scheme 1 outlines 
 the synthesis of novel 
 thioacetamide ( compounds 4a4z ) and 
 sulfinylacetamide ( compounds 5a5 g ) analogues of ( )-1 . the thioacetamide analogues 4a4z were generated via three different 
 synthetic routes .
the first route ( procedure a ) affords the 
 thioacetamides in one 
 step and was employed in the synthesis of compound 4a and the n - methylthioacetamides 4g4i . as opposed to the previously reported two - step synthesis
, thioacetamide 4a was synthesized 
 in one step by coupling 2-mercaptoacetamide with diphenylmethanol 
 in trifluoroacetic acid ( tfa ) at room temperature .
similarly , n - methylthioacetamides 4g4i were synthesized via the coupling reaction between 2-mercapto - n - methylacetamide and diphenylmethanol ( for 4 g ) or the corresponding bis(halophenyl)methanol ( for 4h and 4i ) in tfa . to improve product yields , the reactions 
 for compounds 4h and 4i required heating 
 to 60 c .
reagents and conditions : 
 ( a ) 
 2-mercaptoacetamide or 2-mercapto - n - methylacetamide , 
 tfa , room temperature ( 60 c for substituted phenyl analogues ) , 
 20 h ( procedure a ) ; ( b ) ( i ) thioglycolic acid , tfa , room temperature 
 ( 5560 c for substituted phenyl analogues ) , overnight ; 
 ( ii ) ch3i , k2co3 , acetone , reflux , 
 overnight ; ( iii ) nh4oh , nh4cl , meoh , 50 c , 
 72 h ( procedure b ) ; ( c ) ( i ) thioglycolic acid , tfa , room temperature 
 ( 5560 c for substituted phenyl analogues ) , overnight ; 
 ( ii ) cdi , thf , room temperature , 2 h ; ( iii ) rnh2 , thf , 
 0 c to room temperature , overnight ( procedure c ) ; ( d ) h2o2 ( 30% ) , acoh  meoh ( 1:3 ) , 40 c , overnight . the second synthetic route ( procedure b ) , used 
 for the synthesis 
 of thioacetamides 4b4f , required 
 three steps , similar to previously described methods .
mono- or disubstituted diphenylmethanol was coupled with 
 thioglycolic acid in tfa , followed by esterification with iodomethane 
 in acetone under reflux conditions .
the resulting methyl esters were 
 converted into the primary amides 4b4f through aminolysis with ammonium hydroxide in methanol .
the 
 third route ( procedure c ) also 
 involved three steps and was employed for the synthesis of n - substituted 
 thioacetamides 4j4z .
first , diphenylmethanol 
 or the appropriate bis(halophenyl)methanol was coupled with thioglycolic 
 acid in tfa .
the desired n - substituted thioacetamides 4j4z were then synthesized by coupling the carboxylic 
 acid to the corresponding primary amine via an in situ n , n-carbonyldiimidazole coupling reaction . 

oxidation of the appropriate thioacetamide ( 4b4 g and 4x ) using hydrogen peroxide ( h2o2 ; 30% ) in an acetic acid  methanol solution mixture 
 gave sulfinylacetamides 5a5 g .
scheme 2 outlines the synthesis of the thioethanamine 
 ( 6a6i ) and sulfinylethanamine ( 7a7e ) analogues of ( )-1 .
thioethanamines 6a6c were synthesized 
 by coupling diphenylmethanol or the appropriate bis(halophenyl)methanol 
 with cysteamine hydrochloride in glacial acetic acid in the presence 
 of the lewis acid catalyst boron trifluoride diethyl etherate ( bf3oet2 ) ( procedure d ) .
the n - substituted thioethanamine 6d was synthesized 
 by a reductive amination reaction between the hydrochloride salt of 
 compound 6a and cyclopropanecarboxaldehyde using sodium 
 cyanoborohydride as the reducing agent .
similarly , n - substituted thioethanamine 6e was synthesized by coupling n - butyl bromide 
 to the free base of compound 6a in the presence of csohh2o ( cs ions served as templating catalysts ) .
n - substituted thioethanamines 6f6h were synthesized by the reduction of thioacetamides 4u4w using alane ( lialh4sulfuric 
 acid mixture ) .
lastly , n - substituted 
 thioethanamine 6i was prepared from thioacetamide 4x by reduction with borane in thf ( bh3thf ) . 

sulfinylethanamines 7a7e were synthesized 
 from the appropriate thioethanamines ( 6a , 6e , or 6g6i ) by oxidation of the 
 thioether function using either sodium periodate ( naio4 ) in an ethanol 
water solution ( compounds 7a and 7b ) or h2o2 ( 30% ) in an acetic acid  methanol 
 solution ( compounds 7c7e ) . reagents and conditions : ( a ) 
 cysteamine hydrochloride , bf3oet2 , glacial 
 acoh , 8090 c , 20 min ( 4050 min for substituted 
 analogues ( procedure d ) ) ; ( b ) ( i ) procedure d ; ( ii ) cyclopropane carboxaldehyde , 
 nabh3cn , meoh , 1,2-dichloroethane , room temperature , overnight ; 
 ( c ) ( i ) procedure d ; ( ii ) bubr , csohh2o , 4  
 ms , dmf , room temperature , 20 h ; ( d ) lialh4 , h2so4 , thf ; ( e ) bh3thf , thf , reflux , overnight ; 
 ( f ) naio4 , h2o , etoh , 0 c to room temperature , 
 overnight ; ( g ) h2o2 ( 30% ) , acoh  meoh 
 ( 1:3 ) , 40 c , 24 h.
a series of novel thio- and sulfinylacetamide and -ethanamine analogues 
 of ( )-1 , with or without substituents on the diphenyl 
 rings , were synthesized to investigate the contributions of structural 
 variations to selectivity across mats .
previous sars had suggested 
 that the sulfinyl ( s = o ) function was not critical for binding 
 to the dat , but differential interactions with y156 of dat and y176 
 of sert may affect selectivity for sert .
in addition , we showed that reduction of the amide function to the 
 amine not only improved water solubility , but also enhanced dat affinity . in the current study
para- or meta - substitution 
 of the phenyl rings of ( )-1 with cl or br gave 
 several amide analogues with improved selectivity for dat over sert 
 and net , whereas selectivity was improved at sert over dat and net 
 for the amine analogues .
overall , we identified five highly dat - selective 
 amide analogues ( e.g. , 4e , 2900-fold over sert ) and two 
 sert - selective amine analogues with high affinity ( ki  30 nm ) .
computational modeling of dat and sert 
 led to the identification of key amino acid residues in tm10 that 
 form part of the s1 binding pocket in both dat and sert . by switching 
 the t497 in sert to ala and the a480 in dat to thr and then testing 
 a selected subgroup of analogues , the role of tm10 in dat and sert 
 binding
moreover , we propose that this tm10 position 
 faces the s1 binding site and plays a role in the binding of this 
 class of compounds to the dat similar to the atypical dat inhibitors 
 exemplified by the benztropines , but not to cocaine .
interestingly , in the benztropine class of atypical dat 
 inhibitors similar observations were made in that ( 1 ) converting the 
 tropane amine nitrogen to an amide significantly reduced the binding 
 affinity ( e.g. , n - acetyl-3-[bis(4-fluorophenyl)methoxy]tropane , 
 dat ki = 2340 nm ) to an affinity virtually identical to that of ( )-1 , and ( 2 ) the same order of halogen effect on the amine analogues 
 described herein on decreasing dat affinity ( f > cl > br ) was 
 also 
 reported for the benztropines , and this is in direct opposition to 
 the order observed in the cocaine - like 3-phenyltropane analogues ( e.g. , 
 win 35,428 , 2-carbomethoxy-3-(4-fluorophenyl)tropane ) .
this divergence in dat sar between the benztropines 
 and 3-phenyltropane analogues formed one of the early foundations 
 for our hypothesis that these compounds bind differently to the dat , 
 and these differences may be related to their different behavioral 
 profiles .
importantly , as it was shown that tm10 plays a critical 
 role in propagating the conformational changes of the homologous leut 
 from the s1 binding site to the intracellular gate , such divergent 
 interactions with tm10 are likely to have an impact on the overall 
 transporter conformation and may contribute 
 to the mechanism underlying the unique pharmacology of ( )-1 and its analogues at dat .
anhydrous solvents were purchased from aldrich and were used without 
 further purification , except for tetrahydrofuran , which was freshly 
 distilled from sodium benzophenone ketyl . all other chemicals and 
 reagents were purchased from sigma - aldrich co. llc , combi - blocks , 
 tci america , ochem incorporation , acros organics , maybridge , and alfa 
 aesar . the diphenylmethanols ( 3a  c ,
3e  i ) were commercially available , 
 except 3d , which was synthesized as outlined below .
unless 
 otherwise stated , amine final products were converted into oxalate 
 salts , typically by treating the free base in 2-propanol with a 1:1 
 molar ratio of oxalic acid in acetone . as described , some of the oxalate 
 salts were recrystallized from hot methanol or a methanol  acetone 
 solvent mixture .
spectroscopic data and yields refer to the free base , 
 except for compounds 6b and 6c , which were 
 synthesized as the hydrochloride salts .
, 230400 mesh , 60  ) . 
 compounds 4u and 6f were purified using 
 a teledyne isco combiflash rf instrument . h 
 and c nmr spectra were acquired using a varian mercury 
 plus 400 spectrometer at 400 and 100 mhz , respectively .
chemical shifts 
 are reported in parts per million ( ppm ) and referenced according to 
 deuterated solvent for h spectra ( cdcl3 , 7.26 
 ppm , or dmso - d6 , 2.50 ppm ) and c spectra ( cdcl3 , 77.2 ppm , or dmso - d6 , 39.5 ppm ) .
gas chromatography / mass spectrometry ( gc / ms ) 
 data were acquired ( where obtainable ) using an agilent technologies 
 ( santa clara , ca ) 6890n gas chromatograph equipped with an hp-5ms 
 column ( cross - linked 5% ph me siloxane , 30 m  0.25 mm i.d .  
 0.25 m film thickness ) and a 5973 mass - selective ion detector 
 in electron - impact mode .
ultrapure grade helium was used as the carrier 
 gas at a flow rate of 1.2 ml / min . the injection port and
transfer 
 line temperatures were 250 and 280 c , respectively , and the 
 oven temperature gradient used was as follows : the initial temperature 
 ( 100 c ) was held for 3 min , then increased to 295 c at 
 15 c / min over 13 min , and finally maintained at 295 c 
 for 10 min .
( norcross , ga ) , and the results agree within 0.5% of the 
 calculated values .
melting point determination was conducted using 
 a thomas - hoover melting point apparatus , and the melting points are 
 uncorrected . on the basis of nmr and combustion data , all final compounds 

compound 3d was synthesized by adapting a 
 literature method from bis(4-bromophenyl)methanone 
 ( 10.2 g , 30.0 
 mmol ) and nabh4 ( 2.55 g , 67.4 mmol ) in anhydrous ethanol 
 ( 65 ml ) at 0 c under argon .
the product 3d ( 9.8 
 g , 95% yield ) was recovered as a white solid .
h nmr ( cdcl3 ) :  7.46 ( d , j = 8.6 hz , 4h ) , 7.22 ( d , j = 8.6 hz , 4h ) , 5.76 ( sd , j = 3.5 hz , 1h ) , 2.21 ( sd , j = 3.5 hz , 
 1h ) .
c nmr ( cdcl3 ) :  142.4 , 131.9 , 
 128.3 , 121.9 , 75.2 .
a solution of 2-mercapto - n - methylacetamide ( 10 mmol ) and diphenylmethanol , 3a , 
 or the appropriate substituted diphenylmethanol , 3c or 3d ( 10 mmol ) , in trifluoroacetic acid ( tfa ; 200 mmol ) was 
 stirred at room temperature ( 60 c for substituted analogues ) 
 for 20 h. the solvent was removed in vacuo , and the thick oily residue 
 was washed with water ( 30 ml ) . after the water was decanted , a crude 
 solid product was isolated by addition of diisopropyl ether ( 20 ml ) 
 to the oily residue and vigourous mixing .
the crude solid was filtered 
 and purified by flash column chromatography using 5% meoh / ch2cl2 to give the pure , desired product .
step 1 : thioglycolic acid ( 1 mmol ) was reacted with the appropriate 
 substituted diphenylmethanol , 3e3i ( 1 mmol ) , in tfa ( 14 mmol ) overnight at room temperature .
after 
 solvent removal in vacuo , the residue obtained was washed with water 
 ( 5 ml ) and hexanes ( 15 ml ) to give the carboxylic acid product , which 
 was carried to the next step without further purification .
step 2 : 
 the acid product ( 3 mmol ) from step 1 was reacted with k2co3 ( 4.5 mmol ) and iodomethane ( ch3i ; 4.5 mmol ) 
 in acetone ( 50 ml ) overnight under reflux conditions .
after solvent 
 removal in vacuo , the residue was suspended in water ( 20 ml ) and extracted 
 with ch2cl2 ( 3  20 ml ) .
the combined organic 
 layer was dried over mgso4 and concentrated to give the 
 methyl ester , which was carried to the next step without further purification . 

step 3 : a mixture of the ester ( 3 mmol ) , nh4cl ( 4.2 mmol ) , 
 concentrated nh4oh ( 28.030.0% , 20 ml ) , and meoh 
 ( 5.7 ml ) was stirred at 50 c for 72 h. meoh was removed in vacuo , 
 and the reaction mixture was diluted with water ( 50 ml ) , extracted 
 with ethyl acetate ( 3  50 ml ) , and dried over na2so4 .
the solvent was evaporated , and the recovered crude 
 product was purified by flash column chromatography using 1:1 ethyl 
 acetate / hexanes to afford the pure product .
thioacetamides 4l , 4p , 4s , 4v , and 4w were synthesized 
 in two steps according to a published procedure , while compounds 4j , 4k , 4m4o , 4q , 4r , 4 t , 4u , and 4x4z were synthesized in two steps with slight modifications 
 to the published procedure in the second step .
step 1 is the same 
 as step 1 for procedure b. step 2 : cdi ( 11 mmol ) was added to a solution 
 of the carboxylic acid product ( 10 mmol ) from step 1 in anhydrous 
 thf ( 25 ml ) .
the reaction mixture was stirred at room temperature 
 for 2 h and then cooled to 0 c .
water ( 0.10.2 ml ) was 
 added to the reaction mixture ( to quench excess cdi ) , followed by 
 the dropwise addition of the appropriate amine ( 10 mmol , dissolved 
 in thf ) .
the solvent was removed under vacuum to give a 
 crude residue , which was dissolved in diethyl ether or ethyl acetate . 

the organic solution was washed with aqueous 1.0 m hcl solution ( 55 
 ml ) , water ( 80 ml ) , dilute aqueous nahco3 solution ( 36 
 ml , 1:6 dilution of saturated nahco3 solution ) , and water 
 ( 2  30 ml ) .
the organic layer was dried over mgso4 and concentrated in vacuo to give the pure product .
the bromo - substituted 
 analogues 4q , 4 t , 4x , and 4z required further purification by flash column chromatography 
 as indicated .
compound 4a was synthesized by stirring a 
 solution of 2-mercaptoacetamide 
 ( 0.63 g , 6.9 mmol ; recovered from the 10% ( w / v ) methanol / nh3 solution ) and diphenylmethanol , 3a ( 1.3 g , 7.1 mmol ) , 
 in tfa ( 11.9 g , 104 mmol ) at room temperature for 4 h. the solvent 
 was removed in vacuo , and the brown oily residue was dissolved in 
 chcl3 ( 30 ml ) and washed with water ( 30 ml ) , followed by 
 a dilute nahco3 solution ( 30 ml , 1:3 dilution of saturated 
 nahco3 solution ) and water ( 30 ml ) .
the crude product 
 was purified by flash chromatography using 1:1 ethyl acetate / hexanes 
 to give pure 4a ( 0.31 g , 17% yield ) as a white solid . 

h nmr ( cdcl3 ) :  7.41 ( d , j = 7.6 hz , 4h ) , 7.33 ( t , j = 7.4 hz , 4h ) , 
 7.25 ( tt , j = 7.2 , 1.4 hz , 2h ) , 6.50 ( br s , 1h ) , 
 5.57 ( br s , 1h ) , 5.17 ( s , 1h ) , 3.09 ( s , 2h ) .
c nmr ( cdcl3 ) :  171.2 , 140.3 , 128.9 , 128.4 , 127.8 , 54.9 , 35.7 . 
 anal .
( c15h15nos ) c , h , n. compound 4b was synthesized according 
 to general procedure b to give 4b ( 450 mg , 52% yield ) 
 as a yellow oil .
h nmr ( cdcl3 ) :  7.26 
 7.30 ( m , 4h ) , 7.12 ( d , j = 7.6 hz , 4h ) , 6.54 
 ( br s , 1h ) , 5.53 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.07 ( s , 2h ) , 2.31 ( s , 
 6h ) .
compound 4c was synthesized 
 according 
 to general procedure b to give 4c ( 680 mg , 58% yield ) 
 as a white foam .
h nmr ( cdcl3 ) :  7.61 
 ( d , j = 8.0 hz , 4h ) , 7.53 ( d , j = 
 8.0 hz , 4h ) , 6.29 ( br s , 1h ) , 5.72 ( br s , 1h ) , 5.34 ( s , 1h ) , 3.08 
 ( s , 2h ) .
compound 4d was synthesized 
 according to 
 general procedure b to give 4d ( 810 mg , 61% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.277.33 
 ( m , 2h ) , 7.17 ( d , j = 8.0 hz , 2h ) , 7.12 ( dt , j = 10.0 , 2.0 hz , 2h ) , 6.97 ( td , j = 8.0 , 
 2.4 hz , 2h ) , 6.43 ( br s 1h ) , 6.09 ( br s , 1h ) , 5.19 ( s , 1h ) , 3.09 ( s , 
 2h ) .
compound 4e was synthesized 
 according to 
 general procedure b to give 4e ( 800 mg , 65% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.387.39 
 ( m , 2h ) , 7.257.28 ( m , 6h ) , 6.42 ( br s , 1h ) , 6.05 ( br s , 1h ) , 
 5.15 ( s , 1h ) , 3.09 ( s , 2h ) .
c nmr ( cdcl3 ) : 
  170.9 , 141.6 , 134.8 , 130.1 , 128.3 , 128.1 , 126.5 , 53.4 , 35.4 . 

( c15h13cl2nos ) c , h , n. compound 4f was synthesized 
 according to 
 general procedure b to give 4f ( 750 mg , 58% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.577.58 
 ( m , 1h ) , 7.317.39 ( m , 6h ) , 7.257.29 ( m , 1h ) , 7.18 
 ( t , j = 7.8 hz , 1h ) , 6.49 ( br s , 1h ) , 6.32 ( br s , 
 1h ) , 5.16 ( s , 1h ) , 3.07 ( s , 2h ) .
compound 4 g was synthesized using 
 2-mercapto - n - methylacetamide and diphenylmethanol , 3a , according to general procedure a. the product 4 g ( 3.5 g , 59% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) : 
  7.86 ( br s , 1h ) , 7.42 ( d , j = 8.2 hz , 4h ) , 
 7.33 ( t , j = 7.6 hz , 4h ) , 7.23 ( t , j = 7.2 hz , 2h ) , 5.40 ( s , 1h ) , 2.96 ( s , 2h ) , 2.54 ( sd , j = 4.7 hz , 3h ) .
c nmr ( dmso - d6 ) :  169.6 , 142.2 , 129.5 , 128.9 , 128.1 , 54.0 , 35.8 , 26.7 .
( c16h17nos ) c , h , n. compound 4h was synthesized 
 using 2-mercapto - n - methylacetamide and bis(4-chlorophenyl)methanol , 3c , at 60 c according to general procedure a. the product 4h ( 2.12 g , 79% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) :  7.87 ( br s , 1h ) , 7.387.44 ( m , 8h ) , 
 5.45 ( s , 1h ) , 2.99 ( s , 2h ) , 2.53 ( sd , j = 4.7 hz , 
 3h ) .
c nmr ( dmso - d6 ) :  
 169.3 , 140.8 , 132.8 , 130.8 , 129.6 , 52.4 , 35.8 , 26.6 .
( c16h15cl2nos ) c , h , n. compound 4i was synthesized 
 from 2-mercapto - n - methylacetamide and bis(4-bromophenyl)methanol , 3d , at 60 c according to general procedure a. the product 4i ( 1.86 g , 74% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) :  7.86 ( br s , 1h ) , 7.53 ( dt , j = 8.4 , 2.2 hz , 4h ) , 7.35 ( dt , j = 8.4 , 2.2 hz , 
 4h ) , 5.42 ( s , 1h ) , 2.99 ( s , 2h ) , 2.53 ( sd , j = 4.8 
 hz , 3h ) .
c nmr ( dmso - d6 ) : 
  168.3 , 140.2 , 131.5 , 130.2 , 120.4 , 51.6 , 34.9 , 25.7 .
( c16h15br2nos ) c , h , n. compound 4j was synthesized from 
 2-(benzhydrylthio)acetic acid and allylamine according to the modified 
 general procedure c. the product 4j ( 1.97 g , 86% yield ) 
 was obtained as a viscous yellow oil that solidified over time .
h nmr ( cdcl3 ) :  
 7.40 ( d , j = 7.2 hz , 4h ) , 7.32 ( t , j = 7.4 hz , 4h ) , 7.25 ( t , j = 8.0 hz , 2h ) , 6.67 ( br 
 s , 1h ) , 5.775.86 ( m , 1h ) , 5.19 ( d , jtrans = 17.6 hz , 1h ) , 5.15 ( d , jcis = 10.6 hz , 1h ) , 5.13 ( s , 1h ) , 3.84 
 ( tt , j = 5.6 , 1.6 hz ) , 3.14 ( s , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 140.3 , 133.8 , 128.8 , 128.2 , 
 127.6 , 116.8 , 55.1 , 42.1 , 36.1 .
( c18h19nos ) c , h , n. compound 4k was synthesized 
 from 
 2-(benzhydrylthio)acetic acid and propylamine according to the modified 
 general procedure c. the product 4k ( 1.05 g , 91% yield ) 
 was obtained as a yellow oil that solidified over time .
h nmr ( cdcl3 ) :  7.39 ( d , j = 7.6 hz , 4h ) , 7.32 ( tt , j = 7.2 , 1.6 
 hz , 4h ) , 7.24 ( t , j = 7.2 hz , 2h ) , 6.64 ( br s , 1h ) , 
 5.11 ( s , 1h ) , 3.18 ( q , j = 6.8 hz , 2h ) , 3.11 ( s , 
 2h ) , 1.471.56 ( m , 2h ) , 0.93 ( t , j = 7.4 hz , 
 3h ) .
c nmr ( cdcl3 ) :  168.2 , 140.5 , 
 128.9 , 128.4 , 127.7 , 55.2 , 41.6 , 36.3 , 22.9 , 11.5 .
( c18h21nos ) c , h , n. compound 4l was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and propylamine 
 according to general procedure c. the product 4l ( 320 
 mg , 95% yield ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.327.37 ( m , 4h ) , 
 6.99 7.05 ( m , 4h ) , 6.55 ( br s , 1h ) , 5.14 ( s , 1h ) , 3.20 ( q , j = 6.6 hz , 2h ) , 3.07 ( s , 2h ) , 1.481.58 ( m , 2h ) , 
 0.94 ( t , j = 7.4 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 162.1 ( jcf = 247 hz ) , 136.0 ( jcf = 3.7 hz ) , 129.8 ( jcf = 
 8.1 hz ) , 115.7 ( jcf = 21.4 
 hz ) , 53.2 , 41.5 , 36.0 , 22.8 , 11.4 .
( c18h19f2nos ) c , h , n. compound 4 m was synthesized 
 from 2-((bis(4-chlorophenyl)methyl)thio)acetic acid and propylamine 
 according to the modified general procedure c. the product 4 m ( 2.06 g , 91% yield ) was obtained as a viscous yellow oil that solidified 
 over time .
h nmr ( cdcl3 ) :  7.30 ( s , 8h ) , 6.34 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.20 ( q , j = 6.8 hz , 2h ) , 3.07 ( s , 2h ) , 1.481.57 ( m , 2h ) , 
 0.93 ( t , j = 7.4 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 138.6 , 133.8 , 129.7 , 129.2 , 53.6 , 41.7 , 
 36.1 , 22.9 , 11.5 .
( c18h19cl2nos ) c , h , n. compound 4n was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and propylamine 
 according to the modified general procedure c. the product 4n ( 1.75 g , 80% yield ) was obtained as a light yellow solid .
h nmr ( cdcl3 ) :  7.45 ( d , j = 8.8 hz , 4h ) , 7.24 ( d , j = 8.8 hz , 4h ) , 
 6.41 ( br s , 1h ) , 5.08 ( s , 1h ) , 3.19 ( q , j = 6.8 hz , 
 2h ) , 3.07 ( s , 2h ) , 1.471.56 ( m , 2h ) , 0.93 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 
 139.1 , 132.1 , 130.0 , 121.9 , 53.7 , 41.7 , 36.1 , 22.9 , 11.5 .
( c18h19br2nos ) c , h , n. compound 4o was synthesized 
 from 2-(benzhydrylthio)acetic acid and cyclopropylmethylamine according 
 to the modified general procedure c. the product 4o ( 0.25 
 g , 94% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.41 ( d , j = 7.6 hz , 4h ) , 7.33 
 ( tt , j = 7.4 , 1.9 hz , 4h ) , 7.25 ( tt , j = 7.4 , 1.7 hz , 2h ) , 6.73 ( br s , 1h ) , 5.14 ( s , 1h ) , 3.12 ( s , 2h ) , 
 3.09 ( dd , j = 7.2 , 5.6 hz , 2h ) , 0.901.00 
 ( m , 1h ) , 0.53 ( q , j = 6.4 hz , 2h ) , 0.22 ( q , j = 5.2 hz , 2h ) .
c nmr ( cdcl3 ) : 
  168.1 , 140.5 , 128.9 , 128.4 , 127.7 , 55.1 , 44.7 , 36.3 , 10.8 , 
 3.6 .
( c19h21nos ) c , h , n. compound 4p was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and cyclopropylmethylamine 
 according to general procedure c. the product 4p ( 320 
 mg , 92% yield ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.35 ( dd , j = 8.8 , 5.2 hz , 4h ) , 6.997.05 ( m , 4h ) , 6.58 ( br s , 1h ) , 5.16 
 ( s , 1h ) , 3.11 ( dd , j = 7.0 , 5.4 hz , 2h ) , 3.08 ( s , 
 2h ) , 0.911.01 ( m , 1h ) , 0.520.56 ( m , 2h ) , 0.23 ( q , j = 5.0 hz , 2h ) .
c nmr ( cdcl3 ) : 
  167.9 , 162.1 ( jcf = 
 248 hz ) , 136.0 ( jcf = 3.0 
 hz ) , 129.8 ( jcf = 8.1 hz ) , 
 115.7 ( jcf = 21.4 hz ) , 53.3 , 
 44.6 , 36.0 , 10.7 , 3.4 .
( c19h19f2nos ) c , h , n. compound 4q was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and cyclopropylmethylamine 
 according to the modified general procedure c. purification by flash 
 column chromatography using 1:1 ethyl acetate / hexanes gave the pure 
 product 4q ( 1.08 g , 94% yield ) as a white solid .
h nmr ( cdcl3 ) :  
 7.49 ( dt , j = 8.8 , 2.2 hz , 4h ) , 7.25 ( dt , j = 8.4 , 2.4 hz , 4h ) , 6.56 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.09 
 ( dd , j = 7.2 , 5.6 hz , 2h ) , 3.07 ( s , 2h ) , 0.880.97 
 ( m , 1h ) , 0.53 ( q , j = 6.6 hz , 2h ) , 0.21 ( q , j = 5.2 hz , 2h ) .
c nmr ( cdcl3 ) : 
  167.9 , 139.0 , 132.0 , 130.0 , 121.8 , 53.5 , 44.6 , 35.9 , 10.7 , 
 3.5 .
( c19h19br2nos/4c4h8o2 ) c , h , 
 n. compound 4r was synthesized from 
 2-(benzhydrylthio)acetic acid and n - butylamine according 
 to the modified general procedure c. the product 4r ( 264 
 mg , 87% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.39 ( d , j = 7.2 hz , 4h ) , 7.32 
 ( t , j = 7.4 hz , 4h ) , 7.24 ( tt , j = 7.2 , 1.7 hz , 2h ) , 6.64 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.21 ( q , j = 6.7 hz , 2h ) , 3.10 ( s , 2h ) , 1.431.51 ( m , 2h ) , 
 1.301.39 ( m , 2h ) , 0.93 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) :  168.2 , 140.5 , 128.9 , 128.3 , 
 127.7 , 55.1 , 39.6 , 31.7 , 20.2 , 13.9 .
( c19h23nos ) c , h , n. compound 4s was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and n - butylamine according to general procedure c. the product 4s ( 350 mg , 100% ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.34 ( dd , j = 8.8 , 5.2 hz , 4h ) , 6.997.05 ( m , 4h ) , 6.49 ( br s , 1h ) , 5.13 
 ( s , 1h ) , 3.24 ( q , j = 6.6 hz , 2h ) , 3.07 ( s , 2h ) , 
 1.451.52 ( m , 2h ) , 1.311.40 ( m , 2h ) , 0.94 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) : 
  167.9 , 162.1 ( jcf = 
 247 hz ) , 136.0 ( jcf = 3.7 
 hz ) , 129.8 ( jcf = 8.1 hz ) , 
 115.7 ( jcf = 21.4 hz , 4c ) , 
 53.3 , 39.5 , 36.0 , 31.6 , 20.1 , 13.7 .
( c19h21f2nos ) c , h , n. compound 4 t was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and n - butylamine according to the modified general procedure c. purification 
 by flash column chromatography using 10% meoh / chcl3 gave 
 the pure product 4 t ( 0.50 g , 88% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.45 ( dt , j = 8.4 , 2.0 hz , 4h ) , 7.24 ( dt , j = 8.8 , 2.4 hz , 
 4h ) , 6.40 ( br s , 1h ) , 5.07 ( s , 1h ) , 3.22 ( q , j = 
 6.8 hz , 2h ) , 3.07 ( s , 2h ) , 1.431.51 ( m , 2h ) , 1.301.39 
 ( m , 2h ) , 0.94 ( t , j = 7.2 hz , 3h ) .
c 
 nmr ( cdcl3 ) :  167.9 , 139.1 , 132.1 , 130.0 , 121.9 , 
 53.7 , 39.7 , 36.1 31.7 , 20.2 , 13.9 .
( c19h21br2nos ) c , h , n. compound 4u was synthesized 
 as previously described from 2-(benzhydrylthio)acetic 
 acid and 3-phenyl-1-propylamine according to the modified general 
 procedure c. purification on a teledyne isco combiflash rf instrument using 1:1 ethyl acetate / hexanes gave the pure product 4u ( 1.66 g , 94% yield ) as a white solid .
h nmr ( cdcl3 ) :  7.377.39 
 ( m , 4h ) , 7.287.33 ( m , 6h ) , 7.167.27 ( m , 5h ) , 6.61 
 ( br s , 1h ) , 5.10 ( s , 1h ) , 3.24 ( q , j = 6.8 hz , 2h ) , 
 3.09 ( s , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 1.781.86 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.3 , 141.3 , 
 140.5 , 128.9 , 128.6 , 128.5 , 128.3 , 127.7 , 126.2 , 55.2 , 39.5 , 36.3 , 
 33.4 , 31.2 .
( c24h25nos ) c , h , n. compound 4v was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and 3-phenyl-1-propylamine 
 according to general procedure c. the product 4v ( 1.2 
 g , 100% ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.267.35 ( m , 6h ) , 7.167.22 ( m , 
 3h ) , 6.987.04 ( m , 4h ) , 6.48 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.27 
 ( q , j = 6.8 hz , 2h ) , 3.04 ( s , 2h ) , 2.66 ( t , j = 7.8 hz , 2h ) , 1.811.88 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 162.1 ( jcf = 247 hz ) , 141.1 , 135.9 ( jcf = 2.9 hz ) , 129.8 ( jcf = 8.1 hz ) , 128.4 ( jcf = 21.4 hz ) , 126.1 , 115.8 , 115.6 , 53.3 , 39.4 , 36.0 , 33.2 , 
 31.1 .
( c24h23f2nos ) c , h , n. compound 4w was synthesized 
 as previously described from 2-((bis(4-chlorophenyl)methyl)thio)acetic 
 acid and 3-phenyl-1-propylamine according to general procedure c. 
 the product 4w ( 1 g , 75% ) was obtained as a yellow oil .
h nmr(cdcl3 ) :  7.157.31 ( m , 13h ) , 
 6.38 ( br s , 1h ) , 5.09 ( s , 1h ) , 3.26 ( q , j = 6.6 hz , 
 2h ) , 3.04 ( s , 2h ) , 2.65 ( t , j = 7.6 hz , 2h ) , 1.801.87 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  167.9 , 141.1 , 
 138.4 , 133.6 , 129.5 , 129.0 , 128.5 , 128.3 , 126.1 , 53.4 , 39.4 , 35.9 , 
 33.2 , 31.0 .
( c24h23cl2nos ) 
 c , h , n. compound 4x was synthesized 
 as previously described from 2-((bis(4-bromophenyl)methyl)thio)acetic 
 acid and 3-phenyl-1-propylamine according to the modified general 
 procedure c. purification by flash column chromatography using 7:3 
 ethyl acetate / hexanes and trituration in boiling diisopropyl ether 
 gave the pure product 4x ( 1.94 g , 76% yield ) as a white 
 solid .
h nmr ( dmso - d6 ) :  7.97 ( t , j = 5.4 hz , 1h ) , 
 7.52 ( dt , j = 8.8 , 2.2 hz , 4h ) , 7.35 ( dt , j = 8.8 , 2.3 hz , 4h ) , 7.26 ( t , j = 7.6 
 hz , 2h ) , 7.17 ( d , j = 7.6 hz , 2h ) , 7.157.18 
 ( m , 1h ) , 5.42 ( s , 1h ) , 2.993.04 ( m , 4h ) , 2.55 ( t , j = 7.8 hz , 2h ) , 1.621.70 ( m , 2h ) .
c nmr ( dmso - d6 ) :  168.9 , 142.5 , 
 141.1 , 132.5 , 131.1 , 129.2 , 126.7 , 121.4 , 52.6 , 52.5 , 39.3 , 35.9 , 
 33.4 , 31.6 .
( c24h23br2nos ) 
 c , h , n. compound 4y was synthesized 
 from 2-(benzhydrylthio)acetic acid and 4-phenyl-1-butylamine according 
 to the modified general procedure c. the product 4y ( 0.73 
 g , 96% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.357.38 ( m , 4h ) , 7.287.32 ( m , 
 6h ) , 7.167.26 ( m , 5h ) , 6.61 ( br s , 1h ) , 5.08 ( s , 1h ) , 3.22 
 ( q , j = 6.7 hz , 2h ) , 3.10 ( s , 2h ) , 2.64 ( t , j = 7.4 hz , 2h ) , 1.611.69 ( m , 2h ) , 1.481.55 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.2 , 142.1 , 
 140.4 , 128.9 , 128.52 , 128.50 , 128.3 , 127.7 , 126.0 , 55.2 , 39.7 , 36.2 , 
 35.6 , 29.2 , 28.8 .
( c25h27nos ) c , h , n. compound 4z was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and 4-phenyl-1-butylamine 
 according to the modified general procedure c. purification by flash 
 column chromatography using 1:1 ethyl acetate / hexanes gave the pure 
 product 4z ( 1.2 g , 90% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.43 ( dt , j = 
 8.0 , 2.3 hz , 4h ) , 7.28 ( t , j = 7.4 hz , 2h ) , 7.20 
 ( d , j = 8.4 hz , 4h ) , 7.157.19 ( m , 3h ) , 6.39 
 ( br s , 1h ) , 5.04 ( s , 1h ) , 3.23 ( q , j = 6.7 hz , 2h ) , 
 3.05 ( s , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 1.611.69 
 ( m , 2h ) , 1.481.55 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 142.0 , 139.0 , 132.1 , 130.0 , 128.54 , 128.52 , 126.1 , 
 121.9 , 53.6 , 39.8 , 36.0 , 35.6 , 29.2 , 28.8 .
( c25h25br2nos ) c , h , n. compound 5a was synthesized following 
 a literature procedure .
briefly , h2o2 ( 0.11 ml , 1.1 mmol , 1 equiv ) was added to a 
 solution of compound 4b ( 310 mg , 1.1 mmol , 1 equiv ) in 
 a solvent mixture of acetic acid ( 1.1 ml ) and meoh ( 3.3 ml ) .
the solvent was removed 
 in vacuo , and the isolated crude residue was purified by flash column 
 chromatography using a gradient solvent system , viz .
, 1:1 ethyl acetate / ch2cl2 to 5% meoh / ch2cl2 . the 
 pure product 5a ( 310 mg , 72% ) was obtained as a white 
 solid .
h nmr ( cdcl3 ) :  7.36 ( d , j = 8.2 hz , 2h ) , 7.30 , ( d , j = 8.2 hz , 2h ) , 7.20 ( sd , j = 3.7 hz , 
 4h ) , 7.12 ( br s , 1h ) , 5.72 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.46 ( d , j = 14.8 hz , 1h ) , 3.10 ( d , j = 14.4 hz , 
 1h ) , 2.34 ( s , 6h ) .
c nmr ( cdcl3 ) :  
 166.4 , 138.8 , 138.5 , 131.3 , 131.2 , 130.1 , 129.6 , 129.2 , 128.6 , 71.2 , 
 51.2 , 21.1 .
( c17h19no2s/2h2o ) c , h , n. compound 5b was synthesized 
 as described for 5a using compound 4c ( 680 
 mg , 1.73 mmol ) to give the product 5b ( 510 mg , 72% ) as 
 a white solid .
h nmr ( cdcl3 ) :  7.70 ( dd , j = 8.0 , 6.0 hz , 4h ) , 
 7.60 ( dd , j = 8.6 , 2.6 hz , 4h ) , 6.70 ( br s , 1h ) , 
 5.71 ( br s , 1h ) , 5.40 ( s , 1h ) , 3.56 ( d , j = 14.0 
 hz , 1h ) , 3.12 ( d , j = 14.2 hz , 1h ) .
c nmr ( cdcl3 ) :  165.3 , 137.8 , 137.0 , 131.4 ( jcf = 33.2 hz ) , 131.2 ( jcf = 33.2 hz ) , 129.9 , 129.3 , 126.6 ( jcf = 3.7 hz ) , 126.0 ( jcf = 3.7 hz ) , 123.8 ( jcf = 272 hz ) , 123.6 ( jcf = 273 hz ) , 69.6 , 51.8 .
( c17h13f6no2s/2h2o ) c , h , n. compound 5c was synthesized 
 as described 
 for 5a using compound 4d ( 810 mg , 2.76 mmol ) 
 to give the product 5c ( 600 mg , 70% ) as a white solid . 

h nmr ( cdcl3 ) : 
  7.347.42 ( m , 2h ) , 7.147.27 ( m , 4h ) , 7.047.10 
 ( m , 2h ) , 6.98 ( br s , 1h ) , 6.18 ( br s , 1h ) , 5.33 ( s , 1h ) , 3.49 ( d , j = 13.6 hz , 1h ) , 3.23 ( d , j = 14.0 hz , 
 1h ) .
c nmr ( cdcl3 ) :  166.0 , 163.0 ( jcf = 248 hz ) , 162.8 ( jcf = 248 hz ) , 136.5 , 135.8 , 131.2 ( jcf = 8.1 hz ) , 130.5 ( jcf = 8.1 hz ) , 125.3 , 124.5 ( jcf = 3.0 hz ) , 116.5 ( jcf = 22.8 hz ) , 115.9 ( jcf = 22.1 hz ) , 69.7 , 52.2 .
( c15h13f2no2s ) c , h , n. compound 5d was synthesized 
 as described 
 for 5a using compound 4e ( 800 mg , 2.45 mmol ) 
 to give the product 5d ( 600 mg , 71% ) as a white solid . 

h nmr ( cdcl3 ) : 
  7.437.43 ( m , 2h ) , 7.317.37 ( m , 6h ) , 7.05 ( br 
 s , 1h ) , 6.36 ( br s , 1h ) , 5.36 ( s , 1h ) , 3.47 ( d , j = 13.6 hz , 1h ) , 3.27 ( d , j = 13.6 hz , 1h ) .
c nmr ( cdcl3 ) :  166.3 , 136.3 , 135.6 , 135.4 , 
 134.8 , 130.8 , 130.2 , 129.6 , 129.2 , 129.0 , 128.8 , 127.7 , 126.9 , 69.4 , 
 52.9 .
( c15h13cl2no2s ) c , h , n. compound 5e was synthesized 
 as described 
 for 5a using compound 4f ( 750 mg , 2.23 mmol ) 
 to give the product 5e ( 540 mg , 69% ) as a white solid . 

h nmr ( dmso - d6 ) :  7.657.69 ( m , 2h ) , 7.487.57 
 ( m , 4h ) , 7.307.43 ( m , 5h ) , 5.36 ( s , 1h ) , 3.39 ( d , j = 13.6 hz , 1h ) , 3.20 ( d , j = 13.6 hz , 
 1h ) .
c nmr ( dmso - d6 ) :  
 166.2 , 137.4 , 136.7 , 132.2 , 130.8 , 130.6 , 129.7 , 129.1 , 128.7 , 128.6 , 
 128.4 , 128.1 , 121.6 , 67.5 , 56.4 .
( c15h14brno2s ) c , h , n. compound 5f was synthesized as described 
 for 5a using compound 4 g ( 500 mg , 1.84 mmol ) 
 to give the product 5f ( 427 mg , 81% ) as a yellow oil .
h nmr ( cdcl3 ) :  7.357.49 ( m , 10h ) , 
 7.02 ( br s , 1h ) , 5.18 ( s , 1h ) , 3.44 ( d , j = 14.0 
 hz , 1h ) , 3.13 ( d , j = 14.0 hz , 1h ) , 2.82 ( sd , j = 4.7 hz , 3h ) .
c nmr ( cdcl3 ) :  164.9 , 
 134.9 , 134.2 , 129.7 , 129.6 , 129.13 , 129.08 , 129.01 , 128.9 , 71.7 , 52.3 , 
 26.7 .
( c16h17no2s/4h2o ) c , h , n. compound 5 g was synthesized 
 as described for 5a using compound 4x ( 220 
 mg , 0.41 mmol ) to give the product 5 g ( 100 mg , 44% ) as 
 a colorless oil .
h nmr ( cdcl3 ) :  7.517.55 
 ( m , 4h ) , 7.167.31 ( m , 9h ) , 6.69 ( t , j = 5.4 
 hz , 1h ) , 5.13 ( s , 1h ) , 3.42 ( d , j = 14.0 hz , 1h ) , 
 3.33 ( q , j = 7.0 hz , 2h ) , 3.05 ( d , j = 14.0 hz , 1h ) , 2.67 ( t , j = 7.8 hz , 2h ) , 1.851.89 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  163.7 , 141.3 , 133.4 , 
 132.9 , 132.5 , 132.3 , 131.3 , 130.7 , 128.7 , 128.6 , 126.3 , 123.53 , 123.47 , 
 69.7 , 52.4 , 39.7 , 33.4 , 31.2 .
( c24h23br2no2s/2h2o ) c , h , n. compounds 6a6c were synthesized following a literature procedure .
a solution of cysteamine hydrochloride ( 10 mmol ) , diphenylmethanol , 3a , or the appropriate halogen - substituted diphenylmethanol , 3c or 3d ( 10 mmol ) , and bf3oet2 ( 11 mmol ) in glacial acetic acid ( 40 ml ) was stirred at 9095 
 c for 20 min ( 4050 min for substituted analogues ) .
the 
 reaction mixture was cooled to room temperature , and diethyl ether 
 ( 200 ml ) was added to precipitate a solid ( the hydrochloride salt ) 
 from the mixture .
the solid was filtered and dried under vacuum for 
 3 days in the presence of naoh pellets .
the dried solid was dissolved 
 in hot ethanol and filtered and the solvent removed in vacuo .
finally , 
 the solid was triturated in hot ( boiling ) ethyl acetate to give the 
 pure product as the hydrochloride salt .
compound 6a was synthesized 
 from diphenylmethanol , 3a , 
 according to general procedure d to give the hydrochloride salt in 
 quantitative yield .
the hydrochloride salt of 6a ( 10.1 
 g , 36.1 mmol ) was converted to the free base by being dissolved in 
 saturated aqueous nahco3 solution ( 120 ml ) and extracted 
 into chcl3 ( 150 ml ) . the layers were separated , and the 
 organic layer was washed with distilled water ( 80 ml ) and aqueous 
 brine solution ( 100 ml ) and dried over mgso4 .
the solvent 
 was evaporated in vacuo to give the free base 6a ( 7.90 
 g , 90% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.43 ( d , j = 8.0 hz , 4h ) , 7.31 ( t , j = 7.4 hz , 4h ) , 7.22 ( tt , j = 7.4 , 1.5 hz , 2h ) , 5.16 ( s , 1h ) , 2.81 ( t , j = 6.2 hz , 
 2h ) , 2.51 ( t , j = 6.4 hz , 2h ) .
c nmr ( cdcl3 ) :  141.5 , 128.7 , 128.4 , 127.4 , 54.0 , 41.0 , 36.7 .
( c15h17ns/4c2h2o4 ) c , h , n. compound 6b was synthesized 
 from bis(4-chlorophenyl)methanol , 3c , according to general 
 procedure d with a reaction time 
 of 50 min . the hydrochloride salt product 6b ( 1.06 g , 
 62% yield )
h nmr ( hcl salt , dmso - d6 ) :  8.12 ( br s , 3h ) , 7.48 ( d , j = 
 8.4 hz , 4h ) , 7.42 ( d , j = 8.8 hz , 4h ) , 5.56 ( s , 1h ) , 
 2.94 ( t , j = 7.6 hz , 2h ) , 2.60 ( t , j = 7.2 hz , 2h ) .
c nmr ( hcl salt , dmso - d6 ) :  139.9 , 132.0 , 129.9 , 128.7 , 50.2 , 38.0 , 28.6 . 
 anal .
( c15h15cl2ns/4hcl/4h2o ) c , 
 h , n. compound 6c was synthesized from bis(4-bromophenyl)methanol , 3d , according to general procedure d with a reaction time 
 of 40 min . the hydrochloride salt product 6c ( 4.15 g , 
 72% yield )
h nmr ( hcl salt , dmso - d6 ) :  8.09 ( br s , 3h ) , 7.55 ( dt , j = 
 8.4 , 2.3 hz , 4h ) , 7.41 ( dt , j = 8.8 , 2.2 hz , 4h ) , 
 5.53 ( s , 1h ) , 2.94 ( t , j = 7.4 hz , 2h ) , 2.59 ( t , j = 7.4 hz , 2h ) .
c nmr ( hcl salt , dmso - d6 ) :  140.2 , 131.6 , 130.2 , 120.5 , 50.2 , 
 37.9 , 28.5 .
( c15h15br2nshcl ) 
 c , h , n. compound 6d was synthesized 
 according to general procedure d starting with compound 6a .
a suspension of the hydrochloride 
 salt of 6a ( 1.0 g , 3.6 mmol ) and cyclopropanecarboxaldehyde 
 ( 0.28 g , 4.0 mmol ) in 1,2-dichloroethane ( 62 ml ) was stirred at room 
 temperature under an argon atmosphere for 1.3 h. sodium cyanoborohydride 
 ( 0.69 g , 11 mmol ) dissolved in methanol ( 2.0 ml ) was added to the 
 reaction mixture , and the mixture was stirred at room temperature 
 under an argon atmosphere overnight .
after 19 h of reaction time , 
 saturated nahco3 solution ( 30 ml ) , distilled water ( 30 
 ml ) , and ch2cl2 ( 15 ml ) were added to the reaction 
 mixture , and the resulting mixure was stirred vigorously for 1 h. 
 the layers were separated , and the aqueous layer was washed with ch2cl2 ( 3  25 ml ) .
the combined ch2cl2 extract was washed with water ( 50 ml ) , dried over 
 mgso4 , and concentrated in vacuo to give a crude product . 

the isolated crude was purified by flash column chromatography using 
 an ethyl acetate / hexanes solvent gradient ( from 4:1 to 1:4 ) to give 
 the free base 6d ( 0.50 g , 47% yield ) as a yellow oil . 

some of the isolated free base was converted into the hydrochloride 
 salt in chcl3 using a 1.0 m hcl in ether solution .
h nmr ( cdcl3 ) :  
 7.42 ( d , j = 7.4 hz , 4h ) , 7.30 ( t , j = 7.4 hz , 4h ) , 7.22 ( tt , j = 7.2 , 1.6 hz , 2h ) , 
 5.17 ( s , 1h ) , 2.76 ( t , j = 6.4 hz , 2h ) , 2.59 ( t , j = 6.6 hz , 2h ) , 2.40 ( d , j = 6.8 hz , 2h ) , 
 0.810.97 ( m , 1h ) , 0.440.48 ( m , 2h ) , 0.09 ( qd , j = 4.8 , 1.2 hz , 2h ) .
c nmr ( cdcl3 ) :  141.6 , 128.7 , 128.4 , 127.3 , 54.7 , 54.3 , 48.1 , 32.9 , 11.4 , 
 3.5 .
( c19h23nshcl/4h2o ) c , h , n. compound 6e was synthesized 
 by adapting 
 a literature procedure using compound 6a ( general procedure d ) . a mixture of csohh2o ( 0.29 g , 1.7 mmol ) and activated 4  molecular sieves ( 0.52 
 g ) in anhydrous dmf ( 8.3 ml , freshly distilled and stored over activated 
 4  molecular sieves ) was purged of air under vacuum and flushed 
 with argon gas . after the mixture was stirred for 13 min , the free 
 base of compound 6a ( 0.41 g , 1.7 mmol ) , dissolved in 
 anhydrous dmf ( 4.0 ml ) , was added .
the reaction mixture was stirred 
 under vacuum for 25 min and flushed with argon for 5 min , and n - butyl bromide ( 0.28 g , 2.04 mmol ) was added .
this was 
 followed by another 10 min of vacuum purging , and the reaction was 
 left to stir overnight at room temperature .
the reaction mixture was 
 filtered after 20 h of reaction time , and the undissolved solids were 
 washed with ethyl acetate .
the filtrate was evaporated in vacuo to 
 give a liquid residue , which was taken up in aqueous 1 m naoh ( 30 
 ml ) and extracted with ethyl acetate ( 2  25 ml ) .
the organic 
 extract was washed with brine ( 50 ml ) , dried over a 1:1 na2so4/mgso4 mixture , and concentrated in vacuo . 

the crude product was purified by flash column chromatography using 
 5% diethyl ether / hexanes ( with 0.5% net3 ) to give the free 
 base 6e ( 0.22 g , 44% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.42 ( d , j = 7.2 hz , 4h ) , 7.30 ( t , j = 7.6 hz , 4h ) , 
 7.22 ( tt , j = 7.2 , 1.6 hz , 2h ) , 5.17 ( s , 1h ) , 2.74 
 ( t , j = 6.4 hz , 2h ) , 2.58 ( t , j = 
 6.2 hz , 2h ) , 2.53 ( t , j = 7.2 hz , 2h ) , 1.401.47 
 ( m , 2h ) , 1.271.37 ( m , 2h ) , 0.90 ( t , j = 7.6 
 hz , 3h ) .
c nmr ( cdcl3 ) :  141.6 , 128.7 , 
 128.4 , 127.3 , 54.2 , 49.3 , 48.3 , 32.8 , 32.3 , 20.6 , 14.1 .
( c19h25nsc2h2o4 ) c , h , n. compound 6f was synthesized 
 from compound 4u .
briefly , 
 sulfuric acid ( 98% ; 305 mg , 3.11 mmol ) in thf ( 8.0 ml ) was added dropwise 
 at 0 c to lialh4 ( 227 mg , 5.99 mmol ) in thf ( 13 ml ) , 
 and the mixture was stirred for 15 min at room temperature .
compound 4u ( 563 mg , 1.50 mmol ) in thf ( 11 ml ) was added dropwise to 
 the reduction mixture at room temperature and the resulting mixture 
 stirred overnight .
the reaction mixture was cooled to 0 c and 
 quenched with water ( 5.0 ml ) and 10% naoh ( 20 ml ) successively .
the 
 mixture was filtered , the insolubles were washed with thf , and the 
 filtrate was evaporated to dryness .
the crude product was purified 
 on a teledyne isco combiflash rf instrument using 97:3:0.03 
 chcl3/meoh / nh4oh to give the pure product 6f ( 312 mg , 58% ) as a yellow oil .
h nmr 
 ( cdcl3 ) :  7.42 ( d , j = 7.6 hz , 
 4h ) , 7.277.32 ( m , 6h ) , 7.167.23 ( m , 5h ) , 5.16 ( s , 
 1h ) , 2.73 ( t , j = 6.4 hz , 2h ) , 2.63 ( t , j = 7.8 hz , 2h ) , 2.542.58 ( m , 4h ) , 1.741.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  142.2 , 141.6 , 128.7 , 128.53 , 
 128.47 , 128.4 , 127.4 , 125.9 , 54.2 , 49.1 , 48.3 , 33.7 , 32.8 , 31.8 .
( c24h27ns  c2h2o4 ) c , h , n. compound 6 g was synthesized 
 as described for compound 6f using compound 4v , except that the reaction mixture was stirred at room temperature 
 for 2 h ( instead of overnight ) before being quenched with water and 
 naoh ( 15% instead of 10%).the crude product was purified by flash 
 column chromatography ( 95:5:0.5 chcl3/meoh / nh4oh ) to give the pure product 6 g ( 820 mg , 86.6% ) as a 
 yellow oil .
the free base was converted to the oxalate salt , which 
 was recrystallized from a methanol / acetone mixture .
h nmr ( cdcl3 ) :  7.337.37 
 ( m , 4h ) , 7.167.30 ( m , 5h ) , 6.977.02 ( m , 4h ) , 5.13 
 ( s , 1h ) , 2.72 ( t , j = 6.4 hz , 2h ) , 2.64 ( t , j = 7.8 hz , 2h ) , 2.52 ( m , 4h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  161.9 ( jcf = 246 hz ) , 142.0 , 137.0 ( jcf = 3.0 hz ) , 129.7 ( jcf = 8.1 hz ) , 128.4 , 125.8 , 115.5 ( jcf = 21.4 hz , 4c ) , 52.5 , 48.8 , 48.0 , 33.6 , 32.6 , 
 31.6 .
( c24h25f2nsc2h2o4 ) c , h , n. compound 6h was synthesized 
 as described for 6 g using compound 4w ( 1 
 g , 2.2 mmol ) .
the crude product 6h ( 850 mg ) was obtained 
 as a yellow oil and carried to the next step without further purification .
a solution of 1 m bh3thf complex 
 ( 14 ml , 14.0 mmol ) was added slowly ( in two aliquots ) to a solution 
 of compound 4x ( 1.50 g , 2.81 mmol ) in freshly distilled 
 thf ( 15 ml ) at 2 c .
the reaction mixture was refluxed for 16 
 h , cooled to 0 c , quenched with ch3oh ( 30 ml ) , saturated 
 with aqueous hcl ( 5.0 ml of concentrated hcl ( 37% ) ) , and refluxed 
 for another 23 h , successively .
the solvent was removed in vacuo to 
 give a yellow , oily residue which was taken up in chcl3 ( 50 ml ) and washed with distilled water ( 2  50 ml ) .
the combined 
 aqueous extract was back - washed with chcl3 ( 3  30 
 ml ) and then discarded .
the combined chcl3 extract was 
 washed with water ( 100 ml ) and brine ( 100 ml ) and concentrated in 
 vacuo to give the hydrochloride salt of 6i .
the salt 
 was suspended in a small amount of water and the suspension made basic 
 to a ph of 13 with 10 m naoh ( 20 ml ) .
the basic solution was continuously 
 extracted with chcl3 for 6 h , and the layers were separated . 

solvent was removed from the organic layer to give the crude free 
 base of compound 6i , which was purified by flash column 
 chromatography ( 5% meoh / ch2cl2 ) .
the pure product 6i ( 0.58 g , 40% yield ) was obtained as a yellow oil and converted 
 to the oxalate salt .
h nmr 
 ( cdcl3 ) :  7.43 ( dt , j = 8.4 , 2.3 
 hz , 4h ) , 7.237.30 ( m , 6h ) , 7.167.20 ( m , 3h ) , 5.07 
 ( s , 1h ) , 2.74 ( t , j = 6.6 hz , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 2.532.29 ( m , 4h ) , 1.771.83 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  142.1 , 140.1 , 
 131.9 , 131.6 , 130.0 , 128.5 , 126.0 , 121.5 , 53.0 , 49.0 , 48.3 , 33.7 , 
 32.7 , 31.7 .
( c24h25br2nosc2h2o4 ) c , h , n. compound 7a was synthesized 
 with slight modifications 
 to a published procedure .
briefly , a 
 solution of sodium periodate ( naio4 ; 2.25 g , 10.5 mmol ) 
 in water ( 50 ml ) was added in a dropwise manner to a solution of the 
 hydrochloride salt of compound 6a ( 2.80 g , 10.0 mmol ) 
 in ethanol ( 150 ml ) at 0 c .
the reaction was allowed to stir 
 and warm to room temperature for 20 h under an argon atmosphere . 

the reaction mixture , which contained a white precipitate , was cooled 
 in an ice bath and filtered .
the filtrate was concentrated in vacuo 
 to give a dark yellow , oily residue .
the oily residue ( the hydrochloride 
 salt ) was dissolved in chcl3 , washed with an aqueous nahco3 solution ( 2:3 dilution in water of saturated nahco3 solution ) , distilled water , and aqueous brine , and dried over na2so4 , successively .
after filtration , solvent was 
 removed in vacuo to give the crude , free base of compound 7a .
the crude product was purified by flash column chromatography using 
 a meoh / chcl3 ( with 0.1% nh4oh ) gradient ( from 
 0% to 1% meoh ) to give pure 7a ( 1.12 g , 43% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.50 ( d , j = 7.8 hz , 2h ) , 7.317.44 
 ( m , 8h ) , 4.90 ( s , 1h ) , 3.103.23 ( m , 2h ) , 2.532.65 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  135.8 , 135.2 , 
 129.4 , 128.9 , 128.7 , 128.5 , 128.4 , 73.1 , 54.4 , 36.5 .
( c15h17nosc2h2o4 ) c , h , n. compound 7b was synthesized 
 as described for 7a from compound 6e ( 0.070 
 g , 0.23 mmol ) and naio4 ( 0.053 g , 0.25 mmol ) in an ethanol / water 
 ( etoh / h2o ) mixture ( 4.0 ml/1.2 ml , v / v ) .
the pure free 
 base product 7b ( 0.020 g , 41% yield ) was obtained as 
 a yellow oil after purification of the crude by flash column chromatography 
 using a meoh / chcl3 ( with 0.1% nh4oh ) gradient 
 ( from 0% to 2% meoh ) .
h nmr ( cdcl3 ) :  7.49 ( d , j = 7.6 hz , 2h ) , 7.307.44 
 ( m , 8h ) , 4.92 ( s , 1h ) , 2.993.13 ( m , 2h ) , 2.65 ( t , j = 5.8 hz , 2h ) , 2.56 ( t , j = 7.0 hz , 2h ) , 
 1.401.47 ( m , 2h ) , 1.271.36 ( m , 2h ) , 0.89 ( t , j = 7.4 hz , 3h ) .
c nmr ( cdcl3 ) : 
  135.9 , 135.2 , 129.44 , 129.42 , 128.9 , 128.8 , 128.49 , 128.44 , 
 73.0 , 51.1 , 49.6 , 43.6 , 32.1 , 20.5 , 14.1 .
( c19h25nosc2h2o4/2h2o ) c , h , n. compound 7c was synthesized 
 as described for compound 5a using 6 g ( 900 
 mg , 2.27 mmol ) . the free base product 7c ( 820 mg , 87.5% 
 yield )
was obtained as a yellow oil and converted into the oxalate 
 salt , which was recrystallized from a methanol / acetone mixture .
h nmr ( cdcl3 ) : 
  7.377.44 ( m , 4h ) , 7.057.29 ( m , 9h ) , 5.00 ( s , 
 1h ) , 3.163.22 ( m , 1h ) , 3.043.11 ( m , 1h ) , 2.602.83 
 ( m , 6h ) , 1.801.88 ( m , 2h ) .
c nmr ( cdcl3 ) :  162.8 ( jcf = 248 
 hz ) , 162.6 ( jcf = 249 hz ) , 
 141.1 , 131.0 ( jcf = 8.1 hz ) , 
 130.3 ( jcf = 8.1 hz ) , 130.1 
 ( jcf = 3.7 hz ) , 128.4 , 128.3 , 
 126.0 , 116.4 ( jcf = 21.4 hz ) , 
 115.8 ( jcf = 21.4 hz ) , 70.6 , 
 48.7 , 48.4 , 43.1 , 33.1 , 30.1 .
( c24h25f2nosc2h2o4 ) c , h , n. compound 7d was synthesized 
 as described for compound 5a using 6h ( 850 
 mg , 1.97 mmol ) . the free base product 7d ( 640 mg
, two 
 steps yield 72.6% ) was obtained as a yellow oil and converted into 
 the oxalate salt , which was recrystallized from hot meoh .
h nmr ( cdcl3 ) :  7.157.39 
 ( m , 13h ) , 4.88 ( s , 1h ) , 2.993.08 ( m , 2h ) , 2.572.65 
 ( m , 6h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  
 141.9 , 134.7 , 134.6 , 134.0 , 132.9 , 130.6 , 129.9 , 129.6 , 129.0 , 128.4 , 
 125.9 , 70.6 , 51.2 , 49.1 , 43.1 , 33.5 , 31.4 .
( c24h25cl2nosc2h2o4/2h2o ) c , h , n. compound 7e was synthesized 
 as described for compound 5a using 6i ( 230 
 mg , 0.443 mmol ) .
the free base product 7e ( 130 mg , 55% 
 yield ) was obtained as a yellow oil and converted into the oxalate 
 salt , which was recrystallized from hot meoh .
h nmr ( cdcl3 ) :  7.457.53 
 ( m , 4h ) , 7.157.32 ( m , 7h ) , 4.83 ( s , 1h ) , 2.993.08 
 ( m , 2h ) , 2.572.65 ( m , 6h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  141.9 , 134.5 , 133.3 , 132.5 , 132.3 , 
 132.0 , 131.4 , 130.9 , 130.2 , 128.4 , 125.9 , 122.9 , 122.7 , 70.7 , 51.2 , 
 49.1 , 43.1 , 33.5 , 31.4 .
( c24h25br2nosc2h2o4 ) c , h , n. striata were dissected from male 
 sprague  dawley rat brains ( supplied on ice from bioreclamation 
 ( hicksville , ny ) , prepared by homogenizing tissues in 20 volumes ( w / v ) 
 of ice cold modified sucrose phosphate buffer ( 0.32 m sucrose , 7.74 
 mm na2hpo4 , 2.26 mm nah2po4 , ph adjusted to 7.4 ) using a brinkman polytron ( setting 6 for 20 
 s ) , and centrifuged at 30000 g for 10 min at 4 c . 

the resulting pellet was resuspended in buffer , recentrifuged , and 
 suspended in buffer again to a concentration of 10 mg / ml , original 
 wet weight ( oww ) .
experiments were conducted in assay tubes containing 
 0.5 ml of sucrose phosphate buffer , 0.5 nm [ h]win 35,428 
 ( kd = 5.53 , specific activity 84 ci / mmol ; 
 perkin - elmer life sciences , waltham , ma ) , 1.0 mg of tissue oww , and 
 various concentrations of inhibitor .
the reaction was started with 
 the addition of tissue , and the tubes were incubated for 120 min on 
 ice .
dawley rat brains ( supplied on 
 ice from bioreclamation ) were homogenized in 20 volumes ( w / v ) of 50 
 mm tris buffer ( 120 mm nacl and 5 mm kcl , adjusted to ph 7.4 ) at 25 
 c using a brinkman polytron ( at setting 6 for 20 s ) .
the tissue 
 was centrifuged at 30000 g for 10 min at 4 c . 

the final pellet was resuspended in cold buffer to a concentration 
 of 15 mg / ml oww .
experiments were conducted in assay tubes containing 
 0.5 ml of buffer , 1.4 nm [ h]citalopram ( kd = 1.94 nm , specific activity = 83 ci / mmol ; perkin - elmer 
 life sciences ) , 1.5 mg of brain stem tissue , and various concentrations 
 of inhibitor .
the reaction was started with the addition of the tissue , 
 and the tubes were incubated for 60 min at room temperature .
membranes from frozen frontal cortex 
 dissected from male sprague  dawley rat brains ( supplied on 
 ice from bioreclamation ) were homogenized in 20 volumes ( w / v ) of 50 
 mm tris buffer ( 120 mm nacl and 5 mm kcl , adjusted to ph 7.4 ) at 25 
 c using a brinkman polytron ( at setting 6 for 20 s ) .
the tissue 
 was centrifuged at 30000 g for 10 min at 4 c . 

the final pellet was resuspended in cold buffer to a concentration 
 of 80 mg / ml oww .
experiments were conducted in assay tubes containing 
 0.5 ml of buffer , 0.5 nm [ h]nisoxetine ( kd = 1.0 nm , specific activity 82 ci / mmol ; perkin - elmer 
 life sciences ) , 8 mg of frontal cortex tissue , and various concentrations 
 of inhibitor .
the reaction was started with the addition of the tissue , 
 and the tubes were incubated for 180 min at 04 c .
the solvent 
 used to dissolve the various analogues of modafinil was typically 
 methanol and was present at a final concentration of 5% .
extensive 
 studies previously in this and other laboratories determined that 
 methanol has no effect on binding at the dat and sert
. however , there 
 is an effect of methanol on binding at the net , and therefore , the 
 methanol concentration was controlled in all tubes in that assay . 
 when compounds were not soluble in methanol , we used either ethanol 
 or dmso at final concentrations of no greater than 5% or 6% , respectively . 

previous studies found no effect of either of these solvents at these 
 concentrations on binding at any of the sites .
for all three mat binding 
 assays , incubations were terminated by rapid filtration through whatman 
 gf / b filters , presoaked in 0.3% ( sert ) or 0.05% ( dat , net ) polyethylenimine , 
 using a brandel r48 filtering manifold ( brandel instruments , gaithersburg , 
 md ) .
the filters were washed twice with 5 ml of cold buffer and transferred 
 to scintillation vials .
cytoscint ( mp biomedicals , solon , oh ) ( 3.0 
 ml ) was added , and the vials were counted the next day using a beckman 
 6000 liquid scintillation counter ( beckman coulter instruments , fullerton , 
 ca ) or a tri - carb 2910-b liquid scintillation counter ( perkin - elmer 
 life sciences ) .
the ki values for the 
 modafinil derivatives were obtained using nonlinear least - squares 
 regression ( using graphpad prism software , graphpad software , inc . , 
 san diego , ca ) of the displacement data , giving ic50 values , 
 from which affinities ( ki values ) were 
 calculated using the cheng  prusoff equation .
synthetic cdna encoding the 
 human dat ( syndat ) was subcloned into pcdna3 ( invitrogen , carlsbad , 
 ca ) .
cdna encoding the human sert ( hsert ) was cloned into the pubi1z 
 expression vector .
mutations herein were generated by the quickchange 
 method ( adapted from stratagene , la jolla , ca ) and confirmed by restriction 
 enzyme mapping and dna sequencing .
positive clones were amplified 
 by transformation into xl1 blue competent cells ( stratagene ) , positive 
 colony picked , and grown in lb media overnight at 37 c in an 
 orbital incubator ( infors ) at 200 rpm .
plasmids were harvested using 
 the maxi prep kit provided by qiagen according to the manufacturer s 
 manual .
cos-7 cells were grown 
 in dulbecco s modified eagle s medium 041 01885 supplemented 
 with 10% fetal calf serum , 2 mm l - glutamine , and 0.01 mg / ml 
 gentamicin at 37 c in 10% co2 .
wild - type and mutant 
 constructs were transiently transfected into cos-7 cells with lipo2000 
 ( invitrogen ) according to the manufacturer s manual using cdna : lipo2000 
 ratios of 3:6 and 2:6 for hdat and hsert , respectively .
uptake 
 assays were performed essentially as previously described using [ 2,5,6,7,8-h](dihydroxyphenyl)ethylamine 
 ( [ h]da ; 94.4 ci / mmol , perkin - elmer ) or 5-[1,2-h(n)]hydroxytryptamine ( [ h]-5-ht ; 28 ci / mmol , perkin - elmer ) 
 for hdat- and hsert - expressing cells , respectively .
transiently transfected 
 cos-7 cells were plated in 12-well ( 3  10 cells / well ) 
 or 24-well ( 10 cells / well ) dishes coated with polyornithine 
 to achieve an uptake level of no more than 10% of the total added 
 radioligand .
prior to the experiment , the cells were washed once in 500 l 
 of uptake buffer ( 25 mm hepes , 130 mm nacl , 5.4 mm kcl , 1.2 mm cacl2 , 1.2 mm mgso4 , 1 mm l - ascorbic acid , 
 5 mm d - glucose , and 1 m catechol o - methyltransferase inhibitor ro 41 - 0960 ( sigma ) , ph 7.4 ) at room 
 temperature .
all the tested ligands were solubilized in dmso to obtain 
 a stock concentration of 10 mm . from here the compounds
were further 
 diluted 10-fold in h2o , followed by consecutive dilutions 
 in uptake buffer .
the trace amounts of dmso ( maximum 1% for the highest 
 added concentration ) did not influence the binding affinity ( loland 
 et al . , unpublished experiments ) . the unlabeled ligand ( e.g. ,
modafinil 
 [ ( )-1 ] or analogues ) was added to the cells in 
 10 concentrations from 1 nm to 0.1 mm equally distributed around the 
 expected ic50 value , and uptake was initiated by addition 
 of 10 nm radioligand in a final volume of 500 l .
after 
 3 ( for the hsert ) or 5 ( hdat ) min of incubation , the reaction was 
 stopped by rapid washing with 2  500 l of ice cold uptake 
 buffer , lysed in 250 l ( 300 l for 12-well plates ) of 
 1% sds , and left for 30 min at 37 c with gentle shaking .
all 
 samples were transferred to 24-well counting plates , and 500 l 
 ( or 600 l ) of opti - phase hi safe 3 scintillation fluid ( perkin - elmer ) 
 was added followed by counting of the plates in a wallac tri - lux -scintillation 
 counter ( perkin - elmer ) .
nonspecific uptake was determined in the presence 
 of 5 m paroxetine for hsert - expressing cells and 50 m 
 nomifensine for hdat - expressing cells .
uptake data were analyzed by nonlinear regression analysis 
 using prism 5.0 from graphpad software .
the ic50 values 
 used in the estimation of km for uptake 
 were calculated from the means of pic50 values and the 
 se intervals from the pic50  se .
the ki values were calculated from the ic50 values 
 using the equation ki = ic50/(1 + ( l / km ) ) ( l = concentration of [ h]da or [ h]-5-ht ) .
we docked the modafinil derivative 
 compound 4h in our leut - based sert model .
the preparation 
 and md equilibration of the homology model of sert were previously 
 described .
the compound was constructed 
 and prepared for docking using ligprep ( schrodinger inc . ,
docking of the compound was carried out with glide ( schrodinger 
 inc . ) .
the binding modes shown in figure 2 were 
 chosen on the basis of both the docking scores and the consistency 
 with the ( )-1 pose in the previously modeled dat()-1 complexes .
a solution of 2-mercapto - n - methylacetamide ( 10 mmol ) and diphenylmethanol , 3a , 
 or the appropriate substituted diphenylmethanol , 3c or 3d ( 10 mmol ) , in trifluoroacetic acid ( tfa ; 200 mmol ) was 
 stirred at room temperature ( 60 c for substituted analogues ) 
 for 20 h. the solvent was removed in vacuo , and the thick oily residue 
 was washed with water ( 30 ml ) .
after the water was decanted , a crude 
 solid product was isolated by addition of diisopropyl ether ( 20 ml ) 
 to the oily residue and vigourous mixing .
the crude solid was filtered 
 and purified by flash column chromatography using 5% meoh / ch2cl2 to give the pure , desired product .
step 1 : thioglycolic acid ( 1 mmol ) was reacted with the appropriate 
 substituted diphenylmethanol , 3e3i ( 1 mmol ) , in tfa ( 14 mmol ) overnight at room temperature .
after 
 solvent removal in vacuo , the residue obtained was washed with water 
 ( 5 ml ) and hexanes ( 15 ml ) to give the carboxylic acid product , which 
 was carried to the next step without further purification .
step 2 : 
 the acid product ( 3 mmol ) from step 1 was reacted with k2co3 ( 4.5 mmol ) and iodomethane ( ch3i ; 4.5 mmol ) 
 in acetone ( 50 ml ) overnight under reflux conditions .
after solvent 
 removal in vacuo , the residue was suspended in water ( 20 ml ) and extracted 
 with ch2cl2 ( 3  20 ml ) .
the combined organic 
 layer was dried over mgso4 and concentrated to give the 
 methyl ester , which was carried to the next step without further purification . 

step 3 : a mixture of the ester ( 3 mmol ) , nh4cl ( 4.2 mmol ) , 
 concentrated nh4oh ( 28.030.0% , 20 ml ) , and meoh 
 ( 5.7 ml ) was stirred at 50 c for 72 h. meoh was removed in vacuo , 
 and the reaction mixture was diluted with water ( 50 ml ) , extracted 
 with ethyl acetate ( 3  50 ml ) , and dried over na2so4 .
the solvent was evaporated , and the recovered crude 
 product was purified by flash column chromatography using 1:1 ethyl 
 acetate / hexanes to afford the pure product .
thioacetamides 4l , 4p , 4s , 4v , and 4w were synthesized 
 in two steps according to a published procedure , while compounds 4j , 4k , 4m4o , 4q , 4r , 4 t , 4u , and 4x4z were synthesized in two steps with slight modifications 
 to the published procedure in the second step .
step 1 is the same 
 as step 1 for procedure b. step 2 : cdi ( 11 mmol ) was added to a solution 
 of the carboxylic acid product ( 10 mmol ) from step 1 in anhydrous 
 thf ( 25 ml ) .
the reaction mixture was stirred at room temperature 
 for 2 h and then cooled to 0 c .
water ( 0.10.2 ml ) was 
 added to the reaction mixture ( to quench excess cdi ) , followed by 
 the dropwise addition of the appropriate amine ( 10 mmol , dissolved 
 in thf ) .
the solvent was removed under vacuum to give a 
 crude residue , which was dissolved in diethyl ether or ethyl acetate . 

the organic solution was washed with aqueous 1.0 m hcl solution ( 55 
 ml ) , water ( 80 ml ) , dilute aqueous nahco3 solution ( 36 
 ml , 1:6 dilution of saturated nahco3 solution ) , and water 
 ( 2  30 ml ) .
the organic layer was dried over mgso4 and concentrated in vacuo to give the pure product .
the bromo - substituted 
 analogues 4q , 4 t , 4x , and 4z required further purification by flash column chromatography 
 as indicated .
compound 4a was synthesized by stirring a 
 solution of 2-mercaptoacetamide 
 ( 0.63 g , 6.9 mmol ; recovered from the 10% ( w / v ) methanol / nh3 solution ) and diphenylmethanol , 3a ( 1.3 g , 7.1 mmol ) , 
 in tfa ( 11.9 g , 104 mmol ) at room temperature for 4 h. the solvent 
 was removed in vacuo , and the brown oily residue was dissolved in 
 chcl3 ( 30 ml ) and washed with water ( 30 ml ) , followed by 
 a dilute nahco3 solution ( 30 ml , 1:3 dilution of saturated 
 nahco3 solution ) and water ( 30 ml ) .
the crude product 
 was purified by flash chromatography using 1:1 ethyl acetate / hexanes 
 to give pure 4a ( 0.31 g , 17% yield ) as a white solid . 

h nmr ( cdcl3 ) :  7.41 ( d , j = 7.6 hz , 4h ) , 7.33 ( t , j = 7.4 hz , 4h ) , 
 7.25 ( tt , j = 7.2 , 1.4 hz , 2h ) , 6.50 ( br s , 1h ) , 
 5.57 ( br s , 1h ) , 5.17 ( s , 1h ) , 3.09 ( s , 2h ) .
c nmr ( cdcl3 ) :  171.2 , 140.3 , 128.9 , 128.4 , 127.8 , 54.9 , 35.7 . 

( c15h15nos ) c , h , n. compound 4b was synthesized according 
 to general procedure b to give 4b ( 450 mg , 52% yield ) 
 as a yellow oil .
h nmr ( cdcl3 ) :  7.26 
 7.30 ( m , 4h ) , 7.12 ( d , j = 7.6 hz , 4h ) , 6.54 
 ( br s , 1h ) , 5.53 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.07 ( s , 2h ) , 2.31 ( s , 
 6h ) .
compound 4c was synthesized 
 according 
 to general procedure b to give 4c ( 680 mg , 58% yield ) 
 as a white foam .
h nmr ( cdcl3 ) :  7.61 
 ( d , j = 8.0 hz , 4h ) , 7.53 ( d , j = 
 8.0 hz , 4h ) , 6.29 ( br s , 1h ) , 5.72 ( br s , 1h ) , 5.34 ( s , 1h ) , 3.08 
 ( s , 2h ) .
compound 4d was synthesized 
 according to 
 general procedure b to give 4d ( 810 mg , 61% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.277.33 
 ( m , 2h ) , 7.17 ( d , j = 8.0 hz , 2h ) , 7.12 ( dt , j = 10.0 , 2.0 hz , 2h ) , 6.97 ( td , j = 8.0 , 
 2.4 hz , 2h ) , 6.43 ( br s 1h ) , 6.09 ( br s , 1h ) , 5.19 ( s , 1h ) , 3.09 ( s , 
 2h ) .
compound 4e was synthesized 
 according to 
 general procedure b to give 4e ( 800 mg , 65% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.387.39 
 ( m , 2h ) , 7.257.28 ( m , 6h ) , 6.42 ( br s , 1h ) , 6.05 ( br s , 1h ) , 
 5.15 ( s , 1h ) , 3.09 ( s , 2h ) .
c nmr ( cdcl3 ) : 
  170.9 , 141.6 , 134.8 , 130.1 , 128.3 , 128.1 , 126.5 , 53.4 , 35.4 . 
 anal .
( c15h13cl2nos ) c , h , n. compound 4f was synthesized 
 according to 
 general procedure b to give 4f ( 750 mg , 58% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.577.58 
 ( m , 1h ) , 7.317.39 ( m , 6h ) , 7.257.29 ( m , 1h ) , 7.18 
 ( t , j = 7.8 hz , 1h ) , 6.49 ( br s , 1h ) , 6.32 ( br s , 
 1h ) , 5.16 ( s , 1h ) , 3.07 ( s , 2h ) .
compound 4 g was synthesized using 
 2-mercapto - n - methylacetamide and diphenylmethanol , 3a , according to general procedure a. the product 4 g ( 3.5 g , 59% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) : 
  7.86 ( br s , 1h ) , 7.42 ( d , j = 8.2 hz , 4h ) , 
 7.33 ( t , j = 7.6 hz , 4h ) , 7.23 ( t , j = 7.2 hz , 2h ) , 5.40 ( s , 1h ) , 2.96 ( s , 2h ) , 2.54 ( sd , j = 4.7 hz , 3h ) .
c nmr ( dmso - d6 ) :  169.6 , 142.2 , 129.5 , 128.9 , 128.1 , 54.0 , 35.8 , 26.7 .
( c16h17nos ) c , h , n. compound 4h was synthesized 
 using 2-mercapto - n - methylacetamide and bis(4-chlorophenyl)methanol , 3c , at 60 c according to general procedure a. the product 4h ( 2.12 g , 79% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) :  7.87 ( br s , 1h ) , 7.387.44 ( m , 8h ) , 
 5.45 ( s , 1h ) , 2.99 ( s , 2h ) , 2.53 ( sd , j = 4.7 hz , 
 3h ) .
c nmr ( dmso - d6 ) :  
 169.3 , 140.8 , 132.8 , 130.8 , 129.6 , 52.4 , 35.8 , 26.6 .
( c16h15cl2nos ) c , h , n. compound 4i was synthesized 
 from 2-mercapto - n - methylacetamide and bis(4-bromophenyl)methanol , 3d , at 60 c according to general procedure a. the product 4i ( 1.86 g , 74% yield ) was obtained as a white solid .
h nmr ( dmso - d6 ) :  7.86 ( br s , 1h ) , 7.53 ( dt , j = 8.4 , 2.2 hz , 4h ) , 7.35 ( dt , j = 8.4 , 2.2 hz , 
 4h ) , 5.42 ( s , 1h ) , 2.99 ( s , 2h ) , 2.53 ( sd , j = 4.8 
 hz , 3h ) .
c nmr ( dmso - d6 ) : 
  168.3 , 140.2 , 131.5 , 130.2 , 120.4 , 51.6 , 34.9 , 25.7 . anal . 
 ( c16h15br2nos ) c , h , n. compound 4j was synthesized from 
 2-(benzhydrylthio)acetic acid and allylamine according to the modified 
 general procedure c. the product 4j ( 1.97 g , 86% yield ) 
 was obtained as a viscous yellow oil that solidified over time .
h nmr ( cdcl3 ) :  
 7.40 ( d , j = 7.2 hz , 4h ) , 7.32 ( t , j = 7.4 hz , 4h ) , 7.25 ( t , j = 8.0 hz , 2h ) , 6.67 ( br 
 s , 1h ) , 5.775.86 ( m , 1h ) , 5.19 ( d , jtrans = 17.6 hz , 1h ) , 5.15 ( d , jcis = 10.6 hz , 1h ) , 5.13 ( s , 1h ) , 3.84 
 ( tt , j = 5.6 , 1.6 hz ) , 3.14 ( s , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 140.3 , 133.8 , 128.8 , 128.2 , 
 127.6 , 116.8 , 55.1 , 42.1 , 36.1 .
( c18h19nos ) c , h , n. compound 4k was synthesized 
 from 
 2-(benzhydrylthio)acetic acid and propylamine according to the modified 
 general procedure c. the product 4k ( 1.05 g , 91% yield ) 
 was obtained as a yellow oil that solidified over time .
h nmr ( cdcl3 ) :  7.39 ( d , j = 7.6 hz , 4h ) , 7.32 ( tt , j = 7.2 , 1.6 
 hz , 4h ) , 7.24 ( t , j = 7.2 hz , 2h ) , 6.64 ( br s , 1h ) , 
 5.11 ( s , 1h ) , 3.18 ( q , j = 6.8 hz , 2h ) , 3.11 ( s , 
 2h ) , 1.471.56 ( m , 2h ) , 0.93 ( t , j = 7.4 hz , 
 3h ) .
c nmr ( cdcl3 ) :  168.2 , 140.5 , 
 128.9 , 128.4 , 127.7 , 55.2 , 41.6 , 36.3 , 22.9 , 11.5 .
( c18h21nos ) c , h , n. compound 4l was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and propylamine 
 according to general procedure c. the product 4l ( 320 
 mg , 95% yield ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.327.37 ( m , 4h ) , 
 6.99 7.05 ( m , 4h ) , 6.55 ( br s , 1h ) , 5.14 ( s , 1h ) , 3.20 ( q , j = 6.6 hz , 2h ) , 3.07 ( s , 2h ) , 1.481.58 ( m , 2h ) , 
 0.94 ( t , j = 7.4 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 162.1 ( jcf = 247 hz ) , 136.0 ( jcf = 3.7 hz ) , 129.8 ( jcf = 
 8.1 hz ) , 115.7 ( jcf = 21.4 
 hz ) , 53.2 , 41.5 , 36.0 , 22.8 , 11.4 .
( c18h19f2nos ) c , h , n. compound 4 m was synthesized 
 from 2-((bis(4-chlorophenyl)methyl)thio)acetic acid and propylamine 
 according to the modified general procedure c. the product 4 m ( 2.06 g , 91% yield ) was obtained as a viscous yellow oil that solidified 
 over time .
h nmr ( cdcl3 ) :  7.30 ( s , 8h ) , 6.34 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.20 ( q , j = 6.8 hz , 2h ) , 3.07 ( s , 2h ) , 1.481.57 ( m , 2h ) , 
 0.93 ( t , j = 7.4 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 138.6 , 133.8 , 129.7 , 129.2 , 53.6 , 41.7 , 
 36.1 , 22.9 , 11.5 .
( c18h19cl2nos ) c , h , n. compound 4n was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and propylamine 
 according to the modified general procedure c. the product 4n ( 1.75 g , 80% yield ) was obtained as a light yellow solid .
h nmr ( cdcl3 ) :  7.45 ( d , j = 8.8 hz , 4h ) , 7.24 ( d , j = 8.8 hz , 4h ) , 
 6.41 ( br s , 1h ) , 5.08 ( s , 1h ) , 3.19 ( q , j = 6.8 hz , 
 2h ) , 3.07 ( s , 2h ) , 1.471.56 ( m , 2h ) , 0.93 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) :  168.0 , 
 139.1 , 132.1 , 130.0 , 121.9 , 53.7 , 41.7 , 36.1 , 22.9 , 11.5 .
( c18h19br2nos ) c , h , n. compound 4o was synthesized 
 from 2-(benzhydrylthio)acetic acid and cyclopropylmethylamine according 
 to the modified general procedure c. the product 4o ( 0.25 
 g , 94% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.41 ( d , j = 7.6 hz , 4h ) , 7.33 
 ( tt , j = 7.4 , 1.9 hz , 4h ) , 7.25 ( tt , j = 7.4 , 1.7 hz , 2h ) , 6.73 ( br s , 1h ) , 5.14 ( s , 1h ) , 3.12 ( s , 2h ) , 
 3.09 ( dd , j = 7.2 , 5.6 hz , 2h ) , 0.901.00 
 ( m , 1h ) , 0.53 ( q , j = 6.4 hz , 2h ) , 0.22 ( q , j = 5.2 hz , 2h ) .
c nmr ( cdcl3 ) : 
  168.1 , 140.5 , 128.9 , 128.4 , 127.7 , 55.1 , 44.7 , 36.3 , 10.8 , 
 3.6 .
( c19h21nos ) c , h , n. compound 4p was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and cyclopropylmethylamine 
 according to general procedure c. the product 4p ( 320 
 mg , 92% yield ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.35 ( dd , j = 8.8 , 5.2 hz , 4h ) , 6.997.05 ( m , 4h ) , 6.58 ( br s , 1h ) , 5.16 
 ( s , 1h ) , 3.11 ( dd , j = 7.0 , 5.4 hz , 2h ) , 3.08 ( s , 
 2h ) , 0.911.01 ( m , 1h ) , 0.520.56 ( m , 2h ) , 0.23 ( q , j = 5.0 hz , 2h ) .
c nmr ( cdcl3 ) : 
  167.9 , 162.1 ( jcf = 
 248 hz ) , 136.0 ( jcf = 3.0 
 hz ) , 129.8 ( jcf = 8.1 hz ) , 
 115.7 ( jcf = 21.4 hz ) , 53.3 , 
 44.6 , 36.0 , 10.7 , 3.4 .
( c19h19f2nos ) c , h , n. compound 4q was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and cyclopropylmethylamine 
 according to the modified general procedure c. purification by flash 
 column chromatography using 1:1 ethyl acetate / hexanes gave the pure 
 product 4q ( 1.08 g , 94% yield ) as a white solid .
h nmr ( cdcl3 ) :  
 7.49 ( dt , j = 8.8 , 2.2 hz , 4h ) , 7.25 ( dt , j = 8.4 , 2.4 hz , 4h ) , 6.56 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.09 
 ( dd , j = 7.2 , 5.6 hz , 2h ) , 3.07 ( s , 2h ) , 0.880.97 
 ( m , 1h ) , 0.53 ( q , j = 6.6 hz , 2h ) , 0.21 ( q , j = 5.2 hz , 2h ) .
c nmr ( cdcl3 ) : 
  167.9 , 139.0 , 132.0 , 130.0 , 121.8 , 53.5 , 44.6 , 35.9 , 10.7 , 
 3.5 .
( c19h19br2nos/4c4h8o2 ) c , h , 
 n. compound 4r was synthesized from 
 2-(benzhydrylthio)acetic acid and n - butylamine according 
 to the modified general procedure c. the product 4r ( 264 
 mg , 87% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.39 ( d , j = 7.2 hz , 4h ) , 7.32 
 ( t , j = 7.4 hz , 4h ) , 7.24 ( tt , j = 7.2 , 1.7 hz , 2h ) , 6.64 ( br s , 1h ) , 5.11 ( s , 1h ) , 3.21 ( q , j = 6.7 hz , 2h ) , 3.10 ( s , 2h ) , 1.431.51 ( m , 2h ) , 
 1.301.39 ( m , 2h ) , 0.93 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) :  168.2 , 140.5 , 128.9 , 128.3 , 
 127.7 , 55.1 , 39.6 , 31.7 , 20.2 , 13.9 .
( c19h23nos ) c , h , n. compound 4s was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and n - butylamine according to general procedure c. the product 4s ( 350 mg , 100% ) was obtained as a white solid .
h nmr ( cdcl3 ) :  7.34 ( dd , j = 8.8 , 5.2 hz , 4h ) , 6.997.05 ( m , 4h ) , 6.49 ( br s , 1h ) , 5.13 
 ( s , 1h ) , 3.24 ( q , j = 6.6 hz , 2h ) , 3.07 ( s , 2h ) , 
 1.451.52 ( m , 2h ) , 1.311.40 ( m , 2h ) , 0.94 ( t , j = 7.2 hz , 3h ) .
c nmr ( cdcl3 ) : 
  167.9 , 162.1 ( jcf = 
 247 hz ) , 136.0 ( jcf = 3.7 
 hz ) , 129.8 ( jcf = 8.1 hz ) , 
 115.7 ( jcf = 21.4 hz , 4c ) , 
 53.3 , 39.5 , 36.0 , 31.6 , 20.1 , 13.7 .
( c19h21f2nos ) c , h , n. compound 4 t was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and n - butylamine according to the modified general procedure c. purification 
 by flash column chromatography using 10% meoh / chcl3 gave 
 the pure product 4 t ( 0.50 g , 88% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.45 ( dt , j = 8.4 , 2.0 hz , 4h ) , 7.24 ( dt , j = 8.8 , 2.4 hz , 
 4h ) , 6.40 ( br s , 1h ) , 5.07 ( s , 1h ) , 3.22 ( q , j = 
 6.8 hz , 2h ) , 3.07 ( s , 2h ) , 1.431.51 ( m , 2h ) , 1.301.39 
 ( m , 2h ) , 0.94 ( t , j = 7.2 hz , 3h ) .
c 
 nmr ( cdcl3 ) :  167.9 , 139.1 , 132.1 , 130.0 , 121.9 , 
 53.7 , 39.7 , 36.1 31.7 , 20.2 , 13.9 .
( c19h21br2nos ) c , h , n. compound 4u was synthesized 
 as previously described from 2-(benzhydrylthio)acetic 
 acid and 3-phenyl-1-propylamine according to the modified general 
 procedure c. purification on a teledyne isco combiflash rf instrument using 1:1 ethyl acetate / hexanes gave the pure product 4u ( 1.66 g , 94% yield ) as a white solid .
h nmr ( cdcl3 ) :  7.377.39 
 ( m , 4h ) , 7.287.33 ( m , 6h ) , 7.167.27 ( m , 5h ) , 6.61 
 ( br s , 1h ) , 5.10 ( s , 1h ) , 3.24 ( q , j = 6.8 hz , 2h ) , 
 3.09 ( s , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 1.781.86 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.3 , 141.3 , 
 140.5 , 128.9 , 128.6 , 128.5 , 128.3 , 127.7 , 126.2 , 55.2 , 39.5 , 36.3 , 
 33.4 , 31.2 .
( c24h25nos ) c , h , n. compound 4v was synthesized 
 from 2-((bis(4-fluorophenyl)methyl)thio)acetic acid and 3-phenyl-1-propylamine 
 according to general procedure c. the product 4v ( 1.2 
 g , 100% ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.267.35 ( m , 6h ) , 7.167.22 ( m , 
 3h ) , 6.987.04 ( m , 4h ) , 6.48 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.27 
 ( q , j = 6.8 hz , 2h ) , 3.04 ( s , 2h ) , 2.66 ( t , j = 7.8 hz , 2h ) , 1.811.88 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 162.1 ( jcf = 247 hz ) , 141.1 , 135.9 ( jcf = 2.9 hz ) , 129.8 ( jcf = 8.1 hz ) , 128.4 ( jcf = 21.4 hz ) , 126.1 , 115.8 , 115.6 , 53.3 , 39.4 , 36.0 , 33.2 , 
 31.1 .
( c24h23f2nos ) c , h , n. compound 4w was synthesized 
 as previously described from 2-((bis(4-chlorophenyl)methyl)thio)acetic 
 acid and 3-phenyl-1-propylamine according to general procedure c. 
 the product 4w ( 1 g , 75% ) was obtained as a yellow oil .
h nmr(cdcl3 ) :  7.157.31 ( m , 13h ) , 
 6.38 ( br s , 1h ) , 5.09 ( s , 1h ) , 3.26 ( q , j = 6.6 hz , 
 2h ) , 3.04 ( s , 2h ) , 2.65 ( t , j = 7.6 hz , 2h ) , 1.801.87 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  167.9 , 141.1 , 
 138.4 , 133.6 , 129.5 , 129.0 , 128.5 , 128.3 , 126.1 , 53.4 , 39.4 , 35.9 , 
 33.2 , 31.0 .
( c24h23cl2nos ) 
 c , h , n. compound 4x was synthesized 
 as previously described from 2-((bis(4-bromophenyl)methyl)thio)acetic 
 acid and 3-phenyl-1-propylamine according to the modified general 
 procedure c. purification by flash column chromatography using 7:3 
 ethyl acetate / hexanes and trituration in boiling diisopropyl ether 
 gave the pure product 4x ( 1.94 g , 76% yield ) as a white 
 solid .
h nmr ( dmso - d6 ) :  7.97 ( t , j = 5.4 hz , 1h ) , 
 7.52 ( dt , j = 8.8 , 2.2 hz , 4h ) , 7.35 ( dt , j = 8.8 , 2.3 hz , 4h ) , 7.26 ( t , j = 7.6 
 hz , 2h ) , 7.17 ( d , j = 7.6 hz , 2h ) , 7.157.18 
 ( m , 1h ) , 5.42 ( s , 1h ) , 2.993.04 ( m , 4h ) , 2.55 ( t , j = 7.8 hz , 2h ) , 1.621.70 ( m , 2h ) .
c nmr ( dmso - d6 ) :  168.9 , 142.5 , 
 141.1 , 132.5 , 131.1 , 129.2 , 126.7 , 121.4 , 52.6 , 52.5 , 39.3 , 35.9 , 
 33.4 , 31.6 .
( c24h23br2nos ) 
 c , h , n. compound 4y was synthesized 
 from 2-(benzhydrylthio)acetic acid and 4-phenyl-1-butylamine according 
 to the modified general procedure c. the product 4y ( 0.73 
 g , 96% yield ) was obtained as a yellow oil .
h nmr ( cdcl3 ) :  7.357.38 ( m , 4h ) , 7.287.32 ( m , 
 6h ) , 7.167.26 ( m , 5h ) , 6.61 ( br s , 1h ) , 5.08 ( s , 1h ) , 3.22 
 ( q , j = 6.7 hz , 2h ) , 3.10 ( s , 2h ) , 2.64 ( t , j = 7.4 hz , 2h ) , 1.611.69 ( m , 2h ) , 1.481.55 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.2 , 142.1 , 
 140.4 , 128.9 , 128.52 , 128.50 , 128.3 , 127.7 , 126.0 , 55.2 , 39.7 , 36.2 , 
 35.6 , 29.2 , 28.8 .
( c25h27nos ) c , h , n. compound 4z was synthesized 
 from 2-((bis(4-bromophenyl)methyl)thio)acetic acid and 4-phenyl-1-butylamine 
 according to the modified general procedure c. purification by flash 
 column chromatography using 1:1 ethyl acetate / hexanes gave the pure 
 product 4z ( 1.2 g , 90% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.43 ( dt , j = 
 8.0 , 2.3 hz , 4h ) , 7.28 ( t , j = 7.4 hz , 2h ) , 7.20 
 ( d , j = 8.4 hz , 4h ) , 7.157.19 ( m , 3h ) , 6.39 
 ( br s , 1h ) , 5.04 ( s , 1h ) , 3.23 ( q , j = 6.7 hz , 2h ) , 
 3.05 ( s , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 1.611.69 
 ( m , 2h ) , 1.481.55 ( m , 2h ) .
c nmr ( cdcl3 ) :  168.0 , 142.0 , 139.0 , 132.1 , 130.0 , 128.54 , 128.52 , 126.1 , 
 121.9 , 53.6 , 39.8 , 36.0 , 35.6 , 29.2 , 28.8 .
briefly , h2o2 ( 0.11 ml , 1.1 mmol , 1 equiv ) was added to a 
 solution of compound 4b ( 310 mg , 1.1 mmol , 1 equiv ) in 
 a solvent mixture of acetic acid ( 1.1 ml ) and meoh ( 3.3 ml ) .
the solvent was removed 
 in vacuo , and the isolated crude residue was purified by flash column 
 chromatography using a gradient solvent system , viz .
, 1:1 ethyl acetate / ch2cl2 to 5% meoh / ch2cl2 . the 
 pure product 5a ( 310 mg , 72% ) was obtained as a white 
 solid .
h nmr ( cdcl3 ) :  7.36 ( d , j = 8.2 hz , 2h ) , 7.30 , ( d , j = 8.2 hz , 2h ) , 7.20 ( sd , j = 3.7 hz , 
 4h ) , 7.12 ( br s , 1h ) , 5.72 ( br s , 1h ) , 5.12 ( s , 1h ) , 3.46 ( d , j = 14.8 hz , 1h ) , 3.10 ( d , j = 14.4 hz , 
 1h ) , 2.34 ( s , 6h ) .
c nmr ( cdcl3 ) :  
 166.4 , 138.8 , 138.5 , 131.3 , 131.2 , 130.1 , 129.6 , 129.2 , 128.6 , 71.2 , 
 51.2 , 21.1
( c17h19no2s/2h2o ) c , h , n. compound 5b was synthesized 
 as described for 5a using compound 4c ( 680 
 mg , 1.73 mmol ) to give the product 5b ( 510 mg , 72% ) as 
 a white solid .
h nmr ( cdcl3 ) :  7.70 ( dd , j = 8.0 , 6.0 hz , 4h ) , 
 7.60 ( dd , j = 8.6 , 2.6 hz , 4h ) , 6.70 ( br s , 1h ) , 
 5.71 ( br s , 1h ) , 5.40 ( s , 1h ) , 3.56 ( d , j = 14.0 
 hz , 1h ) , 3.12 ( d , j = 14.2 hz , 1h ) .
c nmr ( cdcl3 ) :  165.3 , 137.8 , 137.0 , 131.4 ( jcf = 33.2 hz ) , 131.2 ( jcf = 33.2 hz ) , 129.9 , 129.3 , 126.6 ( jcf = 3.7 hz ) , 126.0 ( jcf = 3.7 hz ) , 123.8 ( jcf = 272 hz ) , 123.6 ( jcf = 273 hz ) , 69.6 , 51.8 .
( c17h13f6no2s/2h2o ) c , h , n. compound 5c was synthesized 
 as described 
 for 5a using compound 4d ( 810 mg , 2.76 mmol ) 
 to give the product 5c ( 600 mg , 70% ) as a white solid . 

h nmr ( cdcl3 ) : 
  7.347.42 ( m , 2h ) , 7.147.27 ( m , 4h ) , 7.047.10 
 ( m , 2h ) , 6.98 ( br s , 1h ) , 6.18 ( br s , 1h ) , 5.33 ( s , 1h ) , 3.49 ( d , j = 13.6 hz , 1h ) , 3.23 ( d , j = 14.0 hz , 
 1h ) .
c nmr ( cdcl3 ) :  166.0 , 163.0 ( jcf = 248 hz ) , 162.8 ( jcf = 248 hz ) , 136.5 , 135.8 , 131.2 ( jcf = 8.1 hz ) , 130.5 ( jcf = 8.1 hz ) , 125.3 , 124.5 ( jcf = 3.0 hz ) , 116.5 ( jcf = 22.8 hz ) , 115.9 ( jcf = 22.1 hz ) , 69.7 , 52.2 .
( c15h13f2no2s ) c , h , n. compound 5d was synthesized 
 as described 
 for 5a using compound 4e ( 800 mg , 2.45 mmol ) 
 to give the product 5d ( 600 mg , 71% ) as a white solid . 

h nmr ( cdcl3 ) : 
  7.437.43 ( m , 2h ) , 7.317.37 ( m , 6h ) , 7.05 ( br 
 s , 1h ) , 6.36 ( br s , 1h ) , 5.36 ( s , 1h ) , 3.47 ( d , j = 13.6 hz , 1h ) , 3.27 ( d , j = 13.6 hz , 1h ) .
c nmr ( cdcl3 ) :  166.3 , 136.3 , 135.6 , 135.4 , 
 134.8 , 130.8 , 130.2 , 129.6 , 129.2 , 129.0 , 128.8 , 127.7 , 126.9 , 69.4 , 
 52.9 .
( c15h13cl2no2s ) c , h , n. compound 5e was synthesized 
 as described 
 for 5a using compound 4f ( 750 mg , 2.23 mmol ) 
 to give the product 5e ( 540 mg , 69% ) as a white solid . 

h nmr ( dmso - d6 ) :  7.657.69 ( m , 2h ) , 7.487.57 
 ( m , 4h ) , 7.307.43 ( m , 5h ) , 5.36 ( s , 1h ) , 3.39 ( d , j = 13.6 hz , 1h ) , 3.20 ( d , j = 13.6 hz , 
 1h ) .
c nmr ( dmso - d6 ) :  
 166.2 , 137.4 , 136.7 , 132.2 , 130.8 , 130.6 , 129.7 , 129.1 , 128.7 , 128.6 , 
 128.4 , 128.1 , 121.6 , 67.5 , 56.4 .
( c15h14brno2s ) c , h , n. compound 5f was synthesized as described 
 for 5a using compound 4 g ( 500 mg , 1.84 mmol ) 
 to give the product 5f ( 427 mg , 81% ) as a yellow oil .
h nmr ( cdcl3 ) :  7.357.49 ( m , 10h ) , 
 7.02 ( br s , 1h ) , 5.18 ( s , 1h ) , 3.44 ( d , j = 14.0 
 hz , 1h ) , 3.13 ( d , j = 14.0 hz , 1h ) , 2.82 ( sd , j = 4.7 hz , 3h ) .
c nmr ( cdcl3 ) :  164.9 , 
 134.9 , 134.2 , 129.7 , 129.6 , 129.13 , 129.08 , 129.01 , 128.9 , 71.7 , 52.3 , 
 26.7 .
( c16h17no2s/4h2o ) c , h , n. compound 5 g was synthesized 
 as described for 5a using compound 4x ( 220 
 mg , 0.41 mmol ) to give the product 5 g ( 100 mg , 44% ) as 
 a colorless oil .
h nmr ( cdcl3 ) :  7.517.55 
 ( m , 4h ) , 7.167.31 ( m , 9h ) , 6.69 ( t , j = 5.4 
 hz , 1h ) , 5.13 ( s , 1h ) , 3.42 ( d , j = 14.0 hz , 1h ) , 
 3.33 ( q , j = 7.0 hz , 2h ) , 3.05 ( d , j = 14.0 hz , 1h ) , 2.67 ( t , j = 7.8 hz , 2h ) , 1.851.89 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  163.7 , 141.3 , 133.4 , 
 132.9 , 132.5 , 132.3 , 131.3 , 130.7 , 128.7 , 128.6 , 126.3 , 123.53 , 123.47 , 
 69.7 , 52.4 , 39.7 , 33.4 , 31.2 .
compounds 6a6c were synthesized following a literature procedure . a solution of cysteamine hydrochloride ( 10 mmol ) , diphenylmethanol , 3a , or the appropriate halogen - substituted diphenylmethanol , 3c or 3d ( 10 mmol ) , and bf3oet2 ( 11 mmol ) in glacial acetic acid ( 40 ml )
was stirred at 9095 
 c for 20 min ( 4050 min for substituted analogues ) .
the 
 reaction mixture was cooled to room temperature , and diethyl ether 
 ( 200 ml ) was added to precipitate a solid ( the hydrochloride salt ) 
 from the mixture .
the solid was filtered and dried under vacuum for 
 3 days in the presence of naoh pellets .
the dried solid was dissolved 
 in hot ethanol and filtered and the solvent removed in vacuo .
finally , 
 the solid was triturated in hot ( boiling ) ethyl acetate to give the 
 pure product as the hydrochloride salt .
compound 6a was synthesized 
 from diphenylmethanol , 3a , 
 according to general procedure d to give the hydrochloride salt in 
 quantitative yield .
the hydrochloride salt of 6a ( 10.1 
 g , 36.1 mmol ) was converted to the free base by being dissolved in 
 saturated aqueous nahco3 solution ( 120 ml ) and extracted 
 into chcl3 ( 150 ml ) .
the layers were separated , and the 
 organic layer was washed with distilled water ( 80 ml ) and aqueous 
 brine solution ( 100 ml ) and dried over mgso4 .
the solvent 
 was evaporated in vacuo to give the free base 6a ( 7.90 
 g , 90% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.43 ( d , j = 8.0 hz , 4h ) , 7.31 ( t , j = 7.4 hz , 4h ) , 7.22 ( tt , j = 7.4 , 1.5 hz , 2h ) , 5.16 ( s , 1h ) , 2.81 ( t , j = 6.2 hz , 
 2h ) , 2.51 ( t , j = 6.4 hz , 2h ) .
c nmr ( cdcl3 ) :  141.5 , 128.7 , 128.4 , 127.4 , 54.0 , 41.0 , 36.7 .
( c15h17ns/4c2h2o4 ) c , h , n. compound 6b was synthesized 
 from bis(4-chlorophenyl)methanol , 3c , according to general 
 procedure d with a reaction time 
 of 50 min . the hydrochloride salt product 6b ( 1.06 g , 
 62% yield )
h nmr ( hcl salt , dmso - d6 ) :  8.12 ( br s , 3h ) , 7.48 ( d , j = 
 8.4 hz , 4h ) , 7.42 ( d , j = 8.8 hz , 4h ) , 5.56 ( s , 1h ) , 
 2.94 ( t , j = 7.6 hz , 2h ) , 2.60 ( t , j = 7.2 hz , 2h ) .
c nmr ( hcl salt , dmso - d6 ) :  139.9 , 132.0 , 129.9 , 128.7 , 50.2 , 38.0 , 28.6 . 
 anal .
( c15h15cl2ns/4hcl/4h2o ) c , 
 h , n. compound 6c was synthesized from bis(4-bromophenyl)methanol , 3d , according to general procedure d with a reaction time 
 of 40 min . the hydrochloride salt product 6c ( 4.15 g , 
 72% yield )
h nmr ( hcl salt , dmso - d6 ) :  8.09 ( br s , 3h ) , 7.55 ( dt , j = 
 8.4 , 2.3 hz , 4h ) , 7.41 ( dt , j = 8.8 , 2.2 hz , 4h ) , 
 5.53 ( s , 1h ) , 2.94 ( t , j = 7.4 hz , 2h ) , 2.59 ( t , j = 7.4 hz , 2h ) .
c nmr ( hcl salt , dmso - d6 ) :  140.2 , 131.6 , 130.2 , 120.5 , 50.2 , 
 37.9 , 28.5 .
( c15h15br2nshcl ) 
 c , h , n. compound 6d was synthesized 
 according to general procedure d starting with compound 6a .
a suspension of the hydrochloride 
 salt of 6a ( 1.0 g , 3.6 mmol ) and cyclopropanecarboxaldehyde 
 ( 0.28 g , 4.0 mmol ) in 1,2-dichloroethane ( 62 ml ) was stirred at room 
 temperature under an argon atmosphere for 1.3 h. sodium cyanoborohydride 
 ( 0.69 g , 11 mmol ) dissolved in methanol ( 2.0 ml ) was added to the 
 reaction mixture , and the mixture was stirred at room temperature 
 under an argon atmosphere overnight .
after 19 h of reaction time , 
 saturated nahco3 solution ( 30 ml ) , distilled water ( 30 
 ml ) , and ch2cl2 ( 15 ml ) were added to the reaction 
 mixture , and the resulting mixure was stirred vigorously for 1 h. 
 the layers were separated , and the aqueous layer was washed with ch2cl2 ( 3  25 ml ) .
the combined ch2cl2 extract was washed with water ( 50 ml ) , dried over 
 mgso4 , and concentrated in vacuo to give a crude product . 

the isolated crude was purified by flash column chromatography using 
 an ethyl acetate / hexanes solvent gradient ( from 4:1 to 1:4 ) to give 
 the free base 6d ( 0.50 g , 47% yield ) as a yellow oil . 

some of the isolated free base was converted into the hydrochloride 
 salt in chcl3 using a 1.0 m hcl in ether solution .
h nmr ( cdcl3 ) :  
 7.42 ( d , j = 7.4 hz , 4h ) , 7.30 ( t , j = 7.4 hz , 4h ) , 7.22 ( tt , j = 7.2 , 1.6 hz , 2h ) , 
 5.17 ( s , 1h ) , 2.76 ( t , j = 6.4 hz , 2h ) , 2.59 ( t , j = 6.6 hz , 2h ) , 2.40 ( d , j = 6.8 hz , 2h ) , 
 0.810.97 ( m , 1h ) , 0.440.48 ( m , 2h ) , 0.09 ( qd , j = 4.8 , 1.2 hz , 2h ) .
c nmr ( cdcl3 ) :  141.6 , 128.7 , 128.4 , 127.3 , 54.7 , 54.3 , 48.1 , 32.9 , 11.4 , 
 3.5 .
( c19h23nshcl/4h2o ) c , h , n. compound 6e was synthesized 
 by adapting 
 a literature procedure using compound 6a ( general procedure d ) .
a mixture of csohh2o ( 0.29 g , 1.7 mmol ) and activated 4  molecular sieves ( 0.52 
 g ) in anhydrous dmf ( 8.3 ml , freshly distilled and stored over activated 
 4  molecular sieves ) was purged of air under vacuum and flushed 
 with argon gas . after the mixture was stirred for 13 min , the free 
 base of compound 6a ( 0.41 g , 1.7 mmol ) , dissolved in 
 anhydrous dmf ( 4.0 ml ) , was added .
the reaction mixture was stirred 
 under vacuum for 25 min and flushed with argon for 5 min , and n - butyl bromide ( 0.28 g , 2.04 mmol ) was added .
this was 
 followed by another 10 min of vacuum purging , and the reaction was 
 left to stir overnight at room temperature .
the reaction mixture was 
 filtered after 20 h of reaction time , and the undissolved solids were 
 washed with ethyl acetate .
the filtrate was evaporated in vacuo to 
 give a liquid residue , which was taken up in aqueous 1 m naoh ( 30 
 ml ) and extracted with ethyl acetate ( 2  25 ml ) .
the organic 
 extract was washed with brine ( 50 ml ) , dried over a 1:1 na2so4/mgso4 mixture , and concentrated in vacuo . 

the crude product was purified by flash column chromatography using 
 5% diethyl ether / hexanes ( with 0.5% net3 ) to give the free 
 base 6e ( 0.22 g , 44% yield ) as a yellow oil .
h nmr ( cdcl3 ) :  7.42 ( d , j = 7.2 hz , 4h ) , 7.30 ( t , j = 7.6 hz , 4h ) , 
 7.22 ( tt , j = 7.2 , 1.6 hz , 2h ) , 5.17 ( s , 1h ) , 2.74 
 ( t , j = 6.4 hz , 2h ) , 2.58 ( t , j = 
 6.2 hz , 2h ) , 2.53 ( t , j = 7.2 hz , 2h ) , 1.401.47 
 ( m , 2h ) , 1.271.37 ( m , 2h ) , 0.90 ( t , j = 7.6 
 hz , 3h ) .
c nmr ( cdcl3 ) :  141.6 , 128.7 , 
 128.4 , 127.3 , 54.2 , 49.3 , 48.3 , 32.8 , 32.3 , 20.6 , 14.1 .
( c19h25nsc2h2o4 ) c , h , n. compound 6f was synthesized 
 from compound 4u .
briefly , 
 sulfuric acid ( 98% ; 305 mg , 3.11 mmol ) in thf ( 8.0 ml ) was added dropwise 
 at 0 c to lialh4 ( 227 mg , 5.99 mmol ) in thf ( 13 ml ) , 
 and the mixture was stirred for 15 min at room temperature .
compound 4u ( 563 mg , 1.50 mmol ) in thf ( 11 ml ) was added dropwise to 
 the reduction mixture at room temperature and the resulting mixture 
 stirred overnight .
the reaction mixture was cooled to 0 c and 
 quenched with water ( 5.0 ml ) and 10% naoh ( 20 ml ) successively .
the 
 mixture was filtered , the insolubles were washed with thf , and the 
 filtrate was evaporated to dryness .
the crude product was purified 
 on a teledyne isco combiflash rf instrument using 97:3:0.03 
 chcl3/meoh / nh4oh to give the pure product 6f ( 312 mg , 58% ) as a yellow oil .
h nmr 
 ( cdcl3 ) :  7.42 ( d , j = 7.6 hz , 
 4h ) , 7.277.32 ( m , 6h ) , 7.167.23 ( m , 5h ) , 5.16 ( s , 
 1h ) , 2.73 ( t , j = 6.4 hz , 2h ) , 2.63 ( t , j = 7.8 hz , 2h ) , 2.542.58 ( m , 4h ) , 1.741.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  142.2 , 141.6 , 128.7 , 128.53 , 
 128.47 , 128.4 , 127.4 , 125.9 , 54.2 , 49.1 , 48.3 , 33.7 , 32.8 , 31.8 .
( c24h27ns  c2h2o4 ) c , h , n. compound 6 g was synthesized 
 as described for compound 6f using compound 4v , except that the reaction mixture was stirred at room temperature 
 for 2 h ( instead of overnight ) before being quenched with water and 
 naoh ( 15% instead of 10%).the crude product was purified by flash 
 column chromatography ( 95:5:0.5 chcl3/meoh / nh4oh ) to give the pure product 6 g ( 820 mg , 86.6% ) as a 
 yellow oil .
the free base was converted to the oxalate salt , which 
 was recrystallized from a methanol / acetone mixture .
h nmr ( cdcl3 ) :  7.337.37 
 ( m , 4h ) , 7.167.30 ( m , 5h ) , 6.977.02 ( m , 4h ) , 5.13 
 ( s , 1h ) , 2.72 ( t , j = 6.4 hz , 2h ) , 2.64 ( t , j = 7.8 hz , 2h ) , 2.52 ( m , 4h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  161.9 ( jcf = 246 hz ) , 142.0 , 137.0 ( jcf = 3.0 hz ) , 129.7 ( jcf = 8.1 hz ) , 128.4 , 125.8 , 115.5 ( jcf = 21.4 hz , 4c ) , 52.5 , 48.8 , 48.0 , 33.6 , 32.6 , 
 31.6 .
( c24h25f2nsc2h2o4 ) c , h , n. compound 6h was synthesized 
 as described for 6 g using compound 4w ( 1 
 g , 2.2 mmol ) .
the crude product 6h ( 850 mg ) was obtained 
 as a yellow oil and carried to the next step without further purification .
a solution of 1 m bh3thf complex 
 ( 14 ml , 14.0 mmol ) was added slowly ( in two aliquots ) to a solution 
 of compound 4x ( 1.50 g , 2.81 mmol ) in freshly distilled 
 thf ( 15 ml ) at 2 c .
the reaction mixture was refluxed for 16 
 h , cooled to 0 c , quenched with ch3oh ( 30 ml ) , saturated 
 with aqueous hcl ( 5.0 ml of concentrated hcl ( 37% ) ) , and refluxed 
 for another 23 h , successively .
the solvent was removed in vacuo to 
 give a yellow , oily residue which was taken up in chcl3 ( 50 ml ) and washed with distilled water ( 2  50 ml ) .
the combined 
 aqueous extract was back - washed with chcl3 ( 3  30 
 ml ) and then discarded .
the combined chcl3 extract was 
 washed with water ( 100 ml ) and brine ( 100 ml ) and concentrated in 
 vacuo to give the hydrochloride salt of 6i .
the salt 
 was suspended in a small amount of water and the suspension made basic 
 to a ph of 13 with 10 m naoh ( 20 ml ) .
the basic solution was continuously 
 extracted with chcl3 for 6 h , and the layers were separated . 

solvent was removed from the organic layer to give the crude free 
 base of compound 6i , which was purified by flash column 
 chromatography ( 5% meoh / ch2cl2 ) .
the pure product 6i ( 0.58 g , 40% yield ) was obtained as a yellow oil and converted 
 to the oxalate salt .
h nmr 
 ( cdcl3 ) :  7.43 ( dt , j = 8.4 , 2.3 
 hz , 4h ) , 7.237.30 ( m , 6h ) , 7.167.20 ( m , 3h ) , 5.07 
 ( s , 1h ) , 2.74 ( t , j = 6.6 hz , 2h ) , 2.64 ( t , j = 7.6 hz , 2h ) , 2.532.29 ( m , 4h ) , 1.771.83 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  142.1 , 140.1 , 
 131.9 , 131.6 , 130.0 , 128.5 , 126.0 , 121.5 , 53.0 , 49.0 , 48.3 , 33.7 , 
 32.7 , 31.7 .
briefly , a 
 solution of sodium periodate ( naio4 ; 2.25 g , 10.5 mmol ) 
 in water ( 50 ml ) was added in a dropwise manner to a solution of the 
 hydrochloride salt of compound 6a ( 2.80 g , 10.0 mmol ) 
 in ethanol ( 150 ml ) at 0 c .
the reaction was allowed to stir 
 and warm to room temperature for 20 h under an argon atmosphere . 

the reaction mixture , which contained a white precipitate , was cooled 
 in an ice bath and filtered .
the filtrate was concentrated in vacuo 
 to give a dark yellow , oily residue .
the oily residue ( the hydrochloride 
 salt ) was dissolved in chcl3 , washed with an aqueous nahco3 solution ( 2:3 dilution in water of saturated nahco3 solution ) , distilled water , and aqueous brine , and dried over na2so4 , successively .
after filtration , solvent was 
 removed in vacuo to give the crude , free base of compound 7a .
the crude product was purified by flash column chromatography using 
 a meoh / chcl3 ( with 0.1% nh4oh ) gradient ( from 
 0% to 1% meoh ) to give pure 7a ( 1.12 g , 43% yield ) as 
 a yellow oil .
h nmr ( cdcl3 ) :  7.50 ( d , j = 7.8 hz , 2h ) , 7.317.44 
 ( m , 8h ) , 4.90 ( s , 1h ) , 3.103.23 ( m , 2h ) , 2.532.65 
 ( m , 2h ) .
c nmr ( cdcl3 ) :  135.8 , 135.2 , 
 129.4 , 128.9 , 128.7 , 128.5 , 128.4 , 73.1 , 54.4 , 36.5 .
( c15h17nosc2h2o4 ) c , h , n. compound 7b was synthesized 
 as described for 7a from compound 6e ( 0.070 
 g , 0.23 mmol ) and naio4 ( 0.053 g , 0.25 mmol ) in an ethanol / water 
 ( etoh / h2o ) mixture ( 4.0 ml/1.2 ml , v / v ) .
the pure free 
 base product 7b ( 0.020 g , 41% yield ) was obtained as 
 a yellow oil after purification of the crude by flash column chromatography 
 using a meoh / chcl3 ( with 0.1% nh4oh ) gradient 
 ( from 0% to 2% meoh ) .
h nmr ( cdcl3 ) :  7.49 ( d , j = 7.6 hz , 2h ) , 7.307.44 
 ( m , 8h ) , 4.92 ( s , 1h ) , 2.993.13 ( m , 2h ) , 2.65 ( t , j = 5.8 hz , 2h ) , 2.56 ( t , j = 7.0 hz , 2h ) , 
 1.401.47 ( m , 2h ) , 1.271.36 ( m , 2h ) , 0.89 ( t , j = 7.4 hz , 3h ) .
129.44 , 129.42 , 128.9 , 128.8 , 128.49 , 128.44 , 
 73.0 , 51.1 , 49.6 , 43.6 , 32.1 , 20.5 , 14.1 .
( c19h25nosc2h2o4/2h2o ) c , h , n. compound 7c was synthesized 
 as described for compound 5a using 6 g ( 900 
 mg , 2.27 mmol ) . the free base product 7c ( 820 mg , 87.5% 
 yield )
was obtained as a yellow oil and converted into the oxalate 
 salt , which was recrystallized from a methanol / acetone mixture .
h nmr ( cdcl3 ) : 
  7.377.44 ( m , 4h ) , 7.057.29 ( m , 9h ) , 5.00 ( s , 
 1h ) , 3.163.22 ( m , 1h ) , 3.043.11 ( m , 1h ) , 2.602.83 
 ( m , 6h ) , 1.801.88 ( m , 2h ) .
c nmr ( cdcl3 ) :  162.8 ( jcf = 248 
 hz ) , 162.6 ( jcf = 249 hz ) , 
 141.1 , 131.0 ( jcf = 8.1 hz ) , 
 130.3 ( jcf = 8.1 hz ) , 130.1 
 ( jcf = 3.7 hz ) , 128.4 , 128.3 , 
 126.0 , 116.4 ( jcf = 21.4 hz ) , 
 115.8 ( jcf = 21.4 hz ) , 70.6 , 
 48.7 , 48.4 , 43.1 , 33.1 , 30.1 .
( c24h25f2nosc2h2o4 ) c , h , n. compound 7d was synthesized 
 as described for compound 5a using 6h ( 850 
 mg , 1.97 mmol ) . the free base product 7d ( 640 mg , two 
 steps yield 72.6% )
was obtained as a yellow oil and converted into 
 the oxalate salt , which was recrystallized from hot meoh .
h nmr ( cdcl3 ) :  7.157.39 
 ( m , 13h ) , 4.88 ( s , 1h ) , 2.993.08 ( m , 2h ) , 2.572.65 
 ( m , 6h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  
 141.9 , 134.7 , 134.6 , 134.0 , 132.9 , 130.6 , 129.9 , 129.6 , 129.0 , 128.4 , 
 125.9 , 70.6 , 51.2 , 49.1 , 43.1 , 33.5 , 31.4 .
( c24h25cl2nosc2h2o4/2h2o ) c , h , n. compound 7e was synthesized 
 as described for compound 5a using 6i ( 230 
 mg , 0.443 mmol ) .
the free base product 7e ( 130 mg , 55% 
 yield ) was obtained as a yellow oil and converted into the oxalate 
 salt , which was recrystallized from hot meoh .
h nmr ( cdcl3 ) :  7.457.53 
 ( m , 4h ) , 7.157.32 ( m , 7h ) , 4.83 ( s , 1h ) , 2.993.08 
 ( m , 2h ) , 2.572.65 ( m , 6h ) , 1.751.82 ( m , 2h ) .
c nmr ( cdcl3 ) :  141.9 , 134.5 , 133.3 , 132.5 , 132.3 , 
 132.0 , 131.4 , 130.9 , 130.2 , 128.4 , 125.9 , 122.9 , 122.7 , 70.7 , 51.2 , 
 49.1 , 43.1 , 33.5 , 31.4 .
 2-[(diphenylmethyl)sulfinyl]acetamide 
 ( modafinil , ( )-1 ) is a unique dopamine uptake inhibitor 
 that binds the dopamine 
 transporter ( dat ) differently than cocaine and may have potential 
 for the treatment of psychostimulant abuse . to further investigate 
 structural requirements for this divergent binding mode , novel thio- 
 and sulfinylacetamide and ethanamine analogues of ( )-1 were synthesized wherein ( 1 ) the diphenyl rings were substituted 
 with methyl , trifluoromethyl , and halogen substituents and ( 2 ) substituents 
 were added to the terminal amide / amine nitrogen . halogen substitution 
 of the diphenyl rings of ( )-1 gave several amide 
 analogues with improved binding affinity for dat and robust selectivity 
 over the serotonin transporter ( sert ) , whereas affinity improved at 
 sert over dat for the p - halo - substituted amine analogues . 
 
 molecular docking studies , using a subset of analogues with dat and 
 sert homology models , and functional data obtained with dat ( a480 t ) 
 and sert ( t497a ) mutants defined a role for tm10 in the substrate / inhibitor 
 s1 binding sites of dat and sert . 
Chemistry
Conclusion
Experimental
Methods
Thioacetamides
Sulfinylacetamides
Thioethanamines
Sulfinylethanamines