O-ethyl ethanethioate

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

Procedure: To a stirred suspension of 570 mg (60% in oil) (14.2 mmol) of sodium hydride in 9 mL of DMF under atmospheric nitrogen at 0° C. was added dropwise 1.64 mL of ethyl thioacetate. After stirring at room temperature for 1 h, it was cooled to 0° C. A solution of 2 g (7.5 mmol) of 2,6-dimethyl-3-nitro-phenyl trifluoromethanesulfonate in 6 mL of DMF was introduced. After stirring at-0° C. for 20 min. it was partitioned between ethyl ether and 3N HCl. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by chromatography using 5% ethyl acetate: hexanes to provide 1.2 g (60%) of 2,6-dimethyl-4-nitro-thiophenol. 1H NMR (CDCl3): 2.43 (s, 3H), 3.67 (s, 1H), 7.93 (s, 2H). it was cooled to 0° C After stirring at-0° C. for 20 min. it was partitioned between ethyl ether and 3N HCl The combined organic extracts were washed with brine dried over MgSO4 filtered evaporated under reduced pressure The resulting residue was purified by chromatography

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

Procedure: The title compound was prepared in the same manner as in Step 1 of Example C-1, except that an equimolar amount of each of trans-3-methoxy-4-tert-butyldimethylsilyloxy-cinnamic acid prepared in Step 1 of Example C-10 and ethyl thioacetate was used in place of trans-cinnamic acid and ethyl acetate.

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

Procedure: The title compound was prepared in the same manner as in Step 1 of Example C-1, except that an equimolar amount of each of trans-3-methoxy-4-tert-butyldimethylsilyloxy-cinnamic acid prepared in Step 1 of Example C-10 and ethyl thioacetate was used in place of trans-cinnamic acid and ethyl acetate.

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

Procedure: Phosphorus oxychloride (7.9 ml, 85 mmol) was added to dimethylformamide (17.04 ml, 220 mmol) dropwise under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then added dropwise under ice cooling to a solution of 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethanone (21.5 g (100 mmol), prepared as described in T. F. Gallagher et al., Bioorg. Med. Chem., 5, 49–64 (1997)) dissolved in a mixed solution of dimethylformamide (140 ml) and dichloromethane (280 ml). The resulting mixture was stirred at 50° C. for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, water was added, adjusted to pH 9 to 10 by adding an aqueous solution of 6 N sodium hydroxide and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml). To the resulting solution was added ethyl thioacetate (11 ml, 100 mmol), and then triethylamine (25 ml, 180 mmol) with stirring under ice cooling. The resulting mixture was stirred at room temperature for 1 hour, then 80° C. for 3 hours. The resulting mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3), to give the title compound (18.11 g) as a brown viscous oil (yield 55%). The resulting mixture was stirred at 50° C. for 2 hours At the end of this time, the reaction mixture was cooled to room temperature extracted with dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml) The resulting mixture was stirred at room temperature for 1 hour 80° C. for 3 hours The resulting mixture was cooled to room temperature partitioned between water and dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3)

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

Procedure: Phosphorus oxychloride (7.9 ml, 85 mmol) was added to dimethylformamide (17.04 ml, 220 mmol) dropwise under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then added dropwise under ice cooling to a solution of 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethanone (21.5 g (100 mmol), prepared as described in T. F. Gallagher et al., Bioorg. Med. Chem., 5, 49–64 (1997)) dissolved in a mixed solution of dimethylformamide (140 ml) and dichloromethane (280 ml). The resulting mixture was stirred at 50° C. for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, water was added, adjusted to pH 9 to 10 by adding an aqueous solution of 6 N sodium hydroxide and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml). To the resulting solution was added ethyl thioacetate (11 ml, 100 mmol), and then triethylamine (25 ml, 180 mmol) with stirring under ice cooling. The resulting mixture was stirred at room temperature for 1 hour, then 80° C. for 3 hours. The resulting mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3), to give the title compound (18.11 g) as a brown viscous oil (yield 55%). The resulting mixture was stirred at 50° C. for 2 hours At the end of this time, the reaction mixture was cooled to room temperature extracted with dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml) The resulting mixture was stirred at room temperature for 1 hour 80° C. for 3 hours The resulting mixture was cooled to room temperature partitioned between water and dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3)

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

Procedure: To a stirred suspension of 570 mg (60% in oil) (14.2 mmol) of sodium hydride in 9 mL of DMF under atmospheric nitrogen at 0° C. was added dropwise 1.64 mL of ethyl thioacetate. After stirring at room temperature for 1 h, it was cooled to 0° C. A solution of 2 g (7.5 mmol) of 2,6-dimethyl-3-nitro-phenyl trifluoromethanesulfonate in 6 mL of DMF was introduced. After stirring at-0° C. for 20 min. it was partitioned between ethyl ether and 3N HCl. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by chromatography using 5% ethyl acetate: hexanes to provide 1.2 g (60%) of 2,6-dimethyl-4-nitro-thiophenol. 1H NMR (CDCl3): 2.43 (s, 3H), 3.67 (s, 1H), 7.93 (s, 2H). it was cooled to 0° C After stirring at-0° C. for 20 min. it was partitioned between ethyl ether and 3N HCl The combined organic extracts were washed with brine dried over MgSO4 filtered evaporated under reduced pressure The resulting residue was purified by chromatography

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

Procedure: The title compound was prepared in the same manner as in Step 1 of Example C-1, except that an equimolar amount of each of trans-3-methoxy-4-tert-butyldimethylsilyloxy-cinnamic acid prepared in Step 1 of Example C-10 and ethyl thioacetate was used in place of trans-cinnamic acid and ethyl acetate.

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

Procedure: Phosphorus oxychloride (7.9 ml, 85 mmol) was added to dimethylformamide (17.04 ml, 220 mmol) dropwise under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then added dropwise under ice cooling to a solution of 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethanone (21.5 g (100 mmol), prepared as described in T. F. Gallagher et al., Bioorg. Med. Chem., 5, 49–64 (1997)) dissolved in a mixed solution of dimethylformamide (140 ml) and dichloromethane (280 ml). The resulting mixture was stirred at 50° C. for 2 hours. At the end of this time, the reaction mixture was cooled to room temperature, water was added, adjusted to pH 9 to 10 by adding an aqueous solution of 6 N sodium hydroxide and then extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml). To the resulting solution was added ethyl thioacetate (11 ml, 100 mmol), and then triethylamine (25 ml, 180 mmol) with stirring under ice cooling. The resulting mixture was stirred at room temperature for 1 hour, then 80° C. for 3 hours. The resulting mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3), to give the title compound (18.11 g) as a brown viscous oil (yield 55%). The resulting mixture was stirred at 50° C. for 2 hours At the end of this time, the reaction mixture was cooled to room temperature extracted with dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was dissolved in a mixed solution of dichloroethane (100 ml) and pyridine (15 ml) The resulting mixture was stirred at room temperature for 1 hour 80° C. for 3 hours The resulting mixture was cooled to room temperature partitioned between water and dichloromethane The organic layer was washed with water dried over anhydrous magnesium sulfate the solvent was removed by distillation under reduced pressure The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=2:3)