 165 mg , 0.95 mmol ) , ( 4-fluorophenyl)boronic acid ( 99 mg , 1.42 mmol ) , 
 pd(pph3)4 ( 110 mg , 0.095 mmol ) , and na2co3 ( 300 mg , 2.84 mmol ) were dissolved in a mixture of 
 dioxane ( 9 ml ) and water ( 3 ml ) .
then the reaction mixture was refluxed for 19 
 h. after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 010% etoac / hexane .
this afforded 4-(4-fluorophenyl)-5,6-dimethoxypyrimidine 
 as a white solid ( 181 mg , 82% ) ; mp 6264 c .
h nmr ( 400 mhz , cdcl3 )  8.53 ( s , 1h ) , 8.07 ( dd , j = 9 hz , j = 6 hz , 2h ) , 7.177.11 
 ( m , 2h ) , 4.07 ( s , 3h ) , 3.73 ( s , 3h ) .
c nmr ( 100 mhz , 
 cdcl3 )  163.7 ( jc , f = 
 249 hz ) , 164.0 , 154.3 , 152.0,139.4 , 131.4 ( jc , f = 8 hz ) , 131.3 , 115.3 ( jc , f = 21 hz ) , 60.2 , 54.2 .
f nmr ( 376 mhz , cdcl3 )  111.0 . hrms ( esi ) calculated for c12h12fn2o2 ( m + h ) 235.0877 , 
 found 235.0882 .
4,6-dichloro-5-methoxypyrimidine 
 ( 300 mg , 1.68 mmol ) was added to meoh ( 10 ml ) .
it was treated with naome ( 99 mg , 1.85 mmol ) 
 and allowed to warm to room temperature .
after the reaction was 
 completed , it was put under the vacuum to remove meoh .
the resulting 
 residue was diluted with etoac , which was then washed with satd nh4cl , followed by brine .
the residue was purified 
 by flash chromatography on silica gel , eluting with 010% etoac / hexane 
 to provide 4-chloro-5,6-dimethoxypyrimidine as a white solid ( 168 
 mg , 57% ) ; mp 5355 c .
h nmr ( 400 mhz , cdcl3 )  8.27 ( s , 1h ) , 4.03 ( s , 3h ) , 3.88 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  163.6 , 151.6 , 151.3 , 138.2 , 
 60.7 , 54.8 . 2-(4-fluorophenyl)-5-methoxypyrimidin-4(3h)-one ( 58 mg , 0.26 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and the 1 m 
 in dcm bbr3 ( 3 ml , 3 mmol ) was added .
it was then allowed 
 to warm to room temperature and stirred for 24 h. then the solvent 
 was removed under reduced pressure .
it was filtered , and the solid was collected and dried under 
 vacuum to provide 2-(4-fluorophenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 23 mg , 42% ) ; mp 252254 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.88 ( bs , 1h ) , 9.64 ( bs , 1h ) , 8.05 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.54 ( s , 1h ) , 7.337.29 
 ( m , 2h ) .
c nmr ( 100 mhz , dmso - d6 )  163.4 ( jc , f = 246 hz ) , 
 159.0 , 146.9 , 143.4 , 131.7 , 129.4 ( jc , f = 9 hz ) , 129.1 , 115.5 ( jc , f = 22 hz ) .
hrms ( esi ) calculated for c10h8fn2o2 ( m + h ) 207.0564 , found 207.0566 .
2-(4-fluorophenyl)-4,5-dimethoxypyrimidine ( 187 mg , 0.799 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the 
 reaction mixture was then refluxed for 12 h. it was then cooled to 
 room temperature .
the reaction mixture was diluted with etoac and 
 washed with satd nahco3 , followed by brine .
the resulting residue was purified by flash chromatography on silica 
 gel , eluting with 50100% etoac / hexane to give 2-(4-fluorophenyl)-5-methoxypyrimidin-4(3h)-one as a white solid ( 41 mg , 23% ) ; mp 229231 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.79 ( s , 1h ) , 7.68 ( s , 1h ) , 8.08 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.357.30 ( m , 2h ) , 
 3.79 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  163.6 ( jc , f = 247 
 hz ) , 158.1 , 148.4 , 145.4 , 130.4 , 129.6 ( jc , f = 9 hz ) , 129.1 , 115.5 ( jc , f = 22 hz ) , 
 56.0 .
f nmr ( 376 mhz , dmso - d6 )  110.2 . hrms ( esi ) calculated for c11h9fn2o2na ( m + na ) 243.0540 , 
 found 243.0546 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 500 mg , 2.86 mmol ) , ( 4-fluorophenyl)boronic acid ( 601 mg , 4.30 mmol ) , 
 pd(pph3)4 ( 330 mg , 0.29 mmol ) , and na2co3 ( 910 mg , 8.59 mmol ) were dissolved in a mixture of 
 dioxane ( 12 ml ) and water ( 4 ml ) . the air was evacuated and replaced 
 with n2 . then , the reaction mixture was refluxed for 5 
 h. after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 010% etoac / hexane .
this afforded 2-(4-fluorophenyl)-4,5-dimethoxypyrimidine 
 as a white solid ( 123 mg , 77% ) ; mp 114116 c .
h nmr ( 400 mhz , cdcl3 )  8.37 ( dd , j = 9 hz , j = 6 hz , 2h ) , 8.12 ( s , 1h ) , 7.167.12 
 ( m , 2h ) , 4.17 ( s , 3h ) , 3.98 ( s , 3h ) .
c nmr ( 100 mhz , 
 cdcl3 )  163.1 ( jc , f = 
 248 hz ) , 159.7 , 155.3 , 141.0 , 137.2 , 133.6 ( jc , f = 3 hz ) , 129.6 ( jc , f = 8 hz ) , 
 115.3 ( jc , f = 22 hz ) , 56.4 , 54.0 .
f nmr ( 376 mhz , cdcl3 )  111.9 . 
 hrms ( esi ) calculated for c12h12fn2o2 ( m + h ) 235.0877 , found 235.0878 .
2,4-dichloro-5-methoxypyrimidine 
 ( 2.37 g , 13.2 mmol ) and k2co3 ( 1.8 g , 13.2 mmol ) 
 were dissolved in meoh ( 50 ml ) and stirred for 19 h at room temperature . 

the resulting residue 
 was dissolved in etoac and washed with distilled water , followed by 
 brine .
the resulting residue was purified by flash chromatography 
 on silica gel , eluting with 020% etoac / hexane to give 2-chloro-4,5-dimethoxypyrimidine 
 as a white solid ( 1.70 g , 73% ) ; mp 6567 c .
h nmr ( 400 mhz , cdcl3 )  7.84 ( s , 1h ) , 4.03 ( s , 
 3h ) , 3.88 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 ) 
  161.2 , 150.0 , 141.7 , 138.2 , 56.6 , 55.0 .
2-(3-fluorophenyl)-5-methoxypyrimidin-4(3h)-one ( 100 mg , 0.45 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and then 1 m 
 in dcm bbr3 ( 4.54 ml , 4.54 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 18 h. then the 
 solvent was removed under reduced pressure .
the resulting residue 
 was diluted with etoac , which was washed with 2 n hcl , followed by 
 brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 2-(3-fluorophenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 87 mg , 93% ) ; mp 210212 
 c .
h nmr ( 400 mhz , dmso - d6 )  7.89 ( d , j = 8 hz , 1h ) , 7.84 ( dd , j = 10 hz , j = 2 hz , 1h ) , 7.61 ( s , 1h ) , 
 7.577.52 ( m , 1h ) , 7.36 ( td , j = 8 hz , j = 2 hz , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  162.1 ( jc , f = 243 hz ) , 158.9 , 146.5 , 143.8 , 134.7 , 131.5 , 130.6 ( jc , f = 8 hz ) , 123.0 , 117.2 ( jc , f = 20 hz ) , 113.6 ( jc , f = 24 hz ) .
hrms ( esi ) calculated for c10h8fn2o2 ( m + h ) 207.0564 , found 207.0565 .
2-(3-fluorophenyl)-4,5-dimethoxypyrimidine ( 390 mg , 1.67 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 10 ml ) and dioxane ( 10 ml ) . 

the reaction mixture was then refluxed for 18 h. it was then cooled 
 to room temperature .
the reaction mixture was diluted with etoac and 
 washed with water , followed by brine .
the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 0100% etoac / hexane to give 2-(3-fluorophenyl)-5-methoxypyrimidin-4(3h)-one as a white solid ( 237 mg , 63% ) ; mp 122124 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.86 ( bs , 1h ) , 7.91 ( d , j = 8 hz , 1h ) , 
 7.877.83 ( m , 1h ) , 7.71 ( s , 1h ) , 7.587.53 ( m , 1h ) , 
 7.37 ( td , j = 8 hz , j = 2 hz , 1h ) , 
 3.81 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  162.1 ( jc , f = 242 
 hz ) , 157.9 , 147.8 , 145.5 , 134.7 , 130.7 ( jc , f = 9 hz ) , 130.1 , 123.2 ( jc , f = 9 hz ) , 
 117.5 ( jc , f = 22 hz ) , 113.8 ( jc , f = 24 hz ) , 56.1 .
f nmr ( 376 mhz , dmso - d6 )  112.5 . hrms ( esi ) calculated 
 for c11h10fn2o2 ( m + h ) 221.0721 , found 227.0722 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 300 mg , 1.72 mmol ) , ( 3-fluorophenyl)boronic acid ( 343 mg , 2.58 mmol ) , 
 pd(pph3)4 ( 199 mg , 0.17 mmol ) , and na2co3 ( 546 mg , 5.15 mmol ) were dissolved in a mixture of 
 dioxane ( 12 ml ) and water ( 4 ml ) .
then the reaction mixture was refluxed for 8 h. 
 after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 010% etoac / hexane .
this afforded 2-(3-fluorophenyl)-4,5-dimethoxypyrimidine 
 as a white solid ( 393 mg , 98% ) ; mp 8385 c .
h nmr ( 400 mhz , cdcl3 )  8.09 ( dt , j = 8 hz , j = 1 hz , 1h ) , 8.03 ( s , 1h ) , 8.017.98 
 ( m , 1h ) , 7.387.33 ( m , 1h ) , 7.07 ( tdd , j = 
 8 hz , j = 3 hz , j = 1 hz , 1h ) , 4.09 
 ( s , 3h ) , 3.90 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  163.1 ( jc , f = 242 hz ) , 159.5 , 
 154.6 ( jc , f =3 hz ) , 141.3 , 139.8 ( jc , f = 8 hz ) , 136.9 , 129.7 ( jc , f = 8 hz ) , 123.1 ( jc , f = 
 3 hz ) , 116.4 ( jc , f = 22 hz ) , 114.3 ( jc , f = 23 hz ) , 56.2 , 53.9 .
hrms ( esi ) calculated 
 for c12h12fn2o2 ( m + h ) 235.0877 , found 235.0879 .
2-(2-fluorophenyl)-5-methoxypyrimidin-4(3h)-one ( 100 mg , 0.45 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and then 1 m 
 in dcm bbr3 ( 4.54 ml , 4.54 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 18 h. then the 
 solvent was removed under reduced pressure .
the resulting residue 
 was diluted with etoac , which was washed with 2 n hcl , followed by 
 brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 2-(2-fluorophenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 89 mg , 96% ) ; mp 187189 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.80 ( bs , 1h ) , 9.73 ( bs , 1h ) , 7.65 ( t , j = 7 hz , 1h ) , 7.59 ( s , 1h ) , 7.55 ( t , j = 7 hz , 1h ) , 
 7.367.30 ( m , 2h ) .
c nmr ( 100 mhz , dmso - d6 )  159.3 ( jc , f = 248 hz ) , 158.2 , 144.6 , 143.9 , 132.2 ( jc , f = 8 hz ) , 132.1 , 130.8 , 124.5 ( jc , f = 
 3 hz ) , 121.8 ( jc , f = 12 hz ) , 116.1 ( jc , f = 21 hz ) .
f nmr ( 376 mhz , dmso - d6 )  115.2 . hrms ( esi ) calculated 
 for c10h8fn2o2 ( m + h ) 207.0564 , found 207.0565 .
2-(2-fluorophenyl)-4,5-dimethoxypyrimidine 
 ( 400 mg , 1.71 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 10 ml ) and dioxane ( 10 ml ) . 

the reaction mixture was then refluxed for 18 h. it was then cooled 
 to room temperature .
the reaction mixture was diluted with etoac and 
 washed with water , followed by brine .
the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 0100% etoac / hexane , followed by 010% meoh / dcm 
 to give 2-(2-fluorophenyl)-5-methoxypyrimidin-4(3h)-one as a white solid ( 300 mg , 80% ) ; mp 159161 c .
h nmr ( 400 mhz , dmso - d6 )  
 12.81 ( bs , 1h ) , 7.70 ( s , 1h ) , 7.66 ( t , j = 8 hz , 
 1h ) , 7.607.55 ( m , 1h ) , 7.377.31 ( m , 1h ) , 3.80 ( s , 
 3h ) .
c nmr ( 100 mhz , dmso - d6 )  159.3 ( jc , f = 248 hz ) , 157.3 , 
 145.9 , 132.4 ( jc , f = 9 hz ) , 130.8 ( jc , f = 8 hz ) , 130.2 , 124.5 ( jc , f = 3 hz ) , 121.8 , 121.6 , 116.1 ( jc , f = 22 hz ) , 56.0 .
f nmr ( 376 mhz , dmso - d6 )  115.2 . hrms ( esi ) calculated 
 for c11h10fn2o2 ( m + h ) 221.0721 , found 221.0721 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 300 mg , 1.72 mmol ) , ( 2-fluorophenyl)boronic acid ( 343 mg , 2.58 mmol ) , 
 pd(pph3)4 ( 199 mg , 0.17 mmol ) , and na2co3 ( 546 mg , 5.15 mmol ) were dissolved in a mixture of 
 dioxane ( 12 ml ) and water ( 4 ml ) . the air was evacuated and replaced 
 with n2 .
then , the reaction mixture was refluxed for 18 
 h. after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 030% etoac / hexane .
this afforded 2-(2-fluorophenyl)-4,5-dimethoxypyrimidine 
 as a white solid ( 402 mg , 100% ) ; mp 7274 c .
h nmr ( 400 mhz , cdcl3 )  8.11 ( s , 1h ) , 7.97 ( td , j = 8 hz , j = 2 hz , 1h ) , 7.347.29 
 ( m , 1h ) , 7.15 ( td , j = 8 hz , j = 
 1 hz , 1h ) , 7.117.06 ( m , 1h ) , 4.06 ( s , 3h ) , 3.90 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  161.0 ( jc , f = 253 hz ) , 159.5 , 154.2 ( jc , f = 4 hz ) , 140.9 , 137.0 , 131.4 ( jc , f = 2 hz ) , 130.9 ( jc , f = 8 hz ) , 
 126 . 0 ( jc , f = 9 hz ) , 123.8 ( jc , f = 4 hz ) , 116.7 ( jc , f = 
 22 hz ) , 56.2 , 54.1 .
hrms ( esi ) calculated for c12h12fn2o2 ( m + h ) 235.0877 , 
 found 235.0877 .
2-(4-biphenyl)-5-methoxypyrimidin-4(3h)-one ( 50 mg , 0.18 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) . the reaction mixture
was cooled to 0 c , and then 1 m 
 in dcm bbr3 ( 1.80 ml , 1.80 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 18 h. then the 
 solvent was removed under reduced pressure .
the resulting residue 
 was diluted with etoac , which was washed with 2 n hcl , followed by 
 brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 2-(4-biphenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 46 mg , 96% ) ; dec 259261 c .
h nmr ( 400 mhz , dmso - d6 )  
 12.85 ( bs , 1h ) , 9.68 ( bs , 1h ) , 8.13 ( d , j = 8 hz , 
 2h ) , 7.80 ( d , j = 8 hz , 2h ) , 7.75 ( d , j = 7 hz , 2h ) , 7.62 ( s , 1h ) , 7.50 ( t , j = 8 hz , 2h ) , 
 7.41 ( t , j = 7 hz , 1h ) .
c nmr ( 100 mhz , 
 dmso - d6 )  159.1 , 147.5 , 143.5 , 
 141.9 , 139.0 , 131.7 , 131.3 , 129.0 , 128.0 , 128.5 , 126.7 , 126.7
. hrms 
 ( esi ) calculated for c16h13n2o2 ( m + h ) 265.0972 , found 265.0973 .
2-(4-biphenyl)-4,5-dimethoxypyrimidine ( 343 
 mg , 1.73 mmol ) was 
 dissolved in a mixture of 2 n hcl ( 15 ml ) and dioxane ( 15 ml ) .
the 
 reaction mixture was then refluxed for 18 h and became a white suspension . 

the suspension was filtered 
 and solid was collected to give 2-(4-biphenyl)-5-methoxypyrimidin-4(3h)-one as white solid ( 256 mg , 78% ) ; mp 292294 c .
h nmr ( 400 mhz , dmso - d6 )  
 12.83 ( bs , 1h ) , 8.14 ( d , j = 8 hz , 2h ) , 7.81 ( d , j = 8 hz , 2h ) , 7.777.72 ( m , 3h ) , 7.50 ( t , j = 8 hz , 2h ) , 7.42 ( t , j = 7 hz , 1h ) , 
 3.81 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  158.0 , 148.8 , 145.6 , 142.1 , 139.0 , 131.2 , 130.4 , 
 129.0 , 128.0 , 127.7 , 126.74 , 126.70 , 56.1 .
hrms ( esi ) calculated for 
 c17h15n2o2 ( m + h ) 279.1128 , found 279.1128 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 400 mg , 2.29 mmol ) , 4-biphenylboronic acid ( 681 mg , 3.44 mmol ) , pd(pph3)4 ( 264 mg , 0.23 mmol ) , and na2co3 ( 728 mg , 6.87 mmol ) were dissolved in a mixture of dioxane 
 ( 12 ml ) and water ( 4 ml ) . the air was evacuated and replaced with 
 n2 .
then the reaction mixture was refluxed for 8 h. after 
 the reaction was completed , it was cooled to room temperature and 
 it was diluted with etoac and washed with satd nh4cl , followed 
 by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 030% 
 etoac / hexane .
this afforded 2-(4-biphenyl)-4,5-dimethoxypyrimidine 
 as a white solid ( 670 mg , 100% ) ; mp 115117 c .
h nmr ( 400 mhz , cdcl3 )  8.43 ( d , j = 8 hz , 2h ) , 8.15 ( s , 1h ) , 7.70 ( d , j = 8 hz , 2h ) , 
 7.67 ( j = 7 hz , 2h ) , 7.47 ( t , j = 
 8 hz , 2h ) , 7.37 ( t , j = 7 hz , 1h ) , 4.19 ( s , 3h ) , 
 3.98 ( s , 3h ) .
142.5 , 141.1 , 140.7 , 137.3 , 136.4 , 128.8 , 128.1 , 127.5 , 
 126.1 , 56.4 , 54.0 .
hrms ( esi ) calculated for c18h17n2o2 ( m + h ) 293.1285 , found 293.1286 .
2-(3-biphenyl)-5-methoxypyrimidin-4(3h)-one ( 100 mg , 0.36 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and the 1 m 
 in dcm bbr3 ( 3.60 ml , 3.60 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 6 h. then the 
 solvent was removed under reduced pressure .
the resulting residue 
 was diluted with etoac , which was washed with 2 n hcl , followed by 
 brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 2-(3-biphenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 34 mg , 36% ) ; mp 221223 c .
h nmr ( 400 mhz , dmso - d6 )  
 8.30 ( s , 1h ) , 7.99 ( d , j = 7 hz , 1h ) , 7.88 ( d , j = 8 hz , 1h ) , 7.81 ( d , j = 8 hz , 2h ) , 
 7.66 ( s , 1h ) , 7.63 ( t , j = 8 hz , 1h ) , 7.52 ( t , j = 8 hz , 2h ) , 7.43 ( t , j = 7 hz , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  
 158.9 , 147.5 , 143.7 , 140.4 , 139.5 , 133.1 , 132.3 , 129.2 , 128.9 , 128.5 , 
 127.7 , 126.8 , 126.0 , 125.0 .
hrms ( esi ) calculated for c16h13n2o2 ( m + h ) 265.0972 , 
 found 265.0973 .
2-(3-biphenyl)-4,5-dimethoxypyrimidine ( 670 
 mg , 2.29 mmol ) was 
 dissolved in a mixture of 2 n hcl ( 15 ml ) and dioxane ( 15 ml ) .
the 
 reaction mixture was then refluxed for 18 h. it was then cooled to 
 room temperature .
the reaction mixture was diluted with etoac and 
 washed with water , followed by brine .
the solid 
 was collected to give 2-(3-biphenyl)-5-methoxypyrimidin-4(3h)-one as a white solid ( 493 mg , 77% ) ; mp 209211 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.97 ( br s , 1h ) , 8.34 ( s , 1h ) , 8.04 ( d , j = 8 hz , 1h ) , 7.837.80 ( m , 3h ) , 7.73 ( s , 1h ) , 7.59 ( t , j = 8 hz , 1h ) , 7.51 ( t , j = 8 hz , 2h ) , 
 7.41 ( t , j = 7 hz , 1h ) , 3.82 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  157.9 , 
 148.9 , 145.8 , 140.4 , 139.4 , 132.9 , 130.5 , 129.3 , 128.9 , 128.8 , 127.8 , 
 126.9 , 126.2 , 125.2 , 56.1 . hrms ( esi ) calculated for c17h15n2o2 ( m + h ) 279.1128 , 
 found 279.1129 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 400 mg , 2.29 mmol ) , 3-biphenylboronic acid ( 681 mg , 3.44 mmol ) , pd(pph3)4 ( 264 mg , 0.23 mmol ) , and na2co3 ( 728 mg , 6.87 mmol ) were dissolved in a mixture of dioxane 
 ( 12 ml ) and water ( 4 ml ) . the air was evacuated and replaced with 
 n2 .
then the reaction mixture was refluxed for 8 h. after 
 the reaction was completed , it was cooled to room temperature and 
 it was diluted with etoac and washed with satd nh4cl , followed 
 by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 030% 
 etoac / hexane .
this afforded 2-(3-biphenyl)-4,5-dimethoxypyrimidine 
 as a white solid ( 670 mg , 100% ) ; mp 7274 c .
h nmr ( 400 mhz , cdcl3 )  8.62 ( s , 1h ) , 8.36 ( d , j = 8 hz , 1h ) , 8.15 ( s , 1h ) , 7.71 ( d , j = 7 hz , 2h ) , 7.67 ( d , j = 8 hz , 1h ) , 7.54 ( t , j = 8 hz , 2h ) , 7.497.45 ( m , 3h ) , 7.37 ( t , j = 7 hz , 1h ) , 4.18 ( s , 3h ) , 3.97 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  159.7 , 156.1 , 141.4 , 141.17 , 
 141.15 , 137.9 , 137.2 , 128.9 , 128.8 , 128.6 , 127.4 , 127.3 , 126.6 , 126.4 , 
 56.4 , 54.0 . hrms ( esi ) calculated for c18h17n2o2 ( m + h ) 293.1285 , found 293.1286 .
2-(2-biphenyl)-5-methoxypyrimidin-4(3h)-one ( 50 mg , 0.18 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and the 1 m 
 in dcm bbr3 ( 1.80 ml , 1.80 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 18 h. then the 
 solvent was removed under reduced pressure .
the resulting residue 
 was diluted with etoac , which was washed with 2 n hcl , followed by 
 brine .
the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 2-(2-biphenyl)-5-hydroxypyrimidin-4(3h)-one as a white solid ( 31 mg , 64% ) ; mp 271273 c .
h nmr ( 400 mhz , dmso - d6 )  
 7.707.65 ( m , 2h ) , 7.56 ( t , j = 8 hz , 2h ) , 
 7.48 ( s , 1h ) , 7.39 ( t , j = 7 hz , 2h ) , 7.33 ( t , j = 7 hz , 1h ) , 7.23 ( d , j = 7 hz , 2h ) .
c nmr ( 100 mhz , dmso - d6 )  
 158.6 , 156.9 , 148.3 , 140.8 , 140.5 , 139.4 , 131.9 , 130.4 , 130.1 , 129.9 , 
 128.6 , 128.2 , 127.2 . hrms ( esi ) calculated for c16h13n2o2 ( m + h ) 265.0972 , 
 found 265.0974 .
2-(2-biphenyl)-4,5-dimethoxypyrimidine ( 309 
 mg , 1.06 mmol ) was 
 dissolved in a mixture of 2 n hcl ( 15 ml ) and dioxane ( 15 ml ) .
the 
 reaction mixture was then refluxed for 18 h. it was then cooled to 
 room temperature .
the reaction mixture was diluted with etoac and 
 washed with water , followed by brine .
the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 010% meoh / dcm to give 2-(2-biphenyl)-5-methoxypyrimidin-4(3h)-one as colorless oil ( 158 mg , 54% ) .
h nmr 
 ( 400 mhz , dmso - d6 )  12.51 ( bs , 
 1h ) , 7.59 ( t , j = 8 hz , 1h ) , 7.557.47 ( m , 
 4h ) , 7.36 ( t , j = 7 hz , 2h ) , 7.30 ( t , j = 7 hz , 1h ) , 7.23 ( d , j = 7 hz , 2h ) , 3.72 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  
 157.1 , 151.0 , 145.4 , 140.3 , 139.8 , 133.0 , 131.5 , 131.4 , 130.03 , 130.01 , 
 129.8 , 128.6 , 128.2 , 127.2 , 55.8 . hrms ( esi ) calculated for c17h15n2o2 ( m + h ) 279.1128 , found 279.1129 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 500 mg , 2.86 mmol ) , 2-biphenylboronic acid ( 851 mg , 4.30 mmol ) , pd(pph3)4 ( 266 mg , 0.29 mmol ) , and na2co3 ( 909 mg , 8.58 mmol ) were dissolved in a mixture of dioxane 
 ( 21 ml ) and water ( 7 ml ) . the air was evacuated and replaced with 
 n2 . then the reaction mixture was refluxed for 8 h. after 
 the reaction was completed , it was cooled to room temperature and 
 it was diluted with etoac and washed with satd nh4cl , followed 
 by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 030% 
 etoac / hexane .
h nmr ( 400 mhz , dmso - d6 )  8.26 ( s , 1h ) , 7.84 ( dd , j = 7 hz , j = 1 hz , 1h ) , 7.547.45 ( m , 2h ) , 
 7.40 ( dd , j = 7 hz , j = 1 hz , 1h ) , 
 7.307.24 ( m , 3h ) , 7.08 ( d , j = 7 hz , 2h ) , 
 3.85 ( s , 3h ) , 3.30 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 ) 158.1 , 157.2 , 142.2 , 141.1 , 140.0 , 137.7 , 
 137.3 , 130.4 , 130.2 , 128.9 , 128.6 , 127.8 , 127.2 , 126.2 , 56.0 , 52.9 . 

hrms ( esi ) calculated for c18h17n2o2 ( m + h ) 293.1285 , found 293.1290 .
4-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 ( 50 mg , 0.22 mmol ) was dissolved in anhydrous dcm ( 5 ml ) .
the reaction 
 mixture was cooled to 0 c , and then 1 m in dcm bbr3 ( 2.2 ml , 2.2 mmol ) was added .
it was then allowed to warm to room 
 temperature and stirred for 18 h. then the solvent was removed under 
 reduced pressure .
it 
 was filtered , and the solid was collected and dried under vacuum to 
 provide 4-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 as a white solid ( 15 mg , 32% ) ; mp 324326 c .
h nmr ( 400 mhz , dmso - d6 )  13.05 
 ( bs , 1h ) , 9.91 ( bs , 1h ) , 8.18 ( d , j = 8 hz , 2h ) , 
 7.95 ( d , j = 8 hz , 2h ) , 7.64 ( s , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  158.8 , 
 132.5 , 129.4 , 127.6 , 127.2 , 127.1 , 126.7 , 118.4 , 112.5 . hrms ( esi ) 
 calculated for c11h8n3o2 ( m + h ) 214.0611 , found 214.0618 .
4-(4,5-dimethoxypyrimidin-2-yl)benzonitrile ( 53 mg , 0.22 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the 
 reaction mixture was then refluxed for 5 h. it was then cooled to 
 room temperature .
the reaction mixture was diluted with etoac and 
 washed with satd nahco3 , followed by brine .
the resulting residue was purified by flash chromatography on silica 
 gel , eluting with 05% meoh / dcm to give 4-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 as a white solid ( 50 mg , 100% ) ; mp 297299 c .
h nmr ( 400 mhz , dmso - d6 )  12.99 
 ( bs , 1h ) , 8.19 ( d , j = 8 hz , 2h ) , 7.96 ( d , j = 8 hz , 2h ) , 7.75 ( s , 1h ) , 3.81 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 ) 157.8 , 147.4 , 
 146.2 , 136.5 , 132.5 , 130.0 , 127.8 , 118.4 , 112.8 , 56.1 .
hrms ( esi ) 
 calculated for c12h10n3o2 ( m + h ) 228.0768 , found 228.0770 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 100 mg , 0.57 mmol ) , ( 4-cyanophenyl)boronic acid ( 126 mg , 0.86 mmol ) , 
 pd(pph3)4 ( 66 mg , 0.06 mmol ) , and na2co3(182 mg , 1.72 mmol ) were dissolved in a mixture of 
 dioxane ( 9 ml ) and water ( 3 ml ) .
then the reaction mixture was refluxed for 4 h. 
 after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated in vacuo , and the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 020% 
 etoac / hexane .
this afforded 4-(4,5-dimethoxypyrimidin-2-yl)benzonitrile 
 as a white solid ( 69 mg , 74% ) ; mp 170172 c .
h nmr ( 400 mhz , cdcl3 )  8.49 ( d , j = 9 hz , 2h ) , 8.18 ( s , 1h ) , 7.76 ( d , j = 9 hz , 2h ) , 
 4.20 ( s , 3h ) , 4.02 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  159.8 , 154.0 , 141.8 , 141.5 , 137.0 , 132.3 , 128.0 , 
 119.0 , 113.0 , 56.4 , 54.2 .
hrms ( esi ) calculated for c13h12n3o2 ( m + h ) 242.0924 , 
 found 242.0929 .
3-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 ( 50 mg , 0.22 mmol ) was dissolved in anhydrous dcm ( 5 ml ) .
the reaction 
 mixture was cooled to 0 c , and then 1 m in dcm bbr3 ( 2.2 ml , 2.2 mmol ) was added .
it was then allowed to warm to room 
 temperature and stirred for 18 h. then the solvent was removed under 
 reduced pressure .
it 
 was filtered , and the solid was collected and dried under vacuum to 
 provide 3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 as a white solid ( 27 mg , 58% ) ; mp 294296 c .
h nmr ( 400 mhz , dmso - d6 )  8.44 
 ( s , 1h ) , 8.35 ( d , j = 8 hz , 1h ) , 7.93 ( d , j = 8 hz , 1h ) , 7.68 ( t , j = 8 hz , 1h ) , 
 7.61 ( s , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  159.3 , 146.4 , 143.9 , 134.3 , 133.4 , 131.9 , 131.5 , 
 130.4 , 129.8 , 118.4 , 111.7 . hrms ( esi ) calculated for c11h8n3o2 ( m + h ) 214.0611 , 
 found 214.0613 .
3-(4,5-dimethoxypyrimidin-2-yl)benzonitrile ( 138 mg , 0.57 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the 
 reaction mixture was then refluxed for 6 h. it was then cooled to 
 room temperature .
the reaction mixture was diluted with etoac and 
 washed with satd nahco3 , followed by brine .
the resulting residue was purified by flash chromatography on silica 
 gel , eluting with 010% meoh / dcm to give 3-(5-methoxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 as a white solid ( 56 mg , 43% ) ; mp 255257 c .
h nmr ( 400 mhz , dmso - d6 )  12.93 
 ( bs , 1h ) , 8.44 ( s , 1h ) , 8.34 ( d , j = 8 hz , 1h ) , 7.99 
 ( d , j = 8 hz , 1h ) , 7.747.70 ( m , 2h ) , 3.82 
 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  157.9 , 147.5 , 145.9 , 133.9 , 133.7 , 131.7 , 130.7 , 
 130.4 , 129.9 , 118.3 , 111.7 , 56.1 .
hrms ( esi ) calculated for c12h10n3o2 ( m + h ) 228.0768 , found 228.0767 .
2-chloro-4,5-dimethoxypyrimidine 
 ( 100 mg , 0.57 mmol ) , ( 3-cyanophenyl)boronic acid ( 126 mg , 0.86 mmol ) , 
 pd(pph3)4 ( 66 mg , 0.06 mmol ) , and na2co3(182 mg , 1.72 mmol ) were dissolved in a mixture of 
 dioxane ( 9 ml ) and water ( 3 ml ) .
then the reaction mixture was refluxed for 5 h. 
 after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated in vacuo , and the resulting residue 
 was purified by flash chromatography on silica gel , eluting with 020% 
 etoac / hexane .
this afforded 3-(4,5-dimethoxypyrimidin-2-yl)benzonitrile 
 as a white solid ( 138 mg , 100% ) ; mp 134136 c .
h nmr ( 400 mhz , cdcl3 )  8.61 ( s , 1h ) , 8.54 ( d , j = 8 hz , 1h ) , 8.09 ( s , 1h ) , 7.65 ( d , j = 8 hz , 1h ) , 7.51 ( t , j = 8 hz , 1h ) , 4.13 ( s , 3h ) , 
 3.95 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  
 159.8 , 153.6 , 141.7 , 138.5 , 137.0 , 132.8 , 131.6 , 131.3 , 129.2 , 118.9 , 
 112.6 , 56.4 , 54.2 . hrms ( esi ) calculated for c13h12n3o2 ( m + h ) 242.0924 , found 242.0928 .
4-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 ( 68 mg , 0.32 mmol ) and nan3 ( 79 mg , 1.21 mmol ) were dissolved 
 in anhydrous dmf ( 1 ml ) .
it was sealed , and then it was heated at 130 c 
 for 17 h. the reaction was cooled to room temperature and gave a brownish 
 suspension .
the resulting 
 residue was suspended in water and filtered to give 2-(4-(1h - tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3h)-one as a dark - brown solid ( 42 mg , 51% ) ; dec 290292 c .
h nmr ( 400 mhz , dmso - d6 )  
 8.08 ( d , j = 9 hz , 2h ) , 8.03 ( d , j = 8 hz , 2h ) , 7.55 ( s , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  161.0 , 160.2 , 148.9 , 143.3 , 133.8 , 
 132.4 , 131.6 , 126.9 , 125.5 .
hrms ( esi ) calculated for c11h9n6o2 ( m + h ) 257.0781 , 
 found 257.0791 .
3-(5-hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzonitrile 
 ( 108 mg , 0.50 mmol ) and nan3 ( 131 mg , 2.02 mmol ) were dissolved 
 in anhydrous dmf ( 1 ml ) .
it was sealed , and then it was heated at 130 c 
 for 18 h. the reaction was cooled to room temperature and gave a brownish 
 suspension .
the 
 greenish solid was suspended in 2 n hcl , followed by second filtration 
 to provide 2-(3-(1h - tetrazol-5-yl)phenyl)-5-hydroxypyrimidin-4(3h)-one as a beige solid ( 32 mg , 25% ) ; dec 295297 
 c .
h nmr ( 400 mhz , dmso - d6 )  8.67 ( s , 1h ) , 8.11 ( d , j = 8 hz , 1h ) , 
 7.97 ( d , j = 8 hz , 1h ) , 7.63 ( s , 1h ) , 7.56 ( t , j = 8 hz , 1h ) .
c nmr ( 100 mhz , dmso - d6 ) 162.3 , 159.1 , 158.7 , 148.0 , 143.4 , 
 133.1 , 130.4 , 128.9 , 127.9 , 126.5 , 125.1 . hrms ( esi ) calculated for 
 c11h9n6o2 ( m + h ) 257.0781 , found 257.0785 .
5-(4-fluorophenyl)-4-methoxy-2-(methoxymethyl)pyridazin-3(2h)-one ( 55 mg , 0.21 mmol ) was dissolved in anhydrous dcm 
 ( 10 ml ) .
the reaction mixture was cooled to 0 c , and then 1 
 m in dcm bbr3 ( 2.1 ml , 2.1 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 24 h. then the 
 solvent was removed under reduced pressure .
this gave 5-(4-fluorophenyl)-4-methoxypyridazin-3(2h)-one , which was again recharged with 1 m in dcm bbr3 ( 2.1 ml , 2.1 mmol ) .
the filtered solid was purified by flash chromatography 
 on silica gel , eluting with 010% meoh / dcm .
this gave 5-(4-fluorophenyl)-4-hydroxypyridazin-3(2h)-one as a white solid ( 6.2 mg , 14% ) ; mp 274276 
 c .
h nmr ( 400 mhz , dmso - d6 )  12.70 ( s , 1h ) , 7.76 ( s , 1h ) , 7.58 ( j = 
 8 hz , j = 5 hz , 2h ) , 7.217.17 ( m , 2h ) .
c nmr ( 100 mhz , dmso - d6 )  
 161.2 ( jc , f = 243 hz ) , 161.9 , 154.6 , 132.7 , 
 132.4 ( jc , f = 8 hz ) , 127.2 ( jc , f = 4 hz ) , 115.8 , 114.2 ( jc , f = 21 hz ) .
f nmr ( 376 mhz , dmso - d6 )  114.1 . hrms ( esi ) calculated for c10h8fn2o2 ( m + h ) 207.0564 , 
 found 207.0575 . 5-chloro-4-methoxy-2-(methoxymethyl)pyridazin-3(2h)-one ( 58 mg , 0.28 mmol ) , ( 4-fluorophenyl)boronic acid 
 ( 140 mg , 0.43 mmol ) , pd(pph3)4 ( 32 mg , 0.028 
 mmol ) , and na2co3 ( 90 mg , 0.85 mmol ) were dissolved 
 in a mixture of dioxane ( 9 ml ) and water ( 3 ml ) . the air was evacuated 
 and replaced with n2 .
then the reaction mixture was refluxed 
 for 14 h. after the reaction was completed , it was cooled to room 
 temperature , and it was diluted with etoac and washed with satd nh4cl , followed by brine .
the organic layer was dried over na2so4 and concentrated in vacuo , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 030% etoac / hexane .
this afforded 5-(4-fluorophenyl)-4-methoxy-2-(methoxymethyl)pyridazin-3(2h)-one as a white solid ( 56 mg , 74% ) ; mp 123125 
 c .
h nmr ( 400 mhz , cdcl3 )  7.95 
 ( s , 1h ) , 7.53 ( dd , j = 9 hz , j = 
 6 hz , 2h ) , 7.117 .
07 ( m , 2h ) , 5.48 ( s , 2h ) , 3.93 ( s , 3h ) , 
 3.49 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  
 162.6 ( jc , f = 247 hz ) , 161.6 , 154.8 , 132.3 
 ( jc , f = 8 hz ) , 128.5 , 125.7 , 120.7 , 112.9 
 ( jc , f = 22 hz ) , 81.6 , 57.9 , 57.3 .
f nmr ( 376 mhz , cdcl3 )  112.6 . 
 hrms ( esi ) calculated for c13h14fn2o3 ( m + h ) 265.0983 , found 265.0992 .
4,5-dichloro-2-(methoxymethyl)pyridazin-3(2h)-one ( 84 mg , 0.40 mmol ) was added to meoh ( 10 ml ) . then 
 the reaction mixture was cooled to 0 c .
it was treated with 
 naome ( 24 mg , 0.44 mmol ) and allowed to warm to room temperature . 

the reaction mixture was then stirred for 18 h at room temperature . 
 after the reaction
the resulting residue was diluted with etoac , which was then 
 washed with satd nh4cl , followed by brine .
the residue was purified by flash chromatography on silica gel , eluting 
 with 030% etoac / hexane to provide 5-chloro-4-methoxy-2-(methoxymethyl)pyridazin-3(2h)-one as a white solid ( 59 mg , 72% ) ; mp 101103 
 c .
h nmr ( 400 mhz , cdcl3 )  7.85 
 ( s , 1h ) , 5.45 ( s , 2h ) , 4.08 ( s , 3h ) , 3.44 ( s , 3h ) .
c 
 nmr ( 100 mhz , cdcl3 )  159.1 , 155.1 , 127.1 , 116.9 , 
 81.9 , 57.9 , 57.8 .
hrms ( esi ) calculated for c7h10cln2o3 ( m + h ) 205.0374 , found 
 205.0384 .
4,5-dichloropyridazin-3(2h)-one ( 200 
 mg , 1.21 mmol ) and 4-dimethylaminopyridine ( 15 mg , 0.12 mmol ) were 
 dissolved in anhydrous dcm ( 20 ml ) .
then the reaction mixture was 
 cooled to 0 c and treated with net3 ( 0.29 ml , 1.70 
 mmol ) , followed by momcl ( 0.110 ml , 1.454 mmol ) .
the reaction mixture 
 was allowed to warm to room temperature and stirred for 17 h. it was 
 then poured into dcm , and it was washed with satd nh4cl , 
 followed by brine .
the resulting residue was 
 purified by flash chromatography on silica gel , eluting with 030% 
 etoac / hexane to provide 4,5-dichloro-2-(methoxymethyl)pyridazin-3(2h)-one as a white solid ( 84 mg , 33% ) ; mp 6567 c .
h nmr ( 400 mhz , cdcl3 )  7.78 ( s , 1h ) , 5.41 
 ( s , 2h ) , 3.43 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  156.9 , 137.0 , 136.0 , 134.9 , 82.4 , 58.1 .
6-(4-fluorophenyl)-4-methoxypyridazin-3(2h)-one ( 16 mg , 0.074 mmol ) was dissolved in anhydrous dcm 
 ( 5 ml ) .
the reaction mixture was cooled to 0 c , and then 1 m 
 in dcm bbr3 ( 0.74 ml , 0.74 mmol ) was added .
it was then 
 allowed to warm to room temperature and stirred for 36 h. then the 
 solvent was removed under reduced pressure .
it was filtered , and the solid was collected 
 and dried under vacuum to provide 6-(4-fluorophenyl)-4-hydroxypyridazin-3(2h)-one as a white solid ( 5 mg , 35% ) ; mp 281283 c .
h nmr ( 400 mhz , dmso - d6 )  
 13.10 ( bs , 1h ) , 11.02 ( bs , 1h ) , 7.87 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.307.26 ( m,2h ) , 7.19 ( s , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  
 162.6 ( jc , f = 245 hz ) , 157.6 , 155.4 , 145.2 , 
 132.0 ( jc , f = 3 hz ) , 128.0 ( jc , f = 9 hz ) , 115.6 ( jc , f = 
 22 hz ) , 106.0 .
f nmr ( 376 mhz , dmso - d6 )  113.0 . hrms ( esi ) calculated for c10h8fn2o2 ( m + h ) 207.0564 , found 207.0567 .
6-(4-fluorophenyl)-3,4-dimethoxypyridazine 
 ( 122 mg 0.52 mmol ) was 
 dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the reaction 
 mixture was then refluxed for 11 h. it was then cooled to room temperature . 

the reaction mixture was diluted with etoac and washed with satd nahco3 , followed by brine .
the resulting residue was 
 purified by flash chromatography on silica gel , eluting with 010% 
 meoh / dcm to give 6-(4-fluorophenyl)-4-methoxypyridazin-3(2h)-one as a white solid ( 41 mg , 36% ) ; mp 211213 
 c .
h nmr ( 400 mhz , dmso - d6 )  13.05 ( br s , 1h ) , 7.96 ( dd , j = 9 hz , j = 6 hz , 2h ) , 7.347.29 ( m , 2h ) , 7.28 ( s , 1h ) , 3.92 
 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  162.7 ( jc , f = 245 hz ) , 
 156.2 , 155.7 , 144.3 , 132.0 ( jc , f = 3 hz ) , 
 128.2 ( jc , f = 8 hz ) , 115.6 ( jc , f = 22 hz ) , 104.4 , 56.2 .
f nmr ( 376 mhz , 
 dmso - d6 )  112.9 . hrms ( esi ) 
 calculated for c11h10fn2o2 ( m + h ) 221.0721 , found 221.0727 .
6-chloro-3,4-dimethoxypyridazine 
 ( 101 mg , 0.58 mmol ) , ( 4-fluorophenyl)boronic acid ( 122 mg , 0.87 mmol ) , 
 pd(pph3)4 ( 67 mg , 0.06 mmol ) , and na2co3(184 mg , 1.74 mmol ) were dissolved in a mixture of 
 dioxane ( 15 ml ) and water ( 5 ml ) .
then the reaction mixture was refluxed for 3 h. 
 after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 020% etoac / hexane .
this afforded 6-(4-fluorophenyl)-3,4-dimethoxypyridazine 
 as a white solid ( 109 mg , 80% ) ; mp 103105 c .
h nmr ( 400 mhz , cdcl3 )  7.88 ( dd , j = 9 hz , j = 5 hz , 2h ) , 7.107 . 06 ( m , 2h ) , 
 7.00 ( s , 1h ) , 4.14 ( s , 3h ) , 3.93 ( s , 3h ) .
c nmr ( 100 
 mhz , cdcl3 )  163.7 ( jc , f = 247 hz ) , 156.5 , 155.7 , 148.9 , 132.9 ( jc , f = 3 hz ) , 128.5 ( jc , f = 9 hz ) , 115.8 
 ( jc , f = 21 hz ) , 104.7 , 55.7 , 55.2 .
f nmr ( 376 mhz , cdcl3 )  112.2 . 
 hrms ( esi ) calculated for c12h12fn2o2 ( m + h ) 235.0877 , found 235.0885 .
3,4,6-trichloropyridazine 
 ( 200 mg , 1.09 mmol ) was added to meoh ( 15 ml ) .
it was treated with naome ( 117 mg , 2.17 mmol ) 
 and allowed to warm to room temperature .
after the reaction was 
 completed , it was put under the vacuum to remove meoh .
the resulting 
 residue was diluted with etoac , which was then washed with satd nh4cl , followed by brine .
the residue was purified 
 by flash chromatography on silica gel , eluting with 030% etoac / hexane 
 to provide 4-chloro-5,6-dimethoxypyrimidine as a white solid ( 101 
 mg , 53% ) ; mp 117119 c .
h nmr ( 400 mhz , cdcl3 )  6.71 ( s , 1h ) , 4.08 ( s , 3h ) , 3.88 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  156.9 , 151.1 , 149.8 , 108.4 , 
 56.2 , 55.3 . 4-(5-methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile 
 ( 109 mg , 0.48 mmol ) was dissolved in anhydrous dcm ( 5 ml ) .
the reaction 
 mixture was cooled to 0 c , and then 1 m in dcm bbr3 ( 4.8 ml , 4.8 mmol ) was added .
it was then allowed to warm to room 
 temperature and stirred for 20 h. then the solvent was removed under 
 reduced pressure .
the solid was dry loaded 
 on silica gel and was purified by flash chromatography on silica gel , 
 eluting with 010% meoh / dcm .
this afforded 4-(5-hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile 
 as a white solid ( 75 mg , 73% ) ; mp 305307 c .
h nmr ( 400 mhz , dmso - d6 )  13.29 
 ( s , 1h ) , 11.15 ( bs , 1h ) , 8.03 ( d , j = 9 hz , 2h ) , 
 7.92 ( d , j = 9 hz , 2h ) , 7.29 ( s , 1h ) .
c nmr ( 100 mhz , dmso - d6 )  157.7 , 
 154.6 , 144.4 , 139.8 , 132.7 , 126.5 , 118.6 , 111.4 , 106.0 . hrms ( esi ) 
 calculated for c11h8n3o2 ( m + h ) 214.0611 , found 214.0615 .
4-(5,6-dimethoxypyridazin-3-yl)benzonitrile ( 125 mg , 0.52 mmol ) 
 was dissolved in a mixture of 2 n hcl ( 5 ml ) and dioxane ( 5 ml ) .
the 
 reaction mixture was then refluxed for 4 h. it was then cooled to 
 room temperature and then put under reduced pressure .
the product 4-(5-methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile 
 was collected as a white solid ( 82 mg , 70% ) ; mp 271273 c .
h nmr ( 400 mhz , dmso - d6 )  
 13.97 ( bs , 1h ) , 8.02 ( d , j = 8 hz , 2h ) , 7.94 ( d , j = 8 hz , 2h ) , 6.62 ( s , 1h ) , 3.96 ( s , 3h ) .
c nmr ( 100 mhz , dmso - d6 )  156.3 , 
 155.9 , 143.5 , 139.7 , 132.7 , 126.7 , 118.6 , 111.4 , 104.3 , 56.3
. hrms 
 ( esi ) calculated for c12h10n3o2 ( m + h ) 228.0768 , found 228.0774 .
6-chloro-3,4-dimethoxypyridazine 
 ( 298 mg , 1.71 mmol ) , ( 4-cyanophenyl)boronic acid ( 376 mg , 2.56 mmol ) , 
 pd(pph3)4 ( 198 mg , 0.17 mmol ) , and na2co3(543 mg , 5.12 mmol ) were dissolved in a mixture of 
 dioxane ( 15 ml ) and water ( 5 ml ) . the air was evacuated and replaced 
 with n2 .
then the reaction mixture was refluxed for 15 
 h. after the reaction was completed , it was cooled to room temperature 
 and it was diluted with etoac and washed with satd nh4cl , 
 followed by brine .
the organic layer was dried over na2so4 and concentrated under reduced pressure , and the resulting 
 residue was purified by flash chromatography on silica gel , eluting 
 with 030% etoac / hexane .
this afforded 4-(5,6-dimethoxypyridazin-3-yl)benzonitrile 
 as a white solid ( 130 mg , 31% ) ; mp 187189 c .
h nmr ( 400 mhz , cdcl3 )  8.10 ( d , j = 8 hz , 2h ) , 7.77 ( d , j = 8 hz , 2h ) , 7.14 ( s , 1h ) , 
 4.23 ( s , 3h ) , 4.03 ( s , 3h ) .
c nmr ( 100 mhz , cdcl3 )  157.1 , 154.7 , 149.1 , 140.9 , 132.6 , 127.3 , 118.5 , 
 113.0 , 104.9 , 55.9 , 55.3 .
hrms ( esi ) calculated for c13h12n3o2 ( m + h ) 242.0924 , 
 found 242.0931 .
4-(5-methoxy-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile 
 ( 56 mg , 0.26 mmol ) and nan3 ( 69 mg , 1.06 mmol ) were dissolved 
 in anhydrous dmf ( 1 ml ) .
it was sealed , and then it was heated at 130 c 
 for 21 h. the reaction was cooled to room temperature and gave a brownish 
 suspension .
the suspension was filtered and gave a white solid , which 
 was treated with 2 n hcl and filtered again .
this afforded 6-(4-(1h - tetrazol-5-yl)phenyl)-4-hydroxypyridazin-3(2h)-one as a white solid ( 33 mg , 48% ) ; dec 273275 c .
h nmr ( 400 mhz , dmso - d6 )  
 11.13 ( s , 1h ) , 8.09 ( d , j = 8 hz , 2h ) , 7.95 ( d , j = 7 hz , 2h ) , 7.25 ( s , 1h ) .
c nmr ( 100 mhz , 
 dmso - d6 )  158.0 , 157.7 , 154.9 , 
 145.7 , 135.8 , 128.9 , 126.6 , 126.2 , 105.9 .
hrms ( esi ) calculated for 
 c11h9n6o2 ( m + h ) 257.0781 , found 257.0791 .
pandemic 
 h1n1 endonuclease ( residues 1204 ) was expressed and purified 
 as described previously .
the bl21 ( ril ) 
 cells ( stratagene ) were grown to an od600 of 0.8 and induced 
 with 0.15 mm iptg at 17 c for 17 h. cells were harvested by 
 centrifugation and purified on ni - nta ( qiagen ) according to manufacturers 
 recommendations , except the final elution was completed with 500 mm 
 imidazole containing buffer .
the endonuclease was further purified 
 by size exclusion chromatography using hiload 26/60 superdex 75 ( ge 
 healthcare ) .
the buffer used for size exclusion and the final buffer 
 for storage of the protein was 100 mm nacl and 20 mm tris ph 8.0 . 

the protein was concentrated to 5 mg / ml using an ultrafree 10k ( millipore ) , 
 aliquoted , and stored at 80 c .
crystals are formed 
 by mixing in a 1:1 ratio endonuclease ( 5 mg / ml ) with crystallization 
 buffer containing 200 mm mes ph 6.7 , 27% peg8000 , 200 mm ammonium 
 sulfate , 1 mm manganese chloride , 10 mm magnesium acetate , 10 mm taurine , 
 and 50 mm sodium fluoride .
crystals form within a few hours and grow 
 to maximum size in 12 weeks at 20 c .
crystal 
 structures of compounds 11 were determined in complex 
 with endonuclease as previously described.11 was soaked into preformed crystals by stepwise gradient 
 shifting the surrounding crystallization solution to 1 mm manganese 
 sulfate , 200 mm hepes ph 7.7 , 25% ( w / v ) peg 8000 , 50 mm ammonium sulfate , 
 5 mm magnesium acetate , 80 mm l - arginine , 10% dmso containing 
 100 mm 11 , and 10% ( v / v ) ethylene glycol .
crystals were 
 then soaked with the ligand for 2 h at 20 c before being placed 
 into liquid nitrogen for storage .
x - ray diffraction data collection 
 was performed at the cornell high energy synchrotron source ( chess ) 
 f1 beamline .
the diffraction data were indexed , processed , scaled , 
 and merged using hkl2000 . the structure 
 was solved and refined using the software phenix .
the endonuclease assay used a single - stranded dna probe with the 
 sequence ( 6-fam)tggcaatatcagctccaca(mgbnfq ) ( applied biosystems ) . 

reaction buffer contained 50 mm tris ph 7.5 , 50 mm sodium chloride , 
 1 mm dtt , 5 mm magnesium chloride , 0.5 mm manganese sulfate , and 1 
 mm chaps .
dna probe ( 50 nm ) , endonuclease ( 25 nm ) , and compound were 
 mixed on ice and then placed in a varioskan fluorimeter ( thermo scientific ) 
 preincubated at 37 c to detect fluorescence with an excitation 
 of 488 nm and emission of 518 nm .
fluorescence is measured at various 
 time points , and activity / inhibition is calculated with graphpad prism 
 6.0b .
 seasonal 
 and pandemic influenza outbreaks remain a major human 
 health problem . 
 inhibition of the endonuclease activity of influenza 
 rna - dependent rna polymerase is attractive for the development of 
 new agents for the treatment of influenza infection . 
 our earlier studies 
 identified a series of 5- and 6-phenyl substituted 3-hydroxypyridin-2(1h)-ones that were effective inhibitors of influenza endonuclease . 
 
 these agents identified as bimetal chelating ligands binding to the 
 active site of the enzyme . in the present study , 
 several aza analogues 
 of these phenyl substituted 3-hydroxypyridin-2(1h)-one compounds were synthesized and evaluated for their ability 
 to inhibit the endonuclease activity . 
 in contrast to the 4-aza analogue 
 of 6-(4-fluorophenyl)-3-hydroxypyridin-2(1h)-one , 
 the 5-aza analogue ( 5-hydroxy-2-(4-fluorophenyl)pyrimidin-4(3h)-one ) did exhibit significant activity as an endonuclease 
 inhibitor . 
 the 6-aza analogue of 5-(4-fluorophenyl)-3-hydroxypyridin-2(1h)-one ( 6-(4-fluorophenyl)-4-hydroxypyridazin-3(2h)-one ) also retained modest activity as an inhibitor . 
 several 
 varied 6-phenyl-4-hydroxypyridazin-3(2h)-ones and 
 2-phenyl-5-hydroxypyrimidin-4(3h)-ones were synthesized 
 and evaluated as endonuclease inhibitors . 
 the sar observed for these 
 aza analogues are consistent with those previously observed with various 
 phenyl substituted 3-hydroxypyridin-2(1h)-ones . 
Introduction
Chemistry
Results and Discussion
Experimental
Section