tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate

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

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

Procedure: To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39. washed with 1N NaOH, water and brine solution The organic layer was dried over anhydrous Na2SO4 filtered evaporated The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM

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

Procedure: To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39. washed with 1N NaOH, water and brine solution The organic layer was dried over anhydrous Na2SO4 filtered evaporated The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM

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

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

Procedure: To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39. washed with 1N NaOH, water and brine solution The organic layer was dried over anhydrous Na2SO4 filtered evaporated The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 10 L 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of triphenylphosphine (516.6 g, 1.970 mol) in dichloromethane (2,000 ml). The solution was cooled to −15° C. and a solution of carbontetrabromide (327.3 g, 985.8 mmol) in dichloromethane (1,000 ml) was added over a period of 120 minutes. Then a solution of tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (105 g, 493 mmol) in dichloromethane (1,000 ml) was added dropwise over a period of 120 minutes. The resulting solution was allowed warm to warm to 0° C., and stir for 20 minutes. The resulting solution was diluted with 4,000 ml of petroleum ether. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford tert-butyl 2-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate. Into a 10 L 3-necked roundbottom flask purged maintained with an inert atmosphere of nitrogen The resulting solution was allowed warm to warm to 0° C. The mixture was filtered concentrated The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient)

Conditions: temp:-80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 3,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of tert-butyl 2-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (119 g, 463 mmol) in dichloromethane (1,200 ml). The solution was cooled to −80° C. and diisobutylaluminum hydride (362 g, 510 mmol) was added dropwise, while maintaining an internal temperature of −80° C. (3 hours total addition time). The resulting solution was allowed to stir for 2 hours while the temperature was maintained at −80° C. The reaction mixture was then quenched by the adding 500 ml of methanol. After warming to ambient temperature, the mixture was washed with 1,000 ml of NaOH (20% w/w aqueous) and 6 times with 1,000 ml of water. The organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate, which was used without additional purification. Into a 3,000 ml 3-necked roundbottom flask purged maintained with an inert atmosphere of nitrogen while maintaining an internal temperature of −80° C. (3 hours total addition time) was maintained at −80° C The reaction mixture was then quenched by the adding 500 ml of methanol After warming to ambient temperature the mixture was washed with 1,000 ml of NaOH (20% w/w aqueous) and 6 times with 1,000 ml of water The organic layer was dried over sodium sulfate filtered concentrated

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

Procedure: To a stirred solution of compound 38 (2.3 g, 10.80 mmol) in DCM (90 mL) were added successively 2-aminoindane (1.4 mL, 10.80 mmol), Na(OAC)3BH (6.86 g, 32.39 mmol) and acetic acid (2 mL) at 0° C. The resulting mixture was allowed to stir at rt for 16 hours. The reaction mixture was diluted in DCM and washed with 1N NaOH, water and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM to provide compound 39. washed with 1N NaOH, water and brine solution The organic layer was dried over anhydrous Na2SO4 filtered evaporated The crude material was purified by Combiflash® chromatography eluting with 3-4% of methanol-DCM