ethyl 3-morpholin-4-yl-3-oxopropanoate

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

Procedure: To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34. at reflux overnight extracted with DCM (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM)

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

Procedure: To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0° C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33. extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes)

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

Procedure: To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34. at reflux overnight extracted with DCM (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM)

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

Procedure: To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0° C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33. extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes)

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

Procedure: To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34. at reflux overnight extracted with DCM (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM)

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

Procedure: To a stirred solution of morpholine (479 mg, 5.5 mmol, 1.1 eq) and triethylamine (1.01 g, 10 mmol, 10 eq) in DCM (20 mL) at 0° C., ethyl 3-chloro-3-oxopropanoate (750 mg, 5 mmol, 1.0 eq) was added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes) to afford the product ethyl 3-morpholino-3-oxopropanoate 33. extracted with ethyl acetate (3×50 mL) The combined organic layers were washed with brine dried over Na2SO4 filtered The filtrate was concentrated in vacuo the residue was purified by flash column chromatography on silica gel (1-50% ethyl acetate-hexanes)