Sodium 1-propanethiolate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A similar procedure as described in Example 47, step 2 was used, starting from 3,5-dibromoanisole (5.3 g, 19.93 mmol) and sodium 1-propanethiolate (2.47 g, 23.92 mmol) to afford 1-bromo-3-methoxy-5-propylsulfanyl-benzene (2.01 g, 39%) as a light yellow oil: EI(+)-HRMS m/e calcd for C10H13BrOS (M)+ 259.9870, found 259.9870.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-[(propan-2-ylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to afford the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z=274 Found: m/z=218 (M-tert-Bu), Rt=2.51 min.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask was added (R)-3-(2-methoxy-6-(1-methyl-1H-indol-5-yl)pyridin-3-yl)-3-methylpyrrolidin-2-one (534 mg, 1.59 mmol), sodium n-propanethiolate (1287 mg, 13.11 mmol), and DMF (9.5 mL). The mixture was stirred for 17 h at 110° C. Due to incomplete reaction, additional sodium n-propanethiolate (667 mg) was added. The reaction was stirred for 30 h at 110° C. The mixture was diluted with EtOH, concentrated and partitioned between 15% EtOH/DCM and pH 7 phosphate buffer. The aqueous phase was extracted 2× and the combined organic layers were dried over Na2SO4 to provide a crude product. Purification by slurrying at r.t. overnight (3.3 mL EtOAc/0.33 mL EtOH) followed by filtration, wash with EtOAc several times and dried under reduced pressure for 3 days at 60-80° C. provided (R)-6-(1-methyl-1H-indol-5-yl)-3-(3-methyl-2-oxopyrrolidin-3-yl)pyridin-2(1H)-one (495 mg, 97%) as a yellow solid. 1H NMR (600 MHz, methanol-d4) δ: 1.54 (s, 3H), 1.91-1.98 (m, 1H), 2.68-2.79 (m, 1H), 3.48 (dd, 2H), 3.85 (s, 3H), 6.55 (d, 1H), 6.62 (d, 1H), 7.26 (d, 1H), 7.47 (dd, 1H), 7.49-7.51 (m, 1H), 7.63 (d, 1H), 7.89 (d, 1H); MS (ES+)(M+H) 322. was added The reaction was stirred for 30 h at 110° C concentrated partitioned between 15% EtOH/DCM and pH 7 phosphate buffer The aqueous phase was extracted 2× the combined organic layers were dried over Na2SO4 to provide a crude product Purification by slurrying at r.t. overnight (3.3 mL EtOAc/0.33 mL EtOH) followed by filtration wash with EtOAc several times dried under reduced pressure for 3 days at 60-80° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A similar procedure as described in Example 47, step 2 was used, starting from 3,5-dibromoanisole (5.3 g, 19.93 mmol) and sodium 1-propanethiolate (2.47 g, 23.92 mmol) to afford 1-bromo-3-methoxy-5-propylsulfanyl-benzene (2.01 g, 39%) as a light yellow oil: EI(+)-HRMS m/e calcd for C10H13BrOS (M)+ 259.9870, found 259.9870.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A similar procedure as described in Example 47, step 2 was used, starting from 3,5-dibromoanisole (5.3 g, 19.93 mmol) and sodium 1-propanethiolate (2.47 g, 23.92 mmol) to afford 1-bromo-3-methoxy-5-propylsulfanyl-benzene (2.01 g, 39%) as a light yellow oil: EI(+)-HRMS m/e calcd for C10H13BrOS (M)+ 259.9870, found 259.9870.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-[(propan-2-ylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to afford the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z=274 Found: m/z=218 (M-tert-Bu), Rt=2.51 min.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyl 4-[(propan-2-ylsulfanyl)methyl]piperidine-1-carboxylate was prepared from tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (Intermediate 181, 0.320 g, 1.091 mmol) and sodium propanethiolate (0.161 g, 1.636 mmol) according to the method described for Intermediate 183 to afford the title compound (0.180 g, 60%). Method B HPLC-MS: MH+ requires m/z=274 Found: m/z=218 (M-tert-Bu), Rt=2.51 min.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3α-acetylthioandrostane-6,17-dione (1.07 g) in MeOH (30 mL), sodium propanethiolate (0.28 g) was added and the reaction stirred for 20 minutes at room temperature. The mixture was neutralized with 1N HCl. Water was added and the mixture extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4 and evaporated to dryness to give 3α-mercaptoandrostane-6,17-dione (943 mg, 100%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.54 (1H, m), 2.77 (1H, m), 2.54 (1H, d), 2.45-1.10 (19H, m), 0.78 (3H, s), 0.66 (3H, s). was added the mixture extracted with EtOAc The organic layer was separated washed with brine dried over Na2SO4 evaporated to dryness

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve sodium propanethiolate (7.5 g) in DMF (250 mL) at ambient temperature, then chill to −30° C. and add 1-bromo-3,5-difluorobenzene (8.35 mL). After 1 hour, warm to −15° C., and stir for an additional 3 hours. Pour into water (2 L) and extract into hexanes (3×500 mL). Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter and concentrate. Filter through a plug of silica gel, wash with 10:90 ethyl acetate:hexanes and concentrate to give 1-bromo-3-fluoro-5-propylsulfanylbenzene (16.2 g, 90%). The title compound is prepared essentially as described in Preparation 343. warm to −15° C. extract into hexanes (3×500 mL) Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL) dry (magnesium sulfate) filter concentrate Filter through a plug of silica gel wash with 10:90 ethyl acetate hexanes and concentrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3α-acetylthioandrostane-6,17-dione (1.07 g) in MeOH (30 mL), sodium propanethiolate (0.28 g) was added and the reaction stirred for 20 minutes at room temperature. The mixture was neutralized with 1N HCl. Water was added and the mixture extracted with EtOAc. The organic layer was separated, washed with brine, and dried over Na2SO4 and evaporated to dryness to give 3α-mercaptoandrostane-6,17-dione (943 mg, 100%), used without further purification. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.54 (1H, m), 2.77 (1H, m), 2.54 (1H, d), 2.45-1.10 (19H, m), 0.78 (3H, s), 0.66 (3H, s). was added the mixture extracted with EtOAc The organic layer was separated washed with brine dried over Na2SO4 evaporated to dryness

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve sodium propanethiolate (7.5 g) in DMF (250 mL) at ambient temperature, then chill to −30° C. and add 1-bromo-3,5-difluorobenzene (8.35 mL). After 1 hour, warm to −15° C., and stir for an additional 3 hours. Pour into water (2 L) and extract into hexanes (3×500 mL). Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate), filter and concentrate. Filter through a plug of silica gel, wash with 10:90 ethyl acetate:hexanes and concentrate to give 1-bromo-3-fluoro-5-propylsulfanylbenzene (16.2 g, 90%). The title compound is prepared essentially as described in Preparation 343. warm to −15° C. extract into hexanes (3×500 mL) Wash the resulting organic solution with saturated aqueous sodium chloride (100 mL) dry (magnesium sulfate) filter concentrate Filter through a plug of silica gel wash with 10:90 ethyl acetate hexanes and concentrate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Solid sodium 1-propanethiolate (2.35 g, 24.0 mmol) was added to a 100 mL round-bottomed flask containing a solution of 4-chloro-2-methyl-[1,10]phenanthroline (1.10 g, 4.8 mmol) in methanol (50 mL). The reaction mixture was refluxed for 18 hours and allowed to reach room temperature. The solvent was removed in a rotary evaporator and the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) and transferred to a separatory funnel. The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The solid residue was treated with ethyl ether, filtered, and dried yielding 0.98 g of a dark orange solid (76%). The reaction mixture was refluxed for 18 hours to reach room temperature The solvent was removed in a rotary evaporator the residue was treated with methylene choride (100 mL) and saturated NaHCO3 (100 mL) transferred to a separatory funnel The organic layer was washed with brine (100 mL) dried (Na2SO4) filtered concentrated in vacuo The solid residue was treated with ethyl ether filtered dried