sodium;propane-2-thiolate

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

Procedure: tert-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) and sodium 2-propanethiolate (0.147 g, 1.50 mmol) were combined in DMF (3 mL) and stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane to afford the title compound as a colourless oil (0.179 g, 60%). 1H NMR (500 MHZ, CDCl3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d). washed with water (3×10 mL) The organic layer was dried over sodium sulfate concentrated to yield a yellow oil This was purified by FCC eluting with a gradient of 0-20% EtOAc in heptane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (5.51 g, 27 mmol) and sodium 2-propanethiolate (2.90 g, 26.6 mmol, purity 90%; 1 eq.) were initially charged in DMF (125 ml). Potassium carbonate (9.19 g, 66.5 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 4 h. TLC control then showed complete conversion. The reaction mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound was isolated as a solid (6.72 g, 96% of theory). The reaction mixture was concentrated

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (90 g, 258 mmol) was treated with KOH (14.48 g, 258 mmol) in water. The solution was concentrated and azeotroped with toluene (three times). The resulting solid was dissolved in dimethyl sulfoxide (1 L) and sodium 2-propanethiolate (57.0 g, 581 mmol) was added. The mixture was heated to 100° C. and stirred overnight. The solution was cooled to room temperature and MeI (0.048 L, 774 mmol) was added. After stirring for 1 h, water (500 mL) was added slowly with stirring. The solid precipitate was collected by filtration, washed with water, and dried. The filter cake was dissolved in tetrahydrofuran (1.5 L) and cooled in an ice bath. Oxone (317 g, 516 mmol) was added as a solution in water (1.5 L). The ice bath was removed, and stirring was continued for 2 h. The organic phase was separated, and the aqueous phase was extracted with methylene chloride (three times). The THF and methylene chloride extracts were combined, concentrated to approximately 1 L, diluted with methylene chloride (500 mL), and washed with brine. The organic phase was concentrated to afford a brown residue. Methanol was added and the solution was heated to reflux with stirring. The mixture was cooled to room temperature and stirred overnight. The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to afford methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (114 g, 97% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) 68.29-8.36 (m, 2H), 8.17 (d, J=8.78 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J=7.53 Hz, 1H), 7.85 (d, J=7.78 Hz, 1H), 7.76 (t, J=7.78 Hz, 1H), 4.13 (s, 3H), 3.47 (quin, J=6.71 Hz, 1H), 2.45 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H); MS (m/z) 452.1 (M+H+). The solution was concentrated azeotroped with toluene (three times) The resulting solid was dissolved in dimethyl sulfoxide (1 L) The solution was cooled to room temperature After stirring for 1 h with stirring The solid precipitate was collected by filtration washed with water dried The filter cake was dissolved in tetrahydrofuran (1.5 L) cooled in an ice bath The ice bath was removed stirring was continued for 2 h The organic phase was separated the aqueous phase was extracted with methylene chloride (three times) concentrated to approximately 1 L diluted with methylene chloride (500 mL) washed with brine The organic phase was concentrated to afford a brown residue the solution was heated to reflux with stirring The mixture was cooled to room temperature stirred overnight The precipitate was collected by filtration washed with methanol dried under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-Fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (90 g, 258 mmol) was treated with KOH (14.48 g, 258 mmol) in water. The solution was concentrated and azeotroped with toluene (three times). The resulting solid was dissolved in dimethyl sulfoxide (1 L) and sodium 2-propanethiolate (57.0 g, 581 mmol) was added. The mixture was heated to 100° C. and stirred overnight. The solution was cooled to room temperature and MeI (0.048 L, 774 mmol) was added. After stirring for 1 h, water (500 mL) was added slowly with stirring. The solid precipitate was collected by filtration, washed with water, and dried. The filter cake was dissolved in tetrahydrofuran (1.5 L) and cooled in an ice bath. Oxone (317 g, 516 mmol) was added as a solution in water (1.5 L). The ice bath was removed, and stirring was continued for 2 h. The organic phase was separated, and the aqueous phase was extracted with methylene chloride (three times). The THF and methylene chloride extracts were combined, concentrated to approximately 1 L, diluted with methylene chloride (500 mL), and washed with brine. The organic phase was concentrated to afford a brown residue. Methanol was added and the solution was heated to reflux with stirring. The mixture was cooled to room temperature and stirred overnight. The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to afford methyl 3-methyl-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (114 g, 97% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) 68.29-8.36 (m, 2H), 8.17 (d, J=8.78 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J=7.53 Hz, 1H), 7.85 (d, J=7.78 Hz, 1H), 7.76 (t, J=7.78 Hz, 1H), 4.13 (s, 3H), 3.47 (quin, J=6.71 Hz, 1H), 2.45 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H); MS (m/z) 452.1 (M+H+). The solution was concentrated azeotroped with toluene (three times) The resulting solid was dissolved in dimethyl sulfoxide (1 L) The solution was cooled to room temperature After stirring for 1 h with stirring The solid precipitate was collected by filtration washed with water dried The filter cake was dissolved in tetrahydrofuran (1.5 L) cooled in an ice bath The ice bath was removed stirring was continued for 2 h The organic phase was separated the aqueous phase was extracted with methylene chloride (three times) concentrated to approximately 1 L diluted with methylene chloride (500 mL) washed with brine The organic phase was concentrated to afford a brown residue the solution was heated to reflux with stirring The mixture was cooled to room temperature stirred overnight The precipitate was collected by filtration washed with methanol dried under reduced pressure

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

Procedure: Sodium hydride (1.265 g, 31.6 mmol) was added to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred for 20 min. Sodium 2-propanethiolate (2.53 g, 23.20 mmol) was added, and the resulting mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with additional portions of NaH (1.27 g of 60% dispersion in mineral oil, 31.6 mmol) and sodium 2-propanethiolate (2.53 g, 23.20 mmol), and heated at 100° C. for an additional 4 hours. The reaction mixture was cooled to room temperature. Iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 58% yield). This material was used in the next step without further purification. MS (m/z) 450.1 (M+H+). the resulting mixture was stirred at 100° C. overnight heated at 100° C. for an additional 4 hours The reaction mixture was cooled to room temperature the mixture was stirred for 2 hours extracted with methylene chloride (three times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride)

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

Procedure: Sodium hydride (1.265 g, 31.6 mmol) was added to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred for 20 min. Sodium 2-propanethiolate (2.53 g, 23.20 mmol) was added, and the resulting mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with additional portions of NaH (1.27 g of 60% dispersion in mineral oil, 31.6 mmol) and sodium 2-propanethiolate (2.53 g, 23.20 mmol), and heated at 100° C. for an additional 4 hours. The reaction mixture was cooled to room temperature. Iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 58% yield). This material was used in the next step without further purification. MS (m/z) 450.1 (M+H+). the resulting mixture was stirred at 100° C. overnight heated at 100° C. for an additional 4 hours The reaction mixture was cooled to room temperature the mixture was stirred for 2 hours extracted with methylene chloride (three times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride)

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

Procedure: Sodium hydride (1.265 g, 31.6 mmol) was added to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred for 20 min. Sodium 2-propanethiolate (2.53 g, 23.20 mmol) was added, and the resulting mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with NaH (1.27 g of 60% dispersion in mineral oil, 31.6 mmol) and sodium 2-propanethiolate (2.53 g, 23.20 mmol), and heated at 100° C. for an additional 4 hours. The reaction mixture was cooled to room temperature. Iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 58% yield). This material was used in the next step without further purification. MS (m/z) 450.1 (M+H+). the resulting mixture was stirred at 100° C. overnight heated at 100° C. for an additional 4 hours The reaction mixture was cooled to room temperature the mixture was stirred for 2 hours extracted with methylene chloride (three times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride)

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

Procedure: Sodium hydride (1.265 g, 31.6 mmol) was added to a suspension of 6-fluoro-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.0 g, 21.09 mmol) in dimethyl sulfoxide (50 mL), and the mixture was stirred for 20 min. Sodium 2-propanethiolate (2.53 g, 23.20 mmol) was added, and the resulting mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with NaH (1.27 g of 60% dispersion in mineral oil, 31.6 mmol) and sodium 2-propanethiolate (2.53 g, 23.20 mmol), and heated at 100° C. for an additional 4 hours. The reaction mixture was cooled to room temperature. Iodomethane (3.96 mL, 63.3 mmol) was added, and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride) to afford methyl 3-methyl-6-[(1-methylethyl)thio]-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.5 g, 58% yield). This material was used in the next step without further purification. MS (m/z) 450.1 (M+H+). the resulting mixture was stirred at 100° C. overnight heated at 100° C. for an additional 4 hours The reaction mixture was cooled to room temperature the mixture was stirred for 2 hours extracted with methylene chloride (three times) The combined organic extracts were washed with brine dried over Na2SO4 filtered concentrated in vacuo The residue was purified via column chromatography (ISCO, 330 g silica, 0-10% ethyl acetate/methylene chloride)

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

Procedure: (Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g). extracted with ethyl acetate The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: (Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g). extracted with ethyl acetate The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: (Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g). extracted with ethyl acetate The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate The solvent was evaporated under reduced pressure

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

Procedure: (Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (6.0 g) and sodium propane-2-thiolate (4.16 g) was stirred in N,N-dimethylformamide (30 ml) at room temperature for 18 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-[(1-methylethyl)sulfanyl]benzonitrile (7.26 g). extracted with ethyl acetate The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine dried over magnesium sulfate The solvent was evaporated under reduced pressure