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

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

Procedure: Under an atmosphere of argon, (2S,4R)-methyl 4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxylate (200 mg, 331 μmol, Eq: 1.00, [prepared in analogy to General Procedure C, steps C1-C5, using 2-chloro-4-fluorothiophenol in step C2]) and cesium carbonate (194 mg, 595 μmol, Eq: 1.8) were combined with N,N-dimethylacetamide (2 ml) to give a colorless solution. (R)-1,1,1-trifluoropropan-2-ol (90.5 mg, 793 μmol, Eq: 2.4) was added. The reaction mixture was stirred over night at rt. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 5 ml) and extracted with ethyl acetate (5×20 ml). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane) to yield the title compound as a white foam (178 mg, 67.1%, MS (m/e)=594.07 [M+H+]) to give a colorless solution The crude reaction mixture was concentrated in vacuo The residue was poured into HCl (0.5 M, 5 ml) extracted with ethyl acetate (5×20 ml) The organic layers were dried over Na2SO4 concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% EtOAc in heptane)

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

Procedure: The title compound is prepared from (R)-1,1,1-trifluoro-propan-2-ol and 4-nitrophenyl chloroformate following a procedure analogous to that described for Intermediate 20.

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

Procedure: The title compound is prepared from (R)-1,1,1-trifluoro-propan-2-ol and 4-nitrophenyl chloroformate following a procedure analogous to that described for Intermediate 20.

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

Procedure: The title compound is prepared in 76% yield (592 mg, colorless oil) from 6-chloronicotinonitrile (500 mg, 3.61 mmol) and (R)-1,1,1-trifluoropropan-2-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.

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

Procedure: The title compound is prepared in 76% yield (592 mg, colorless oil) from 6-chloronicotinonitrile (500 mg, 3.61 mmol) and (R)-1,1,1-trifluoropropan-2-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) and (2R)-1,1,1-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0° C., followed by stirring at 80° C. for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (70 mg) as a pale yellow solid. the reaction filtered dried The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) crystallized with diisopropyl ether

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) and (2R)-1,1,1-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0° C., followed by stirring at 80° C. for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (70 mg) as a pale yellow solid. the reaction filtered dried The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) crystallized with diisopropyl ether

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixture was cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over a period of 1 h and stirring was continued for 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS 350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h while the internal temperature was kept between 5 to 15° C. Following addition, the mixture was allowed to warm to RT and stirring was continued for another 12 h. The reaction mixture was acidified and partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as a dark liquid (14.5 g). MS (m/e): 206.1 (MH+). was kept between 5 to 15° C addition to warm to RT stirring was continued for another 12 h partitioned between ethyl acetate and water The organic layer was separated dried over Na2SO4 evaporated to dryness The residue was dissolved in methanol (150 ml) Pd on carbon (10% Pd, 1 g) was added The mixture was then hydrogenated at RT for 12 hours The catalyst was removed by filtration the filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixture was cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over a period of 1 h and stirring was continued for 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS 350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h while the internal temperature was kept between 5 to 15° C. Following addition, the mixture was allowed to warm to RT and stirring was continued for another 12 h. The reaction mixture was acidified and partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as a dark liquid (14.5 g). MS (m/e): 206.1 (MH+). was kept between 5 to 15° C addition to warm to RT stirring was continued for another 12 h partitioned between ethyl acetate and water The organic layer was separated dried over Na2SO4 evaporated to dryness The residue was dissolved in methanol (150 ml) Pd on carbon (10% Pd, 1 g) was added The mixture was then hydrogenated at RT for 12 hours The catalyst was removed by filtration the filtrate was concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (55%, 3.22 g) was added to DMF (20 mL) and the mixture was cooled to 0° C. Then, (R)-1,1,1-trifluoro-2-propanol (8.5 g) [CAS 17628-73-8] was added over a period of 1 h and stirring was continued for 30 minutes at 0° C. A solution of 1-fluoro-4-nitro-benzene [CAS 350-46-9] (10 g) in DMF (15 mL) was added over a period of 1.5 h while the internal temperature was kept between 5 to 15° C. Following addition, the mixture was allowed to warm to RT and stirring was continued for another 12 h. The reaction mixture was acidified and partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4 and evaporated to dryness. The residue was dissolved in methanol (150 ml) and Pd on carbon (10% Pd, 1 g) was added. The mixture was then hydrogenated at RT for 12 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to provide crude 4-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine as a dark liquid (14.5 g). MS (m/e): 206.1 (MH+). was kept between 5 to 15° C addition to warm to RT stirring was continued for another 12 h partitioned between ethyl acetate and water The organic layer was separated dried over Na2SO4 evaporated to dryness The residue was dissolved in methanol (150 ml) Pd on carbon (10% Pd, 1 g) was added The mixture was then hydrogenated at RT for 12 hours The catalyst was removed by filtration the filtrate was concentrated in vacuo

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

Procedure: Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-1,1,1-trifluoropropan-2-ol.

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) and (2R)-1,1,1-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0° C., followed by stirring at 80° C. for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (70 mg) as a pale yellow solid. the reaction filtered dried The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) crystallized with diisopropyl ether