2-(3-chloro-2-methylphenyl)acetamide

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

Procedure: To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressue then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+. the ice bath was removed After 10 min the reaction was stirred for 2 h diluted with water and CH2Cl2 The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min

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

Procedure: To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressue then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+. the ice bath was removed After 10 min the reaction was stirred for 2 h diluted with water and CH2Cl2 The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min

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

Procedure: To a solution of (2S,3R)-3-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25A) (87 mg, 0.32 mmol) in CH2Cl2 (1.3 mL) at 0° C. was added Hunig's base (111 mL, 0.64 mmol). After stirring for 15 min, 2-chloro-4-isocyanato-3-methylbenzonitrile (23A) was added, and after an additional 10 min, the ice bath was removed. The reaction was stirred for 2 h and then diluted with water. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified using preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (67 mg) as a white film; LC/MS m/z 661 [2M+23]+. after an additional 10 min the ice bath was removed The reaction was stirred for 2 h diluted with water The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated under reduced pressure The resulting solid was purified eluting with 40-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 15 min

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

Procedure: To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressure then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+. the ice bath was removed After 10 min the reaction was stirred for 2 h diluted with water and CH2Cl2 The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min

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

Procedure: To a solution of (2S,3R)-3-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25A) (87 mg, 0.32 mmol) in CH2Cl2 (1.3 mL) at 0° C. was added Hunig's base (111 mL, 0.64 mmol). After stirring for 15 min, 2-chloro-4-isocyanato-3-methylbenzonitrile (23A) was added, and after an additional 10 min, the ice bath was removed. The reaction was stirred for 2 h and then diluted with water. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified using preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (67 mg) as a white film; LC/MS m/z 661 [2M+23]+. after an additional 10 min the ice bath was removed The reaction was stirred for 2 h diluted with water The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated under reduced pressure The resulting solid was purified eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min

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

Procedure: To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressue then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+. the ice bath was removed After 10 min the reaction was stirred for 2 h diluted with water and CH2Cl2 The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm eluting with 60-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 15 min

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

Procedure: To a solution of (2S,3R)-3-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25A) (87 mg, 0.32 mmol) in CH2Cl2 (1.3 mL) at 0° C. was added Hunig's base (111 mL, 0.64 mmol). After stirring for 15 min, 2-chloro-4-isocyanato-3-methylbenzonitrile (23A) was added, and after an additional 10 min, the ice bath was removed. The reaction was stirred for 2 h and then diluted with water. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified using preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (67 mg) as a white film; LC/MS m/z 661 [2M+23]+. after an additional 10 min the ice bath was removed The reaction was stirred for 2 h diluted with water The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated under reduced pressure The resulting solid was purified eluting with 40-100% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 15 min

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

Procedure: To a solution of (2R,3R)-[3-(tert-Butyldimethylsilanyloxy)-2-methylpyrrolidin-2-yl]methanol trifluoroacetic acid salt (58C) (167 mg, 0.61 mmol) in CH2Cl2 (2.5 mL) at 0° C. were added molecular sieves followed by Hunig's base (0.21 mL, 1.22 mL). After stirring for 15 min, 2-Chloro-4-isocyanato-3-methylbenzonitrile (23A) was added and the ice bath was removed. After 10 min, the reaction was stirred for 2 h and then diluted with water and CH2Cl2. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm, eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min; Flow rate at 10 mL/min; UV detection at 220 nm) to provide the title compound (17 mg) as a white film (LC/MS m/z 438 [M+H]+) and di-acylated product (80 mg) as a white solid (LC/MS m/z 630 [M+H]+). The di-acylated product (80 mg, 0.13 mmol) was dissolved in EtOH (2 mL) and treated with 21% NaOEt (48 □L, 0.13 mmol) at rt for 4 h. The reaction was concentrated under reduced pressure then diluted with water and EtOAc. The layers were separated, and the aqueous layer acidified with 1 N HCl then re-extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (43 mg) as a white film. LC/MS m/z 438 [M+H]+. the ice bath was removed After 10 min the reaction was stirred for 2 h diluted with water and CH2Cl2 The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated The resulting solid was purified via preparative HPLC (Luna C-18, 250×21.2 mm eluting with 60-100% solvent B (A=90% H2O-10% MeOH-0.1% TFA and B=10% H2O-90% MeOH-0.1% TFA) over 15 min

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

Procedure: To a solution of (2S,3R)-3-hydroxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (25A) (87 mg, 0.32 mmol) in CH2Cl2 (1.3 mL) at 0° C. was added Hunig's base (111 mL, 0.64 mmol). After stirring for 15 min, 2-chloro-4-isocyanato-3-methylbenzonitrile (23A) was added, and after an additional 10 min, the ice bath was removed. The reaction was stirred for 2 h and then diluted with water. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting solid was purified using preparative HPLC (Luna C-18, 21.2×100 mm, eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (67 mg) as a white film; LC/MS m/z 661 [2M+23]+. after an additional 10 min the ice bath was removed The reaction was stirred for 2 h diluted with water The layers were separated the organic layer was washed with brine dried (MgSO4) filtered concentrated under reduced pressure The resulting solid was purified eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min