it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed . as used herein , the use of the singular includes the plural unless specifically stated otherwise . it will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers , such that the compounds may exist in enantiomeric as well as in diastereomeric forms . unless it is specifically noted otherwise , the scope of the present invention includes all enantiomers , diastereomers and racemic mixtures . some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases , and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention . the present invention includes all pharmaceutically acceptable isotopically enriched compounds . any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2 h ( or d ) in place of protium 1 h ( or h ) or use of 13 c enriched material in place of 12 c and the like . similar substitutions can be employed for n , o and s . the use of isotopes may assist in analytical as well as therapeutic aspects of the invention . for example , use of deuterium may increase the in vivo half - life by altering the metabolism ( rate ) of the compounds of the invention . these compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents . the following examples are for illustrative purposes only and are not intended , nor should they be construed as limiting the invention in any manner . those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention . as will be evident to those skilled in the art , individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner . for example , in the case of diasteroisomeric isomers , chromatographic separation may be employed . compound names were generated with acdlab version 12 . 5 and intermediates and reagent names used in the examples were generated with software such as chem bio draw ultra version 12 . 0 or auto nom 2000 from mdl isis draw 2 . 5 sp1 . a sample of 2 -( 3 , 5 - difluorophenyl )- 1 -( 3 , 4 - dimethylphenyl ) ethanone [ cas 1450736 - 61 - 4 ] ( 5 . 0 g , 19 . 2 mmole ) was dissolved in thf and set to − 78 ° c . lithium diisopropyl amide ( 10 . 6 ml , 1 . 1 eq .) was added dropwise and the resulting mixture was stirred for 30 minutes . a solution of methyl 4 -[( 4 - bromobutyl ) thio ] benzoate [ cas 1456736 - 45 - 4 ] ( 6 . 4 g , 1 . 1 eq ) in thf was then added dropwise and the reaction mixture was allowed to stir overnight . it was then refluxed at 90 ° c . for overnight . the reaction mixture was cooled to room temperature , then to 0 ° c . after which it was quenched with 1m hcl to ph 2 . the resulting mixture was extracted with etoac ( 3 × 100 ml ). the combined organic layers were washed with saturated nacl , dried with mgso 4 , filtered , concentrated and purified by mplc to give 3 . 76 g ( 40 %) of intermediate 1 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 31 - 1 . 54 ( m , 2h ) 1 . 63 - 1 . 91 ( m , 3h ) 2 . 09 - 2 . 24 ( m , 1h ) 2 . 28 ( s , 6h ) 2 . 94 ( t , j = 7 . 33 hz , 2h ) 3 . 89 ( s , 3h ) 4 . 50 ( t , j = 7 . 18 hz , 1h ) 6 . 57 - 6 . 70 ( m , 1h ) 6 . 79 - 6 . 88 ( m , 2h ) 7 . 17 ( d , j = 7 . 62 hz , 1h ) 7 . 24 ( d , j = 8 . 79 hz , 2h ) 7 . 60 - 7 . 68 ( m , 1h ) 7 . 71 ( s , 1h ) 7 . 90 ( d , j = 8 . 50 hz , 2h ). a sample of intermediate 1 ( 3 . 76 g , 7 . 8 mmoles ) was dissolved in 2 ml of thf and diluted with meoh . the resulting solution was cooled to 0 ° c . and nabh 4 ( 295 mg , 1 . 0 eq ) was added . the reaction mixture was stirred at 0 ° c . for 2 hours . it was then quenched with 1m hcl and the solvent was evaporated . the residue was dissolved in etoac and washed with saturated nacl , dried with mgso 4 , filtered , concentrated and purified by mplc to give 3 . 48 g ( 92 %) of intermediate 2 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 01 - 1 . 27 ( m , 2h ) 1 . 32 - 1 . 66 ( m , 4h ) 2 . 25 ( s , 6h ) 2 . 68 - 2 . 91 ( m , 3h ) 3 . 89 ( s , 3h ) 4 . 63 ( d , j = 8 . 20 hz , 1h ) 6 . 58 - 6 . 82 ( m , 3h ) 6 . 95 - 7 . 13 ( m , 3h ) 7 . 19 ( d , j = 8 . 79 hz , 2h ) 7 . 89 ( d , j = 8 . 50 hz , 2h ). a sample of intermediate 2 ( 3 . 48 g , 7 . 2 mmoles ) was dissolved in toluene . molecular sieves ( 200 mg ) were added followed by p - tsoh ( 1 . 5 g , 1 . 1 eq ). the resulting mixture was refluxed at 110 ° c . for 3 hours after which it was cooled to room temperature . the solvent was evaporated and the residue was dissolved in et 2 o . the solution was washed with saturated nahco 3 ( 2 × 20 ml ), h 2 o ( 1 × 20 ml ) and brine . it was then dried over mgso 4 , filtered , concentrated and purified by mplc to give 2 . 9 g ( 87 %) of intermediate 3 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 39 - 1 . 61 ( m , 2h ) 1 . 64 - 1 . 84 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 46 ( t , j = 7 . 30 hz , 2h ) 2 . 97 ( t , j = 7 . 18 hz , 2h ) 3 . 89 ( s , 3h ) 6 . 40 ( s , 1h ) 6 . 55 - 6 . 74 ( m , 5h ) 6 . 86 ( d , j = 7 . 91 hz , 1h ) 7 . 26 ( d , j = 8 . 79 hz , 2h ) 7 . 91 ( d , j = 8 . 79 hz , 2h ). a sample of intermediate 3 ( 2 . 9 g , 6 . 22 mmoles ) was dissolved in thf and cooled to − 30 ° c . lithium aluminum hydride ( 1 . 0 m , 6 . 8 ml , 1 . 1 eq ) was added dropwise and the resulting mixture was stirred at − 30 ° c . for 1 hour . ether and celite were added to the reaction mixture followed by 1m hcl until ph 2 - 3 . the resulting solution was filtered over celite and the filtrate was concentrated and purified by mplc to give 2 . 25 g ( 83 %) of intermediate 4 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 43 - 1 . 79 ( m , 4h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 38 - 2 . 51 ( m , 2h ) 2 . 90 ( t , j = 7 . 18 hz , 2h ) 4 . 64 ( s , 2h ) 6 . 38 ( s , 1h ) 6 . 50 - 6 . 75 ( m , 5h ) 6 . 86 ( d , j = 7 . 91 hz , 1h ) 7 . 14 - 7 . 40 ( m , 4h ). a solution of oxalyl chloride ( 240 μl , 1 . 1 eq ) in 5 . 0 ml of ch 2 cl 2 was cooled to − 78 ° c . dimethylsulfoxide ( 401 μl , 2 . 2 eq ) was added and the resulting mixture was stirred for 30 minutes . a solution of intermediate 4 ( 1 . 125 g , 2 . 6 mmoles ) in 5 ml ch 2 cl 2 was added and the reaction mixture was stirred at − 78 ° c . for 2 hours . triethylamine ( 1 . 8 ml , 5 . 0 eq ) was added and the resulting mixture was stirred for 30 minutes . water was added to quench the reaction mixture and stirring was continued until the solution is at room temperature . the layers were isolated and the organic layer was washed with brine , dried with mgso 4 , filtered , concentrated and purified by mplc to give intermediate 5 ( 866 mg ). 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 46 - 1 . 62 ( m , 2h ) 1 . 68 - 1 . 85 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 48 ( t , j = 7 . 03 hz , 2h ) 3 . 00 ( t , j = 7 . 33 hz , 2h ) 6 . 41 ( s , 1h ) 6 . 54 - 6 . 75 ( m , 5h ) 6 . 86 ( d , j = 7 . 91 hz , 1h ) 7 . 33 ( d , j = 8 . 50 hz , 2h ) 7 . 75 ( d , j = 8 . 79 hz , 2h ) 9 . 91 ( s , 1h ). a mixture of 2 -( 3 , 5 - difluorophenyl )- 1 -( 3 , 4 - dimethylphenyl ) ethanone [ cas 1450736 - 61 - 4 ] ( 2 . 3 g , 8 . 8 mmoles ), lda ( 6 . 6 ml , 1 . 5 eq ), and methyl 4 -( 3 - iodopropoxy ) benzoate [ cas 152936 - 91 - 9 ] ( 4 . 25 g , 1 . 5 eq ) were reacted to give 3 . 7 g ( 93 %) of intermediate 6 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 65 - 1 . 90 ( m , 2h ) 1 . 91 - 2 . 04 ( m , 1h ) 2 . 25 - 2 . 32 ( m , 6h ) 2 . 30 - 2 . 43 ( m , 1h ) 3 . 88 ( s , 3h ) 4 . 01 ( t , j = 6 . 15 hz , 2h ) 4 . 61 ( t , j = 7 . 18 hz , 1h ) 6 . 52 - 6 . 73 ( m , 1h ) 6 . 82 - 6 . 90 ( m , 4h ) 7 . 17 ( d , j = 7 . 91 hz , 1h ) 7 . 55 - 7 . 77 ( m , 2h ) 7 . 93 - 7 . 98 ( m , 2h ). a mixture of intermediate 6 ( 4 . 06 g , 9 . 0 mmoles ), and nabh 4 ( 340 mg , 1 . 0 eq ) were reacted to give 3 . 17 g ( 78 %) of intermediate 7 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 48 - 1 . 64 ( m , 4h ) 2 . 25 ( s , 3h ) 2 . 26 ( s , 3h ) 3 . 79 - 3 . 86 ( m , 2h ) 3 . 87 ( s , 3h ) 4 . 59 - 4 . 73 ( m , 2h ) 6 . 65 - 6 . 92 ( m , 4h ) 6 . 97 - 7 . 14 ( m , 4h ) 7 . 91 - 8 . 03 ( m , 2h ). a mixture of intermediate 7 ( 3 . 17 g , 7 . 0 mmoles ), molecular sieves ( 200 mg ) and p - tsoh ( 1 . 6 g , 1 . 2 eq ) were reacted to give quantitative yield of intermediate 8 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 78 - 2 . 00 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 52 - 2 . 73 ( m , 2h ) 3 . 89 ( s , 3h ) 4 . 03 ( t , j = 6 . 20 hz , 2h ) 6 . 45 ( s , 1h ) 6 . 53 - 6 . 64 ( m , 1h ) 6 . 67 - 6 . 76 ( m , 4h ) 6 . 80 - 6 . 97 ( m , 3h ) 7 . 99 ( d , j = 8 . 79 hz , 2h ). a mixture of intermediate 8 ( 3 . 32 g , 7 . 6 mmoles ) and lah ( 1 . 0 m , 8 . 4 ml , 1 . 1 eq ) were reacted to give 2 . 6 g ( 84 %) of intermediate 9 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 82 - 1 . 92 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 16 ( s , 3h ) 2 . 51 - 2 . 72 ( m , 2h ) 3 . 98 ( t , j = 6 . 30 hz , 2h ) 4 . 59 - 4 . 63 ( m , 2h ) 6 . 46 ( s , 1h ) 6 . 54 - 6 . 65 ( m , 1h ) 6 . 66 - 6 . 75 ( m , 4h ) 6 . 83 - 6 . 90 ( m , 3h ) 7 . 24 - 7 . 30 ( m , 2h ). a mixture of intermediate 9 ( 2 . 6 g , 6 . 4 mmoles ), 2 . 0 g of molecular sieves , nmo ( 1 . 5 g , 2 . 0 eq ) and tpap ( 100 mg ) were reacted to give 2 . 0 g ( 77 %) of intermediate 10 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 76 - 2 . 01 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 65 ( t , j = 7 . 30 hz , 2h ) 4 . 06 ( t , j = 6 . 15 hz , 2h ) 6 . 46 ( s , 1h ) 6 . 54 - 6 . 64 ( m , 1h ) 6 . 67 - 6 . 77 ( m , 4h ) 6 . 87 ( d , j = 8 . 20 hz , 1h ) 6 . 99 ( d , j = 8 . 80 hz , 2h ) 7 . 83 ( d , j = 8 . 80 hz , 2h ) 9 . 89 ( s , j = 3 . 22 hz , 1h ). a sample of 2 -( 3 , 5 - difluorophenyl )- 1 -( 3 , 4 - dimethylphenyl ) ethanone [ cas 1450736 - 61 - 4 ] ( 5 . 0 g , 19 . 2 mmole ) was dissolved in thf and cooled to − 78 ° c . lithium diisopropyl amide ( 10 . 6 ml , 1 . 1 eq .) was added dropwise and the resulting mixture was stirred for 30 minutes . a solution of methyl 4 -[( 3 - bromopropyl ) thio ] benzoate [ cas 134520 - 57 - 3 ] ( 6 . 1 g , 1 . 1 eq ) in thf was then added dropwise and the reaction mixture was allowed to stir overnight . it was then refluxed at 90 ° c . overnight . the reaction mixture was cooled to room temperature , then to 0 ° c . after which it was quenched with 1m hcl to ph 2 . the resulting mixture was extracted with etoac ( 3 × 100 ml ) and the combined organic layers were washed with saturated nacl , dried with mgso 4 , filtered , concentrated and purified by mplc to give 4 . 28 g ( 48 %) of intermediate 11 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 53 - 1 . 78 ( m , 2h ) 1 . 86 - 2 . 11 ( m , 1h ) 2 . 28 ( s , 6h ) 2 . 31 - 2 . 38 ( m , 1h ) 2 . 89 - 3 . 06 ( m , 2h ) 3 . 89 ( s , 3h ) 4 . 51 ( t , j = 7 . 33 hz , 1h ) 6 . 57 - 6 . 71 ( m , 1h ) 6 . 78 - 6 . 88 ( m , 2h ) 7 . 14 - 7 . 29 ( m , 3h ) 7 . 62 - 7 . 66 ( m , 1h ) 7 . 69 - 7 . 72 ( m , 1h ) 7 . 90 ( d , j = 7 . 66 hz , 2h ). a sample of intermediate 11 ( 4 . 28 g , 9 . 1 mmoles ) was dissolved in 5 ml of thf and diluted with meoh . the resulting solution was cooled to 0 ° c . and nabh 4 ( 346 mg , 1 . 0 eq ) was added . the reaction mixture was stirred at 0 ° c . for 2 hours . it was then quenched with 1m hcl and the solvent was evaporated . the residue was dissolved in etoac and washed with saturated nacl , dried with mgso 4 , filtered , concentrated and purified by mplc to give 3 . 73 g ( 87 %) of intermediate 12 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 31 - 1 . 50 ( m , 2h ) 1 . 53 - 1 . 72 ( m , 2h ) 2 . 26 ( s , 6h ) 2 . 70 - 2 . 90 ( m , 3h ) 3 . 89 ( s , 3h ) 4 . 63 ( d , j = 8 . 20 hz , 1h ) 6 . 56 - 6 . 85 ( m , 3h ) 6 . 90 - 7 . 05 ( m , 2h ) 7 . 07 - 7 . 21 ( m , 3h ) 7 . 83 - 7 . 89 ( m , 2h ). a mixture of intermediate 12 ( 880 mg , 1 . 9 mmoles ), molecular sieve ( 50 mg ) and p - tsoh ( 392 mg , 1 . 1 eq ) were reacted to give 685 mg ( 81 %) of intermediate 13 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 62 - 1 . 86 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 55 - 2 . 73 ( m , 2h ) 3 . 00 ( t , j = 7 . 18 hz , 2h ) 3 . 90 ( s , 3h ) 6 . 44 ( s , 1h ) 6 . 53 - 6 . 77 ( m , 5h ) 6 . 87 ( d , j = 7 . 91 hz , 1h ) 7 . 26 ( d , j = 8 . 50 hz , 2h ) 7 . 91 ( d , j = 8 . 50 hz , 2h ). a mixture of intermediate 13 ( 685 mg , 1 . 5 mmoles ) and lah ( 1 . 0 m , 1 . 7 ml , 1 . 1 eq ) were reacted to give 550 mg ( 86 %) of intermediate 14 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 61 - 1 . 80 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 16 ( s , 3h ) 2 . 58 ( t , j = 7 . 30 hz , 2h ) 2 . 92 ( t , j = 7 . 18 hz , 2h ) 4 . 55 - 4 . 72 ( m , 2h ) 6 . 42 ( s , 1h ) 6 . 48 - 6 . 77 ( m , 5h ) 6 . 86 ( d , j = 7 . 91 hz , 1h ) 7 . 17 - 7 . 38 ( m , 4h ). a mixture of intermediate 14 ( 440 mg , 1 . 03 mmoles ), oxalyl - cl ( 96 μl , 1 . 1 eq ), dmso ( 162 μl , 2 . 2 eq ) and triethylamine ( 720 μl , 5 . 0 eq ) were reacted to give 286 mg ( 65 %) of intermediate 15 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 59 - 1 . 89 ( m , 2h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 62 ( t , j = 7 . 00 hz , 2h ) 3 . 02 ( t , j = 7 . 33 hz , 2h ) 6 . 46 ( s , 1h ) 6 . 54 - 6 . 76 ( m , 5h ) 6 . 87 ( d , j = 7 . 91 hz , 1h ) 7 . 32 ( d , j = 8 . 50 hz , 2h ) 7 . 74 ( d , j = 8 . 79 hz , 2h ) 9 . 92 ( s , 1h ). a mixture of 2 -( 3 - chlorophenyl )- 1 -( 3 , 4 - dimethylphenyl ) ethanone [ cas 1275947 - 05 - 1 ] ( 2 . 0 g , 7 . 7 moles ), lda ( 7 . 8 ml , 1 . 5 eq ), and 4 -( 3 - iodopropoxylbenzoate ) [ cas 152936 - 91 - 9 ] ( 3 . 2 g , 1 . 5 eq ) were reacted to give 1 . 64 g ( 47 %) of intermediate 16 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 66 - 1 . 88 ( m , 2h ) 1 . 90 - 2 . 10 ( m , 1h ) 2 . 27 ( s , 6h ) 2 . 29 - 2 . 41 ( m , 1h ) 3 . 87 ( s , 3h ) 4 . 00 ( t , j = 6 . 30 hz , 2h ) 4 . 60 ( t , j = 7 . 33 hz , 1h ) 6 . 84 ( d , j = 9 . 08 hz , 2h ) 7 . 13 - 7 . 24 ( m , 4h ) 7 . 32 ( br . s , 1h ) 7 . 68 ( d , j = 7 . 70 hz , 1h ) 7 . 73 ( s , 1h ) 7 . 95 ( d , j = 9 . 08 hz , 2h ). a mixture of intermediate 16 ( 1 . 96 g , 4 . 35 mmoles ), nabh 4 ( 164 mg , 1 . 0 eq ) were reacted to give quantitative yield of intermediate 17 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 42 - 1 . 71 ( m , 4h ) 2 . 20 - 2 . 26 ( m , 6h ) 2 . 83 - 2 . 92 ( m , 1h ) 3 . 76 - 3 . 83 ( m , 2h ) 3 . 86 ( s , 3h ) 4 . 65 ( d , j = 8 . 20 hz , 1h ) 6 . 75 ( d , j = 8 . 79 hz , 2h ) 6 . 93 - 7 . 18 ( m , 5h ) 7 . 19 - 7 . 32 ( m , 2h ) 7 . 92 ( d , j = 8 . 79 hz , 2h ). a mixture of intermediate 17 ( 2 . 25 g , 5 . 0 mmoles ), molecular sieves ( 100 mg ) and p - tsoh ( 1 . 1 g , 1 . 2 eq ) were reacted to give 2 . 0 g ( 86 %) of intermediate 18 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 83 - 1 . 93 ( m , 2h ) 2 . 07 ( s , 3h ) 2 . 14 ( s , 3h ) 2 . 65 ( t , j = 7 . 18 hz , 2h ) 3 . 87 ( s , 3h ) 4 . 01 ( t , j = 6 . 30 hz , 2h ) 6 . 43 ( s , 1h ) 6 . 56 - 6 . 60 ( m , 1h ) 6 . 69 ( s , j = 5 . 89 , 5 . 89 hz , 1h ) 6 . 78 - 6 . 91 ( m , 3h ) 7 . 02 - 7 . 09 ( m , 1h ) 7 . 17 - 7 . 26 ( m , 3h ) 7 . 93 - 8 . 00 ( m , 2h ). a mixture of intermediate 18 ( 1 . 6 g , 3 . 7 mmoles ) and lah ( 1 . 0 m , 4 . 0 ml , 1 . 1 eq ) were reacted to give 1 . 15 g ( 77 %) of intermediate 19 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 84 - 1 . 91 ( m , 2h ) 2 . 08 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 61 - 2 . 67 ( m , 2h ) 3 . 97 ( t , j = 6 . 30 hz , 2h ) 4 . 60 ( d , j = 5 . 27 hz , 2h ) 6 . 43 ( s , 1h ) 6 . 57 - 6 . 60 ( m , 1h ) 6 . 69 - 6 . 71 ( m , 1h ) 6 . 82 - 6 . 90 ( m , 3h ) 7 . 02 - 7 . 06 ( m , 1h ) 7 . 17 - 7 . 29 ( m , 5h ) a mixture of intermediate 19 ( 1 . 24 g , 3 . 0 mmoles ), 1 . 0 g of molecular sieves , nmo ( 714 mg , 2 . 0 eq ) and tpap ( 50 mg ) were reacted to give 857 mg ( 70 %) of intermediate 20 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 86 - 1 . 95 ( m , 2h ) 2 . 08 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 66 ( t , j = 7 . 60 hz , 2h ) 4 . 06 ( t , j = 6 . 30 hz , 2h ) 6 . 44 ( s , 1h ) 6 . 54 - 6 . 63 ( m , 1h ) 6 . 69 ( s , 1h ) 6 . 84 ( d , j = 6 . 28 hz , 1h ) 6 . 94 - 7 . 01 ( m , 2h ) 7 . 03 - 7 . 09 ( m , 1h ) 7 . 18 - 7 . 27 ( m , 3h ) 7 . 83 ( d , j = 7 . 98 hz , 2h ) 9 . 88 ( s , j = 3 . 23 hz , 1h ). a mixture of ( e )-( 4 -(( 4 -( 2 , 3 - difluorophenyl )- 5 -( 3 , 4 - dimethylphenyl ) pent - 4 - en - 1 - yl ) oxy ) phenyl ) methanol ( 1 . 2 g , 2 . 9 mmoles ), 1 . 0 g of molecular sieve , nmo ( 690 mg , 2 . 0 eq ) and tpap ( 50 mg ) were reacted to give 980 mg ( 82 %) of intermediate 21 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 81 - 1 . 99 ( m , 2h ) 2 . 08 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 69 ( t , j = 7 . 62 hz , 2h ) 4 . 08 ( t , j = 6 . 30 hz , 2h ) 6 . 50 - 6 . 64 ( m , 2h ) 6 . 69 ( s , 1h ) 6 . 79 - 6 . 93 ( m , 2h ) 6 . 94 - 7 . 18 ( m , 4h ) 7 . 83 ( d , j = 8 . 50 hz , 2h ) 9 . 89 ( s , 1h ). a mixture of ( e )-( 4 -(( 5 -( 3 , 4 - dimethylphenyl )- 4 -( thiophen - 3 - yl ) pent - 4 - en - 1 - yl ) oxy ) phenyl ) methanol ( 1 . 64 g , 4 . 3 mmoles ), 1 . 0 g of molecular sieve , nmo ( 1 . 0 g , 2 . 0 eq ) and tpap ( 60 mg ) were reacted to give 324 mg of intermediate 22 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 84 - 1 . 99 ( m , 2h ) 2 . 11 ( s , 3h ) 2 . 18 ( s , 3h ) 2 . 24 ( d , j = 3 . 22 hz , 4h ) 2 . 58 - 2 . 73 ( m , 2h ) 2 . 89 ( t , j = 7 . 62 hz , 1h ) 3 . 93 - 4 . 10 ( m , 3h ) 6 . 42 ( s , 1h ) 6 . 72 ( d , j = 12 . 89 hz , 2h ) 6 . 84 - 6 . 93 ( m , 3h ) 6 . 98 ( d , j = 8 . 50 hz , 2h ) 7 . 07 ( s , 2h ) 7 . 19 - 7 . 27 ( m , 1h ) 7 . 27 - 7 . 36 ( m , 2h ) 7 . 75 - 7 . 88 ( m , 3h ) 9 . 88 ( s , 1h ). a mixture of ( e )-( 4 -(( 3 -( 3 , 5 - difluorophenyl )- 4 -( 3 , 4 - dimethylphenyl ) but - 3 - en - 1 - yl ) thio ) phenyl ) methanol ( 987 mg , 2 . 4 mmoles ), 500 mg of molecular sieve , nmo ( 562 mg , 2 . 0 eq ) and tpap ( 40 mg ) were reacted to give intermediate 23 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 2 . 23 ( s , 3h ) 2 . 28 ( s , 3h ) 2 . 96 - 3 . 09 ( m , 4h ) 6 . 70 - 6 . 80 ( m , 1h ) 6 . 81 ( s , 1h ) 6 . 92 - 7 . 01 ( m , 2h ) 7 . 03 ( d , j = 5 . 57 hz , 2h ) 7 . 07 - 7 . 13 ( m , 1h ) 7 . 20 ( d , j = 8 . 50 hz , 2h ) 7 . 66 ( d , j = 8 . 20 hz , 2h ) 9 . 91 ( s , 1h ). ( mixture of isomers ) a mixture of intermediate 21 ( 156 mg , 0 . 38 mmoles ), azetidine carboxylic acid ( 39 mg , 1 . 0 eq ), hoac ( 5 drops ) and nacnbh 3 ( 24 . 2 mg , 1 . 0 eq ) were reacted to give compound 1 . 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 73 - 1 . 95 ( m , 2h ) 2 . 07 ( s , 3h ) 2 . 14 ( s , 3h ) 2 . 65 ( t , j = 7 . 18 hz , 2h ) 3 . 20 - 3 . 42 ( m , 1h ) 3 . 82 - 4 . 02 ( m , 4h ) 4 . 07 ( s , 2h ) 4 . 12 - 4 . 28 ( m , 2h ) 6 . 52 - 6 . 64 ( m , 2h ) 6 . 70 ( s , 1h ) 6 . 78 - 6 . 94 ( m , 4h ) 6 . 96 - 7 . 14 ( m , 2h ) 7 . 34 ( d , j = 8 . 50 hz , 2h ). a mixture of intermediate 22 ( 162 mg , 0 . 43 mmoles ), azetidine carboxylic acid ( 43 . 5 mg , 1 . 0 eq ), hoac ( 5 drops ) and nacnbh 3 ( 27 . 0 mg , 1 . 0 eq ) were reacted to give compound 2 . ( mixture of isomers ): 1 h nmr ( 300 mhz , cdcl 3 ) δ ppm 1 . 79 - 1 . 96 ( m , 2h ) 1 . 97 - 2 . 06 ( m , 1h ) 2 . 10 ( s , 3h ) 2 . 17 ( s , 3h ) 2 . 25 ( s , 4h ) 2 . 53 - 2 . 69 ( m , 2h ) 2 . 77 - 2 . 94 ( m , 1h ) 3 . 23 - 3 . 42 ( m , 2h ) 3 . 80 - 4 . 02 ( m , 7h ) 4 . 02 - 4 . 23 ( m , 6h ) 6 . 30 - 6 . 49 ( m , 1h ) 6 . 69 ( d , j = 6 . 74 hz , 1h ) 6 . 76 ( s , 1h ) 6 . 78 - 6 . 93 ( m , 6h ) 7 . 00 - 7 . 05 ( m , 1h ) 7 . 08 ( br . s , 2h ) 7 . 16 - 7 . 24 ( m , 1h ) 7 . 25 - 7 . 37 ( m , 5h ). a mixture of intermediate 23 ( 265 mg , 0 . 65 mmoles ), azetidine carboxylic acid ( 65 . 0 mg , 1 . 0 eq ), hoac ( 5 drops ) and nacnbh 3 ( 41 . 0 mg , 1 . 0 eq ) were reacted to give compound 3 . ( mixture of isomers ): 1 h nmr ( 300 mhz , dmso - d 6 ) δ ppm 2 . 04 ( s , 3h ) 2 . 09 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 20 ( s , 3h ) 2 . 67 - 2 . 78 ( m , 1h ) 2 . 85 - 2 . 97 ( m , 3h ) 3 . 13 ( d , j = 2 . 93 hz , 3h ) 3 . 32 ( br . s ., 2h ) 3 . 46 ( s , 2h ) 6 . 47 ( s , 1h ) 6 . 50 - 6 . 58 ( m , 1h ) 6 . 71 ( s , 1h ) 6 . 78 - 6 . 91 ( m , 2h ) 6 . 94 - 7 . 11 ( m , 1h ) 7 . 10 - 7 . 27 ( m , 5h ). a sample of intermediate 5 ( 100 mg , 0 . 23 mmoles ) was dissolved in minimum thf . methanol ( 5 ml ) was then added followed by 5 drops of hoac . azetidine - 3 - carboxylic acid ( 23 mg , 1 . 0 eq ) was added and the resulting mixture was stirred at room temperature for 30 minutes . nacnbh 3 ( 14 . 4 mg , 1 . 0 eq ) was dissolved in 0 . 5 ml meoh and added to the reaction . the resulting mixture was stirred at room temperature for 3 hours . it was then quenched with water and concentrated on the rotary evaporator . the crude mixture was purified by mplc to give compound 4 . 1 h nmr ( 300 mhz , cd 3 od ) δ ppm 1 . 46 - 1 . 58 ( m , 2h ) 1 . 62 - 1 . 74 ( m , 2h ) 2 . 08 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 51 ( t , j = 7 . 18 hz , 2h ) 2 . 96 ( t , j = 7 . 03 hz , 2h ) 3 . 36 ( t , j = 8 . 20 hz , 1h ) 4 . 00 - 4 . 15 ( m , 4h ) 4 . 24 ( s , 2h ) 6 . 45 ( s , 1h ) 6 . 60 ( d , j = 7 . 90 hz , 1h ) 6 . 63 - 6 . 73 ( m , 3h ) 6 . 84 ( m , 2h ) 7 . 33 ( br . s , 4h ). a mixture of intermediate 20 ( 236 mg , 0 . 58 mmoles ), azetidine carboxylic acid ( 59 mg , 1 . 0 eq ), hoac ( 10 drops ) and nacnbh 3 ( 36 . 7 mg , 1 eq ) were reacted to give compound 5 . 1 h nmr ( 300 mhz , cd 3 od ) δ ppm 1 . 78 - 1 . 88 ( m , 2h ) 2 . 05 ( s , 3h ) 2 . 14 ( s , 3h ) 2 . 69 ( t , j = 7 . 03 hz , 2h ) 3 . 33 - 3 . 43 ( m , 1h ) 4 . 02 ( t , j = 6 . 15 hz , 2h ) 4 . 12 ( d , j = 8 . 20 hz , 4h ) 4 . 24 ( s , 2h ) 6 . 47 ( s , 1h ) 6 . 54 - 6 . 58 ( m , 1h ) 6 . 65 ( s , 1h ) 6 . 81 ( d , j = 7 . 91 hz , 1h ) 6 . 94 - 7 . 00 ( m , 2h ) 7 . 06 - 7 . 11 ( m , 1h ) 7 . 15 - 7 . 18 ( m , 1h ) 7 . 23 - 7 . 29 ( m , 2h ) 7 . 35 ( d , j = 8 . 79 hz , 2h ). a mixture of intermediate 10 ( 200 mg , 0 . 5 mmoles ), azetidine carboxylic acid ( 49 . 75 mg , 1 . 0 eq ), hoac ( 10 drops ) and nacnbh 3 ( 31 mg , 1 eq ) were reacted to give compound 6 . 1 h nmr ( 300 mhz , cd 3 od ) δ ppm 1 . 79 - 1 . 91 ( m , 2h ) 2 . 07 ( s , 3h ) 2 . 15 ( s , 3h ) 2 . 68 ( t , j = 7 . 03 hz , 2h ) 3 . 36 ( t , j = 8 . 50 hz , 1h ) 4 . 02 ( t , j = 6 . 15 hz , 2h ) 4 . 11 ( d , j = 8 . 50 hz , 4h ) 4 . 23 ( s , 2h ) 6 . 50 ( s , 1h ) 6 . 55 - 6 . 61 ( m , 1h ) 6 . 68 ( s , 1h ) 6 . 71 - 6 . 88 ( m , 4h ) 6 . 94 - 7 . 00 ( m , 2h ) 7 . 36 ( d , j = 8 . 50 hz , 2h ). a mixture of intermediate 15 ( 143 mg , 0 . 34 mmoles ), azetidine carboxylic acid ( 34 mg , 1 . 0 eq ), hoac ( 7 drops ) and nacnbh 3 ( 21 . 2 mg , 1 eq ) were reacted to give compound 7 . 1 h nmr ( 300 mhz , dmso - d 6 ) δ ppm 1 . 28 - 1 . 57 ( m , 2h ) 1 . 76 - 1 . 95 ( m , 1h ) 1 . 97 - 2 . 14 ( m , 1h ) 2 . 23 ( s , 6h ) 2 . 85 - 3 . 02 ( m , 2h ) 3 . 06 - 3 . 19 ( m , 2h ) 3 . 23 - 3 . 34 ( m , 2h ) 3 . 44 ( s , 2h ) 4 . 91 ( t , j = 7 . 90 hz , 1h ) 6 . 97 - 7 . 19 ( m , 8h ) 7 . 23 ( d , j = 7 . 91 hz , 1h ) 7 . 73 - 7 . 81 ( m , 2h ). compounds were synthesized and tested for s1p1 activity using the gtp γ 35 s binding assay . these compounds may be assessed for their ability to activate or block activation of the human s1p1 receptor in cells stably expressing the s1p1 receptor . gtp γ 35 s binding was measured in the medium containing ( mm ) hepes 25 , ph 7 . 4 , mgcl 2 10 , nacl 100 , dithitothreitol 0 . 5 , digitonin 0 . 003 %, 0 . 2 nm gtp γ 35 5 , and 5 μg membrane protein in a volume of 150 μl . test compounds were included in the concentration range from 0 . 08 to 5 , 000 nm unless indicated otherwise . membranes were incubated with 100 μm 5 ′- adenylylimmidodiphosphate for 30 min , and subsequently with 10 μm gdp for 10 min on ice . drug solutions and membrane were mixed , and then reactions were initiated by adding gtp γ 35 s and continued for 30 min at 25 ° c . reaction mixtures were filtered over whatman gf / b filters under vacuum , and washed three times with 3 ml of ice - cold buffer ( hepes 25 , ph7 . 4 , mgcl 2 10 and nacl 100 ). filters were dried and mixed with scintillant , and counted for 35 s activity using a β - counter . agonist - induced gtp γ 35 s binding was obtained by subtracting that in the absence of agonist . binding data were analyzed using a non - linear regression method . in case of antagonist assay , the reaction mixture contained 10 nm s1p in the presence of test antagonist at concentrations ranging from 0 . 08 to 5000 nm . table 1 shows activity potency : s1p1 receptor from gtp γ 35 s : nm , ( ec 50 ). s1p1 receptor from gtp γ 35 s : nm , ( ec 50 ).