1,3-difluoropropan-2-one

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound. the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL) The mixture was extracted with dichloromethane (25 mL) the organic layer was dried over anhydrous magnesium sulfate filtered concentrated The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) stirred for one hour The mixture was concentrated

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

Procedure: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for one hour, the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with dichloromethane (25 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. The mixture was concentrated to give the title compound. the reaction was quenched with saturated aqueous NaHCO3 solution (5 mL) The mixture was extracted with dichloromethane (25 mL) the organic layer was dried over anhydrous magnesium sulfate filtered concentrated The resulting residue was treated with HCl (4.0M in 1,4-dioxane, 4 mL) and methanol (1 mL) stirred for one hour The mixture was concentrated

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

Procedure: To a solution of EXAMPLE 391H (318 mg) in dichloromethane (4 mL) was added 1,3-difluoropropan-2-one (282 mg) and sodium acetoxyborohydride (318 mg). The mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate (300 mL) and washed with 2N aqueous NaOH and brine, and dried over Na2SO4. Filtration and concentration gave the crude product which was dissolved in tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL). LiOH.H2O (450 mg) was added and the mixture was stirred overnight. The mixture was neutralized with 2N aqueous HCl and extracted with ethyl acetate (300 mL) and dichloromethane (300 mL) respectively. The organic extracts were combined and dried over Na2SO4. Filtration and concentration provided the title compound. washed with 2N aqueous NaOH and brine dried over Na2SO4 Filtration and concentration gave the crude product which the mixture was stirred overnight extracted with ethyl acetate (300 mL) and dichloromethane (300 mL) respectively dried over Na2SO4 Filtration and concentration

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

Procedure: A solution of (R)-tert-butyl piperidin-3-ylcarbamate (0.500 g), 1,3-difluoropropan-2-one (0.258 g) and sodium triacetoxyhydroborate (0.794 g) were stirred together in dichloromethane (5 mL) overnight. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with dichloromethane (30 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The crude material was treated with HCl (4.0M dioxane, 2 mL) in methanol (2 mL). After stirring for 2 hours, the reaction was concentrated to provide the title compound. The reaction was quenched with saturated aqueous NaHCO3 (10 mL) extracted with dichloromethane (30 mL) The organic layer was washed with brine (20 mL) dried over magnesium sulfate filtered concentrated The crude material was treated with HCl (4.0M dioxane, 2 mL) in methanol (2 mL) the reaction was concentrated

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

Procedure: To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (−15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound. resulted (−15 drops) were added After 3 hours eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes)

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

Procedure: To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (−15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound. resulted (−15 drops) were added After 3 hours eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes)

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

Procedure: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for 1 hour, the reaction was quenched with saturated NaHCO3 solution (5 mL). The product was extracted into dichloromethane (25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was treated with HCl (4.0M in dioxane, 4 mL) and methanol (1 mL) and stirred for 1 hour. The mixture was concentrated to provide the title compound. the reaction was quenched with saturated NaHCO3 solution (5 mL) The product was extracted into dichloromethane (25 mL) dried over magnesium sulfate filtered concentrated The resulting crude material was treated with HCl (4.0M in dioxane, 4 mL) and methanol (1 mL) stirred for 1 hour The mixture was concentrated

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

Procedure: To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (0.853 g). After stirring for 1 hour, the reaction was quenched with saturated NaHCO3 solution (5 mL). The product was extracted into dichloromethane (25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was treated with HCl (4.0M in dioxane, 4 mL) and methanol (1 mL) and stirred for 1 hour. The mixture was concentrated to provide the title compound. the reaction was quenched with saturated NaHCO3 solution (5 mL) The product was extracted into dichloromethane (25 mL) dried over magnesium sulfate filtered concentrated The resulting crude material was treated with HCl (4.0M in dioxane, 4 mL) and methanol (1 mL) stirred for 1 hour The mixture was concentrated

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

Procedure: To a solution of 2-bromo-1-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (25 mL) at 0° C. was slowly added i-PrMgCl (24 mL, 24 mmol). After being stirred for 1 h at 0° C., the reaction mixture was cooled to −78° C. Then a solution of 1,3-difluoropropan-2-one (0.85 g, 9.04 mmol) in dry THF (25 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with HCl (2 N) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, eluting with PE:EA (5:1) to give 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, yield 55%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 H), 7.46 (s, 1 H), 7.21 (d, 1 H), 6.21 (s, 1 H),4.97-4.94 (m, 1 H), 4.85-4.82 (m, 2 H), 4.74-4.71 (m, 1 H), 2.26 (s, 3 H) ppm. at 0° C. the reaction mixture was cooled to −78° C The mixture was stirred at −70° C. for 1 h dry ice bath was removed extracted with EA (60 mL×2) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography over silica gel eluting with PE

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

Procedure: To a solution of 2-bromo-1-iodo-4-methylbenzene (18.5 g, 62.3 mmol) in THF (25 mL) at 0° C. was slowly added i-PrMgCl (24 mL, 24 mmol). After being stirred for 1 h at 0° C., the reaction mixture was cooled to −78° C. Then a solution of 1,3-difluoropropan-2-one (0.85 g, 9.04 mmol) in dry THF (25 mL) was added. The mixture was stirred at −70° C. for 1 h, and then dry ice bath was removed. The solution was acidified with HCl (2 N) and extracted with EA (60 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, eluting with PE:EA (5:1) to give 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, yield 55%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, 1 H), 7.46 (s, 1 H), 7.21 (d, 1 H), 6.21 (s, 1 H),4.97-4.94 (m, 1 H), 4.85-4.82 (m, 2 H), 4.74-4.71 (m, 1 H), 2.26 (s, 3 H) ppm. at 0° C. the reaction mixture was cooled to −78° C The mixture was stirred at −70° C. for 1 h dry ice bath was removed extracted with EA (60 mL×2) The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by column chromatography over silica gel eluting with PE