5-morpholin-4-ylpent-3-yn-2-one

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

Procedure: 5-Morpholin-4-yl-pent-3-yn-2-one (1 g, 6 mmol) and 2-hexyl-isothiourea hydrobromide (1.06 g, 7 mmol) were dissolved under nitrogen in DMF (10 mL), then N,N-diisopropyl ethylamine (4.1 mL, 24 mmol) was added and stirring at the room temperature continued for 18 hours.

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Prop-2-ynyl-morpholine (22 g, 176 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −40° C. Then a 2 M solution of isopropyl magnesium chloride in THF (97 mL, 193 mmol) was added while keeping the temperature below −20° C. Stirring at −40° C. to −30° C. was continued for 30 min. In a separate flask, N-methoxy-N-methylacetamide (20 g, 193 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −10° C. in ice/MeOH. The Grignard solution prepared above was transferred to the Weinreb amide solution at −10° C. via teflon tubing under slightly positive nitrogen pressure in vessel 1. There was no exotherm. Stirring at −10° C. to 0° C. was continued for 2 h. Ther resulting white suspension was poured on a 1:1-mixture of ice and saturated NH4Cl solution (400 mL). Extraction: 2×AcOEt, 1× saturated NaCl solution. One obtained a yellow oil (26.1 g, 89%). Chromatography on silica gel in heptane/ethyl acetate 1:2 gave 19.4 g (66%) of a brown oil which was distilled in the Kugelrohr at 130° C./0.2 mbar. One obtained 15.8 g (53%) of a yellow oil. the temperature below −20° C The Grignard solution prepared Stirring at −10° C. to 0° C. was continued for 2 h Ther resulting white suspension was poured on a 1 Extraction

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Prop-2-ynyl-morpholine (22 g, 176 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −40° C. Then a 2 M solution of isopropyl magnesium chloride in THF (97 mL, 193 mmol) was added while keeping the temperature below −20° C. Stirring at −40° C. to −30° C. was continued for 30 min. In a separate flask, N-methoxy-N-methylacetamide (20 g, 193 mmol) was dissolved under nitrogen in THF (40 mL) and cooled to −10° C. in ice/MeOH. The Grignard solution prepared above was transferred to the Weinreb amide solution at −10° C. via teflon tubing under slightly positive nitrogen pressure in vessel 1. There was no exotherm. Stirring at −10° C. to 0° C. was continued for 2 h. Ther resulting white suspension was poured on a 1:1-mixture of ice and saturated NH4Cl solution (400 mL). Extraction: 2×AcOEt, 1× saturated NaCl solution. One obtained a yellow oil (26.1 g, 89%). Chromatography on silica gel in heptane/ethyl acetate 1:2 gave 19.4 g (66%) of a brown oil which was distilled in the Kugelrohr at 130° C./0.2 mbar. One obtained 15.8 g (53%) of a yellow oil. the temperature below −20° C The Grignard solution prepared Stirring at −10° C. to 0° C. was continued for 2 h Ther resulting white suspension was poured on a 1 Extraction

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

Procedure: To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid. (The reaction quickly turned dark red ) The reaction was stirred overnight at RT evaporated to dryness under vacuum Dried under vacuum overnight The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL) filtered from insoluble material washed with (9:1) CH2Cl2, MeOH the filtrate evaporated to dryness under vacuum The dark solid was triturated with a solution of (1:1) EtOAc in hexanes filtered washed with (1:1) EtOAc in hexanes dried under vacuum to give a brown solid ( removed a lot The crude product was purified by silica gel chromatography (Analogix evaporated to dryness triturated with hexanes dried under vacuum

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

Procedure: To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid. (The reaction quickly turned dark red ) The reaction was stirred overnight at RT evaporated to dryness under vacuum Dried under vacuum overnight The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL) filtered from insoluble material washed with (9:1) CH2Cl2, MeOH the filtrate evaporated to dryness under vacuum The dark solid was triturated with a solution of (1:1) EtOAc in hexanes filtered washed with (1:1) EtOAc in hexanes dried under vacuum to give a brown solid ( removed a lot The crude product was purified by silica gel chromatography (Analogix evaporated to dryness triturated with hexanes dried under vacuum

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

Procedure: To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4 H), 3.56 (s, 2 H), 2.49-2.43 (m, 4 H), 2.34 (s, 3 H). MS(ES)+m/e 168.0 [M+H]+. was added dropwise via The reaction was stirred for 2 hr ( quenched with aq. NH4Cl extracted with EtOAc washed with brine dried (Na2SO4) filtered evaporated to dryness under vacuum The remaining was purified by silica gel chromatography (Analogix evaporated to dryness

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

Procedure: To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid. (The reaction quickly turned dark red ) The reaction was stirred overnight at RT evaporated to dryness under vacuum Dried under vacuum overnight The remaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL) filtered from insoluble material washed with (9:1) CH2Cl2, MeOH the filtrate evaporated to dryness under vacuum The dark solid was triturated with a solution of (1:1) EtOAc in hexanes filtered washed with (1:1) EtOAc in hexanes dried under vacuum to give a brown solid ( removed a lot The crude product was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 15% CH2Cl2/20% (5% NH4OH in MeOH) in CH2Cl2) evaporated to dryness triturated with hexanes dried under vacuum

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

Procedure: To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+ m/e 168.0 [M+H]+. was added dropwise via The reaction was stirred for 2 hr ( quenched with aq. NH4Cl extracted with EtOAc washed with brine dried (Na2SO4) filtered evaporated to dryness under vacuum The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 80% EtOAc in hexanes) evaporated to dryness

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

Procedure: To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+ m/e 168.0 [M+H]+. was added dropwise via The reaction was stirred for 2 hr ( quenched with aq. NH4Cl extracted with EtOAc washed with brine dried (Na2SO4) filtered evaporated to dryness under vacuum The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 80% EtOAc in hexanes) evaporated to dryness

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

Procedure: To a stirred solution of 21 wt % sodium ethoxide in EtOH (4.2 g, 12.96 mmol) in EtOH (30 mL) was added 2-cyanoacetamide (1.1 g, 13.08 mmol). The reaction was stirred for 15 min. then a solution of 5-(4-morpholinyl)-3-pentyn-2-one (2.0 g, 11.96 mmol) in EtOH was added to the reaction in one portion. (The reaction quickly turned dark red.) The reaction was stirred overnight at RT, neutralized with 6 N HCl (2.17 mL, 13.02 mmol) and evaporated to dryness under vacuum. Dried under vacuum overnight. The reamaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL), filtered from insoluble material, washed with (9:1) CH2Cl2, MeOH, and the filtrate evaporated to dryness under vacuum. The dark solid was triturated with a solution of (1:1) EtOAc in hexanes, filtered, washed with (1:1) EtOAc in hexanes, and dried under vacuum to give a brown solid (removed a lot of fast running non-polar impurities). The crude product was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 15% CH2Cl2/20%(5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness, triturated with hexanes and dried under vacuum to give the product 6-methyl-4-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (0.90 g, 3.86 mmol, 32.3% yield) as a light tan solid. (The reaction quickly turned dark red ) The reaction was stirred overnight at RT evaporated to dryness under vacuum Dried under vacuum overnight The reamaining dark solid was triturated with a solution of (9:1) CH2Cl2, MeOH (50 mL) filtered from insoluble material washed with (9:1) CH2Cl2, MeOH the filtrate evaporated to dryness under vacuum The dark solid was triturated with a solution of (1:1) EtOAc in hexanes filtered washed with (1:1) EtOAc in hexanes dried under vacuum to give a brown solid ( removed a lot The crude product was purified by silica gel chromatography (Analogix evaporated to dryness triturated with hexanes dried under vacuum

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

Procedure: To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+ m/e 168.0 [M+H]+. was added dropwise via The reaction was stirred for 2 hr ( quenched with aq. NH4Cl extracted with EtOAc washed with brine dried (Na2SO4) filtered evaporated to dryness under vacuum The remaining was purified by silica gel chromatography (Analogix evaporated to dryness

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

Procedure: To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+ m/e 168.0 [M+H]+. was added dropwise via The reaction was stirred for 2 hr ( quenched with aq. NH4Cl extracted with EtOAc washed with brine dried (Na2SO4) filtered evaporated to dryness under vacuum The remaining was purified by silica gel chromatography (Analogix evaporated to dryness