(2S)-1,1,1-trifluoropropan-2-ol

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

Procedure: The title compound was prepared in an analogous manner as described for example 24j, starting from [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.409 g, 1 mmol), KOH (0.06 g, 1.05 mmol) and (S)-1,1,1-trifluoro-propan-2-ol (0.583 g, 5 mmol) and was obtained as a yellow oil, which was used as such in the next step: TLC (hexane-EtOAc 1:1) Rf=0.37; HPLC RtA=2.36 min; ESIMS [M+H-isobutylene]+=443. was obtained as a yellow oil, which HPLC RtA=2.36 min

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

Procedure: To a solution of methyl 5-bromo-6-(4-chlorophenyl)pyrazine-2-carboxylate (0.847 g, 2.59 mmol, Eq: 1.00) in dry DMSO (8 ml) was added cesium carbonate (1.54 g, 2.84 mmol, Eq: 1.1) and (S)-1,1,1-trifluoro-2-propanol (324 mg, 233 μl, 2.84 mmol, Eq: 1.1) and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was dried over MgSO4 evaporated and purified by flash chromatography (silica gel, 100 g, 10% to 50% EtOAc in heptane) to yield the title compound as light yellow oil (0.724 g, 77.6%), MS 361.1 (M+H)+. The reaction mixture was partitioned between water and ethyl acetate the phases were separated the organic phase was dried over MgSO4 evaporated purified by flash chromatography (silica gel, 100 g, 10% to 50% EtOAc in heptane)

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

Procedure: Triethylamine (2.3 mL) is added to a solution of 4-dimethylaminopyridine (13 mg), (S)-1,1,1-trifluoro-propan-2-ol (75% in tert-butyl methyl ether; 2.00 g), and 4-nitrophenyl chloroformate (2.90 g) in dichloromethane (80 mL) chilled in an ice bath. The solution is stirred in the cooling bath for 30 min and then at room temperature overnight. The solution is washed with 10% aqueous K2CO3 solution and water and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane) to give the title compound. chilled in an ice bath at room temperature overnight The solution is washed with 10% aqueous K2CO3 solution and water dried (MgSO4) The solvent is evaporated the residue is chromatographed on silica gel (dichloromethane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 ml) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (135 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1 M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent:hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow oil. the resulting mixture was cooled to room temperature was stirred at room temperature for 1 hour extracted with CHCl3 The extract was washed with water dried over Na2SO4 concentrated The residue was purified with silica gel column chromatography (eluent:hexane/EtOAc=1/0˜50/50)

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

Procedure: The title compound was prepared in an analogous manner as described for example 24j, starting from [(3R,4S,5S)-5-(3,5-difluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.409 g, 1 mmol), KOH (0.06 g, 1.05 mmol) and (S)-1,1,1-trifluoro-propan-2-ol (0.583 g, 5 mmol) and was obtained as a yellow oil, which was used as such in the next step: TLC (hexane-EtOAc 1:1) Rf=0.37; HPLC RtA=2.36 min; ESIMS [M+H-isobutylene]+=443. was obtained as a yellow oil, which HPLC RtA=2.36 min

Conditions: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-1,1,1-Trifluoro-propan-2-ol (100 g, 877 mmol) was dissolved in dimethylacetamide (600 mL) and the solution was cooled to 2° C. (ice bath). A solution of sodium tert-butoxide (77.5 g, 790 mmol) in dimethylacetamide (100 mL) was added at 2° C. and the mixture was stirred for 15 min. This solution was treated with a solution of 2-chloro-4-fluoro-1-tritylsulfanyl-benzene (200 g, 494 mmol) in dimethylacetamide (100 mL) at room temperature and subsequently stirred for 3 h at 50° C. It was then poured into a mixture of brine (200 mL), ice (1.2 kg) and water (2.0 L), and extracted with tert-butyl-methylether (2×1000 mL). The combined organic extracts were washed with brine/water 1:1 (v/v, 300 mL) and concentrated in vacuo to give the crude product as a yellow viscous oil. The oil was dissolved in ethanol (1.6 L), before water (240 mL) was slowly added at room temperature. The resulting suspension was stirred for 14 h, cooled to 2° C. (ice bath) and stirred for another 2 h, before it was filtered. The solid was washed with ethanol/water 4:1 (v/v, 500 mL) and dried in vacuo to afford the title compound as a white crystalline solid (238 g, 97%). 1H NMR (CDCl3, 400 MHz): δ 1.43 (d, J=6.5 Hz, 3H), 4.50 (qq, J=6.2 Hz, 6.2 Hz, 1H), 6.44 (dd, J=2.8 Hz, 8.7 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 7.18-7.27 (m, 9H), 7.33-7.39 (m, 6H). subsequently stirred for 3 h at 50° C extracted with tert-butyl-methylether (2×1000 mL) The combined organic extracts were washed with brine/water 1:1 (v/v, 300 mL) concentrated in vacuo to give the crude product as a yellow viscous oil was slowly added at room temperature The resulting suspension was stirred for 14 h cooled to 2° C. (ice bath) stirred for another 2 h, before it was filtered The solid was washed with ethanol/water 4:1 (v/v, 500 mL) dried in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 mL) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (1.35 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow foam. the resulting mixture was cooled to room temperature was stirred at room temperature for 1 hour extracted with CHCl3 The extract was washed with water dried over Na2SO4 concentrated The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-1,1,1-trifluoro-2-propanol (1.95 g) in CHCl3 (30 mL) was added 4-nitrophenyl chloroformate (5.16 g) and pyridine (1.35 g) at room temperature. After 1-hour stirring at 60° C., the resulting mixture was cooled to room temperature. To the resulting mixture was added 2-(dimethylamino)ethanol (1.52 g) and was stirred at room temperature for 1 hour. The mixture was poured into 1M aqueous solution of HCl and extracted with CHCl3. The extract was washed with water and then dried over Na2SO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give 4-nitrophenyl (2S)-1,1,1-trifluoropropan-2-yl carbonate as a pale yellow foam. the resulting mixture was cooled to room temperature was stirred at room temperature for 1 hour extracted with CHCl3 The extract was washed with water dried over Na2SO4 concentrated The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50)

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

Procedure: In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H). addition The mixture was poured into ice the solid was filtered washed with additional water The brown solid was further dried in vacuo

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

Procedure: In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H). addition The mixture was poured into ice the solid was filtered washed with additional water The brown solid was further dried in vacuo

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

Procedure: In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 ml) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H). addition The mixture was poured into ice the solid was filtered washed with additional water The brown solid was further dried in vacuo

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

Procedure: In a 4-neck flask, commercially available 2-chloro-5-nitropyridine (71.9 g) and (S)-1,1,1-trifluoropropan-2-ol (54.3 g) were dissolved in DMF (610 mL) and sodium hydride (20 g, 55%) was added at a temperature of 16 to 18° C. (ice cooling). Following addition, the mixture was allowed to stir for 1 hour. The mixture was poured into ice and was allowed to hydrolyze. The suspension was warmed to RT over a period of 12 hours and the solid was filtered and washed with additional water and then with a small amount of hexanes (50 mL). The brown solid was further dried in vacuo to provide the title compound. (81.9 g). 1H-NMR (δ, CDCl3): 9.06 (m, 1H), 8.43 (dd, 1H), 6.93 (d, 1H), 5.87 (m, 1H); 1.54 (m, 3H). addition The mixture was poured into ice the solid was filtered washed with additional water The brown solid was further dried in vacuo