(4R)-4-(hydroxymethyl)-1-[(1R)-1-phenylethyl]pyrrolidin-2-one

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

Procedure: 100 mg (R)-4-(hydroxymethyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (2.1) was placed in 2 mL dimethylacetamide and 20 mg sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg 6.37 was added and the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried to provide protected Example 78 as intermediate. The intermediate was then treated with 2 mL of trifluoroacetic acid and heated for 30 min at 160° C. in the microwave. The reaction mixture was diluted with water and acetonitrile and purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-fried. the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C The reaction mixture was purified by chromatography (RP-HPLC-MS) The corresponding fractions were freeze-dried to provide heated for 30 min at 160° C. in the microwave purified by chromatography (RP-HPLC-MS)

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

Procedure: 100 mg (R)-4-(hydroxymethyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (2.1) was placed in 2 mL dimethylacetamide and 20 mg sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg 6.37 was added and the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried to provide protected Example 78 as intermediate. The intermediate was then treated with 2 mL of trifluoroacetic acid and heated for 30 min at 160° C. in the microwave. The reaction mixture was diluted with water and acetonitrile and purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-fried. the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C The reaction mixture was purified by chromatography (RP-HPLC-MS) The corresponding fractions were freeze-dried to provide heated for 30 min at 160° C. in the microwave purified by chromatography (RP-HPLC-MS)

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

Procedure: 5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated. the reaction solution was slowly warmed to 25° C. The reaction mixture was concentrated diluted in dichloromethane washed with sodium bicarbonate solution The water phase was extracted with dichloromethane (×2) the combined organic phases were dried over magnesium sulfate concentrated

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

Procedure: 5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated. the reaction solution was slowly warmed to 25° C. The reaction mixture was concentrated diluted in dichloromethane washed with sodium bicarbonate solution The water phase was extracted with dichloromethane (×2) the combined organic phases were dried over magnesium sulfate concentrated

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

Procedure: 5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated. the reaction solution was slowly warmed to 25° C. The reaction mixture was concentrated diluted in dichloromethane washed with sodium bicarbonate solution The water phase was extracted with dichloromethane (×2) the combined organic phases were dried over magnesium sulfate concentrated

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

Procedure: 100 mg (R)-4-(hydroxymethyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (2.1) was placed in 2 mL dimethylacetamide and 20 mg sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg 6.37 was added and the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried to provide protected Example 78 as intermediate. The intermediate was then treated with 2 mL of trifluoroacetic acid and heated for 30 min at 160° C. in the microwave. The reaction mixture was diluted with water and acetonitrile and purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-fried. the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C The reaction mixture was purified by chromatography (RP-HPLC-MS) The corresponding fractions were freeze-dried to provide heated for 30 min at 160° C. in the microwave purified by chromatography (RP-HPLC-MS)

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

Procedure: 100 mg (R)-4-(hydroxymethyl)-1-((R)-1-phenylethyl)pyrrolidine-2-one (2.1) was placed in 2 mL dimethylacetamide and 20 mg sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg 6.37 was added and the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C. The reaction mixture was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried to provide protected Example 78 as intermediate. The intermediate was then treated with 2 mL of trifluoroacetic acid and heated for 30 min at 160° C. in the microwave. The reaction mixture was diluted with water and acetonitrile and purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-fried. the mixture was stirred for 3 h at 50° C., further 4 h at 80° C. and overnight at 50° C The reaction mixture was purified by chromatography (RP-HPLC-MS) The corresponding fractions were freeze-dried to provide heated for 30 min at 160° C. in the microwave purified by chromatography (RP-HPLC-MS)

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

Procedure: 5 g (1′R,3R)-1-(1′Phenylethyl)-5-oxo-3-pyrrolidine carboxylic acid was dissolved in 50 mL tetrahydrofuran, then the solution was cooled to 0° C. 16.5 mL borane dimethyl sulfide (2 M in tetrahydrofuran) was added dropwise over 30 min and the reaction solution was slowly warmed to 25° C. and stirred for a further 2 h at 25° C. The reaction mixture was concentrated, diluted in dichloromethane and washed with sodium bicarbonate solution. The water phase was extracted with dichloromethane (×2) and the combined organic phases were dried over magnesium sulfate and concentrated. the reaction solution was slowly warmed to 25° C. The reaction mixture was concentrated diluted in dichloromethane washed with sodium bicarbonate solution The water phase was extracted with dichloromethane (×2) the combined organic phases were dried over magnesium sulfate concentrated