1-piperidin-4-ylpyrrolidin-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:

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

Procedure: N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (870 mg) in methanol (2.4 mL) was added to a solution of 4-(2-oxopyrrolidin-1-yl)piperidine (0.460 g) and acetic acid (0.16 mL) in methanol (2.4 mL). After 5 minutes, sodium cyanoborohydride (0.173 g) in methanol (2.4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (1.0 g) as a white solid; MS: m/z=502(M+1). Analysis for C27H33Cl2N3O2 ·1.50 HCl: Calculated: C, 58.20; H, 6.24; N, 7.54; Found: C, 58.18; H, 6.27; N, 7.44. stirred for 30 minutes extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight

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

Procedure: N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (870 mg) in methanol (2.4 mL) was added to a solution of 4-(2-oxopyrrolidin-1-yl)piperidine (0.460 g) and acetic acid (0.16 mL) in methanol (2.4 mL). After 5 minutes, sodium cyanoborohydride (0.173 g) in methanol (2.4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (1.0 g) as a white solid; MS: m/z=502(M+1). Analysis for C27H33Cl2N3O2 ·1.50 HCl: Calculated: C, 58.20; H, 6.24; N, 7.54; Found: C, 58.18; H, 6.27; N, 7.44. stirred for 30 minutes extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight

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

Procedure: N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (870 mg) in methanol (2.4 mL) was added to a solution of 4-(2-oxopyrrolidin-1-yl)piperidine (0.460 g) and acetic acid (0.16 mL) in methanol (2.4 mL). After 5 minutes, sodium cyanoborohydride (0.173 g) in methanol (2.4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (1.0 g) as a white solid; MS: m/z=502(M+1). Analysis for C27H33Cl2N3O2.1.50 HCl: Calculated: C, 58.20; H, 6.24; N, 7.54; Found: C, 58.18; H, 6.27; N, 7.44. stirred for 30 minutes extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight

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

Procedure: N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (870 mg) in methanol (2.4 mL) was added to a solution of 4-(2-oxopyrrolidin-1-yl)piperidine (0.460 g) and acetic acid (0.16 mL) in methanol (2.4 mL). After 5 minutes, sodium cyanoborohydride (0.173 g) in methanol (2.4 mL) was added in a single portion. After being stirred for 3 hours, the reaction mixture was diluted with aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane. The organic extracts were dried, evaporated, and chromatographed, with dichloromethane:methanol (gradient 98:2, 90:10) as the eluent. The resulting material was dissolved in dichloromethane, precipitated out as the hydrochloride salt with ethereal hydrogen chloride, evaporated, and placed under high vacuum overnight to give the title compound (1.0 g) as a white solid; MS: m/z=502(M+1). Analysis for C27H33Cl2N3O2.1.50 HCl: Calculated: C, 58.20; H, 6.24; N, 7.54; Found: C, 58.18; H, 6.27; N, 7.44. stirred for 30 minutes extracted with dichloromethane The organic extracts were dried evaporated chromatographed, with dichloromethane The resulting material was dissolved in dichloromethane precipitated out as the hydrochloride salt with ethereal hydrogen chloride evaporated placed under high vacuum overnight

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

Procedure: To a solution of 2-[4-(chloromethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine hydrochloride (70 mg, 0.223 mmol) and 1-piperidin-4-yl-pyrrolidin-2-one (64 mg, 0.379 mmol, 1.7 equiv.) in CH3CN (1.3 mL) was added Et3N (110 μL, 0.759 mmol, 3.4 equiv.). The reaction was allowed to stir at 60° C. for 6 h. The solution was cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a cream-colored solid (52 mg, 57%). 1H NMR (600 MHz, DMSO-d6): 8.45 (dd, J=4.7, 1.5, 1H), 8.09 (dd, J=8.1, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.47-7.40 (m, 4H), 3.80-3.69 (m, 1H), 3.52 (s, 2H), 3.35-3.29 (m, 2H), 2.91-2.85 (m, 2H), 2.20 (t, J=8.1, 2H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.54-1.48 (m, 2H). MS (ESI): mass calcd. for C22H24N4O2S, 408.16; m/z found, 409.2 [M+H]+. The solution was cooled to rt filtered purified

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

Procedure: To a solution of 2-[4-(chloromethyl)phenoxy][1,3]thiazolo[5,4-b]pyridine hydrochloride (70 mg, 0.223 mmol) and 1-piperidin-4-yl-pyrrolidin-2-one (64 mg, 0.379 mmol, 1.7 equiv.) in CH3CN (1.3 mL) was added Et3N (110 μL, 0.759 mmol, 3.4 equiv.). The reaction was allowed to stir at 60° C. for 6 h. The solution was cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a cream-colored solid (52 mg, 57%). 1H NMR (600 MHz, DMSO-d6): 8.45 (dd, J=4.7, 1.5, 1H), 8.09 (dd, J=8.1, 1.5, 1H), 7.50 (dd, J=8.2, 4.8, 1H), 7.47-7.40 (m, 4H), 3.80-3.69 (m, 1H), 3.52 (s, 2H), 3.35-3.29 (m, 2H), 2.91-2.85 (m, 2H), 2.20 (t, J=8.1, 2H), 2.07-2.00 (m, 2H), 1.94-1.85 (m, 2H), 1.73-1.62 (m, 2H), 1.54-1.48 (m, 2H). MS (ESI): mass calcd. for C22H24N4O2S, 408.16; m/z found, 409.2 [M+H]+. The solution was cooled to rt filtered purified

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

Procedure: After 3-((6-chloronaphthalen-2-yl)sulfonyl)propinoic acid (0.30 g), HOBt (0.23 g) and WSC (0.29 g) were dissolved in DMF (10 mL), 1-(piperidin-4-yl)-2-pyrrolidinone (0.17 g) and triethylamine (0.10 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol 10/1) to obtain the title compound (0.17 g, 39%) as a colorless powder. The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol 10/1)

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

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

Procedure: After 3-((6-chloronaphthalen-2-yl)sulfonyl)propinoic acid (0.30 g), HOBt (0.23 g) and WSC (0.29 g) were dissolved in DMF (10 mL), 1-(piperidin-4-yl)-2-pyrrolidinone (0.17 g) and triethylamine (0.10 g) were added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and diluted with ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol 10/1) to obtain the title compound (0.17 g, 39%) as a colorless powder. The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate The organic layer was separated dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by basic silica gel column chromatography (ethyl acetate to ethyl acetate/methanol 10/1)