oxane-4-carbonyl chloride

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:

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

Procedure: [1-(4-Methylamino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.13 g, 0.35 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.18 ml, 0.7 mmol) in one portion followed by the drop wise addition of tetrahydro-2H-pyran-4-carbonyl chloride (0.06 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was concentrated, diluted with DCM (200 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.17 g, 98% yield) as a white powder which was taken on without further purification. Tr=1.89 min m/z (ES+) (M+Na+) 504. After this time the mixture was concentrated diluted with DCM (200 ml) washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml) The organic layer was separated dried (MgSO4) filtered concentrated

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 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, 1.35 mmol) in 4 mL of CH2Cl2 was added tetrahydro-pyran-4-carbonyl chloride (0.210 mL, 1.637 mmol) and Et3N (0.380 mL, 2.73 mmol). The reaction mixture was stirred at room temperature for 30 min then was quenched with H2O, extracted with CH2Cl2, filtered and evaporated under vacuum. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5) gave [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (420 mg, 73% yield) as a yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.37-1.64 (m, 4H) 1.95-2.29 (m, 2H) 2.56-2.83 (m, 4H) 3.28-3.91 (m, 13H) 5.54-5.68 (m, 1H) 7.24-7.36 (m, 5H) 8.54-8.59 (m, 1H). LCMS: [M+H]+=423.6, Rt(7)=0.68. then was quenched with H2O extracted with CH2Cl2 filtered evaporated under vacuum Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5)

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

Procedure: To a solution of 6-benzyl-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (420 mg, 1.35 mmol) in 4 mL of CH2Cl2 was added tetrahydro-pyran-4-carbonyl chloride (0.210 mL, 1.637 mmol) and Et3N (0.380 mL, 2.73 mmol). The reaction mixture was stirred at room temperature for 30 min then was quenched with H2O, extracted with CH2Cl2, filtered and evaporated under vacuum. Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5) gave [(S)-3-(6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidin-1-yl]-(tetrahydro-pyran-4-yl)-methanone (420 mg, 73% yield) as a yellow foam. 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 1.37-1.64 (m, 4H) 1.95-2.29 (m, 2H) 2.56-2.83 (m, 4H) 3.28-3.91 (m, 13H) 5.54-5.68 (m, 1H) 7.24-7.36 (m, 5H) 8.54-8.59 (m, 1H). LCMS: [M+H]+=423.6, Rt(7)=0.68. then was quenched with H2O extracted with CH2Cl2 filtered evaporated under vacuum Purification by flash-chromatography on silica gel (CH2Cl2/MeOH 95/5)

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The (S)-pyrrolidin-3-ol hydrochloride (3.69 g, 29.9 mmol) and triethylamine (6.65 g, 9.16 mL, 65.7 mmol) were put in CH2Cl2 (15 mL). The suspension was cooled at ˜3° C. To this mixture, a solution of tetrahydro-pyran-4-carbonyl chloride (4.67 g, 29.9 mmol) in CH2Cl2 (15 mL) was added slowly. Then the resulting reaction mixture was stirred for 1.5 h at 3-10° C. The reaction mixture was then concentrated to give a powder. To this powder, addition of EtOAc (100 mL). The solid was filtered and washed with EtOAc. The recovered filtrate was then concentrated to give ((S)-3-hydroxy-pyrrolidin-1-yl)-(tetrahydro-pyran-4-yl)-methanone as beige powder. (6.77 g, 98% yield). 1H-NMR (400 MHz, Methanol-d4, 298 K): δ ppm 1.59-2.15 (m, 6H) 2.69-2.86 (m, 1H) 3.43-3.75 (m, 6H) 3.94-4.00 (m, 2H) 4.37-4.48 (m, 1H). LCMS: [M+H]+=199.9, Rt(6)=0.86 min Then the resulting reaction mixture The reaction mixture was then concentrated to give a powder The solid was filtered washed with EtOAc The recovered filtrate was then concentrated

Conditions: temp:3.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The (S)-pyrrolidin-3-ol hydrochloride (3.69 g, 29.9 mmol) and triethylamine (6.65 g, 9.16 mL, 65.7 mmol) were put in CH2Cl2 (15 mL). The suspension was cooled at ˜3° C. To this mixture, a solution of tetrahydro-pyran-4-carbonyl chloride (4.67 g, 29.9 mmol) in CH2Cl2 (15 mL) was added slowly. Then the resulting reaction mixture was stirred for 1.5 h at 3-10° C. The reaction mixture was then concentrated to give a powder. To this powder, addition of EtOAc (100 mL). The solid was filtered and washed with EtOAc. The recovered filtrate was then concentrated to give ((S)-3-hydroxy-pyrrolidin-1-yl)-(tetrahydro-pyran-4-yl)-methanone as beige powder. (6.77 g, 98% yield). 1H-NMR (400 MHz, Methanol-d4, 298 K): δ ppm 1.59-2.15 (m, 6H) 2.69-2.86 (m, 1H) 3.43-3.75 (m, 6H) 3.94-4.00 (m, 2H) 4.37-4.48 (m, 1H). LCMS: [M+H]+=199.9, Rt(6)=0.86 min Then the resulting reaction mixture The reaction mixture was then concentrated to give a powder The solid was filtered washed with EtOAc The recovered filtrate was then concentrated

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

Procedure: To a solution of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.4 mmol) in tetrahydrofurane (2 ml) were subsequently added N-ethyl-diisopropylamine (194 □1, 1.1 mmol) and tetrahydropyran-4-carbonyl chloride (77 mg, 0.52 mmol, dissolved in 0.5 ml tetrahydrofurane) and the mixture refluxed for 3 h. The mixture was then cooled to 0° C., methanol (0.4 ml) was added and the mixture slowly warmed to 20° C. Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) and extracted with saturated aqueous sodium carbonate. After back extraction of the aqueous phase with two portions of dichloromethane (3 ml), the combined organic phases were dryed with Na2SO4 and the solvent evaporated. The crude product was was then chromatographed over SiO2, eluting with CH2Cl2/MeOH 98:2, the product fractions were pooled and the solvent evaporated, to afford the title compound as a beige powder (142 mg, 76% yield), MS: m/e=378(M+H+). the mixture refluxed for 3 h the mixture slowly warmed to 20° C Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) extracted with saturated aqueous sodium carbonate After back extraction of the aqueous phase with two portions of dichloromethane (3 ml) the solvent evaporated The crude product was was then chromatographed over SiO2 eluting with CH2Cl2/MeOH 98:2 the solvent evaporated

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

Procedure: To a solution of 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol (100 mg, 0.4 mmol) in tetrahydrofurane (2 ml) were subsequently added N-ethyl-diisopropylamine (194 □1, 1.1 mmol) and tetrahydropyran-4-carbonyl chloride (77 mg, 0.52 mmol, dissolved in 0.5 ml tetrahydrofurane) and the mixture refluxed for 3 h. The mixture was then cooled to 0° C., methanol (0.4 ml) was added and the mixture slowly warmed to 20° C. Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) and extracted with saturated aqueous sodium carbonate. After back extraction of the aqueous phase with two portions of dichloromethane (3 ml), the combined organic phases were dryed with Na2SO4 and the solvent evaporated. The crude product was was then chromatographed over SiO2, eluting with CH2Cl2/MeOH 98:2, the product fractions were pooled and the solvent evaporated, to afford the title compound as a beige powder (142 mg, 76% yield), MS: m/e=378(M+H+). the mixture refluxed for 3 h the mixture slowly warmed to 20° C Then the mixture was evaporated to dryness, dichloromethane was added (3 ml) extracted with saturated aqueous sodium carbonate After back extraction of the aqueous phase with two portions of dichloromethane (3 ml) the solvent evaporated The crude product was was then chromatographed over SiO2 eluting with CH2Cl2/MeOH 98:2 the solvent evaporated