5-chloro-2,3-dihydro-1H-pyridin-6-one

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part A. 3-Chloro-5,6-dihydro-2(1H)-pyridinone (10.0 g, 38.17 mmol) and (1Z)-1-[chloro(methylsulfonyl)methylene]-2-(4-methoxyphenyl)hydrazine (5.0 g, 38.17 mmol) were stirred in toluene (200 mL) at RT under N2. Et3N (30 mL, 215.24 mmol) in toluene (150 mL) was added dropwise to the solution. After addition, the mixture was heated at 85° C. overnight. After cooling, H2O was added. It was extracted with EtOAc (2×). The organic layers were washed with H2O (2×) and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, CH2Cl2, then CH2Cl2:EtOAc=1:1, then EtOAc) to give 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (3.85 g, yield: 31%). LC/MS (ESI+) 322.4 (M+H)+, tR=1.79 min (10–90% CH3CN/H2O in a 4-min run). After addition After cooling It was extracted with EtOAc (2×) The organic layers were washed with H2O (2×) and brine dried over MgSO4 filtered concentrated to dryness The residue was purified by flash column chromatography (silica gel, CH2Cl2

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part A. 3-Chloro-5,6-dihydro-2(1H)-pyridinone (10.0 g, 38.17 mmol) and (1Z)-1-[chloro(methylsulfonyl)methylene]-2-(4-methoxyphenyl)hydrazine (5.0 g, 38.17 mmol) were stirred in toluene (200 mL) at RT under N2. Et3N (30 mL, 215.24 mmol) in toluene (150 mL) was added dropwise to the solution. After addition, the mixture was heated at 85° C. overnight. After cooling, H2O was added. It was extracted with EtOAc (2×). The organic layers were washed with H2O (2×) and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, CH2Cl2, then CH2Cl2:EtOAc=1:1, then EtOAc) to give 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (3.85 g, yield: 31%). LC/MS (ESI+) 322.4 (M+H)+, tR=1.79 min (10–90% CH3CN/H2O in a 4-min run). After addition After cooling It was extracted with EtOAc (2×) The organic layers were washed with H2O (2×) and brine dried over MgSO4 filtered concentrated to dryness The residue was purified by flash column chromatography (silica gel, CH2Cl2

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution)

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution)

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution)

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Part A. 3-Chloro-5,6-dihydro-2(1H)-pyridinone (10.0 g, 38.17 mmol) and (1Z)-1-[chloro(methylsulfonyl)methylene]-2-(4-methoxyphenyl)hydrazine (5.0 g, 38.17 mmol) were stirred in toluene (200 mL) at RT under N2. Et3N (30 mL, 215.24 mmol) in toluene (150 mL) was added dropwise to the solution. After addition, the mixture was heated at 85° C. overnight. After cooling, H2O was added. It was extracted with EtOAc (2×). The organic layers were washed with H2O (2×) and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, CH2Cl2, then CH2Cl2:EtOAc=1:1, then EtOAc) to give 1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (3.85 g, yield: 31%). LC/MS (ESI+) 322.4 (M+H)+, tR=1.79 min (10–90% CH3CN/H2O in a 4-min run). After addition After cooling It was extracted with EtOAc (2×) The organic layers were washed with H2O (2×) and brine dried over MgSO4 filtered concentrated to dryness The residue was purified by flash column chromatography (silica gel, CH2Cl2

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15-40% EtOAc/hexane gradient elution)

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

Procedure: A solution of 3-chloro-5,6-dihydro-1H-pyridin-2-one (44, 1.0 g, 7.6 mmol) in THF (4 mL) was treated with morpholine (663 mg, 0.67 mL, 7.6 mmol, 1.0 equiv) and triethylamine (TEA, 1.54 g, 2.1 mL, 15.2 mmol, 2.0 equiv) at room temperature, and the resulting reaction mixture was warmed up to reflux for 6 h. When HPLC and TLC showed the reaction was deemed complete, the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL), and the resulting mixture was stirred at room temperature for 10 min. The two layers were separated, and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution) to afford the desired 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 595 mg, 1.384 g theoretical, 43%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo and was found to be essentially pure to do the following reaction without further purification. For 45, CIMS m/z 181 (M+−H, C9H14N2O2). the resulting reaction mixture was warmed up to reflux for 6 h the reaction mixture was quenched with water (10 mL) and EtOAc (20 mL) The two layers were separated the aqueous layer was extracted with EtOAc (3×20 mL) The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL) dried over MgSO4 concentrated in vacuo The residue was then purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution)