(2S,4S)-1-tert-Butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate

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

Procedure: (2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3. cooled in an ice bath The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL) dried over Na2SO4 The solvent was evaporated

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

Procedure: (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H20N2O4, 244.3. found 245.3. The mixture was filtered the filtrate evaporated

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

Procedure: (2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3. cooled in an ice bath The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL) dried over Na2SO4 The solvent was evaporated

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

Procedure: (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+1-1]+ calcd for C11H20N2O4, 244.3. found 245.3. The mixture was filtered the filtrate evaporated

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

Procedure: (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+1-1]+ calcd for C11H20N2O4, 244.3. found 245.3. The mixture was filtered the filtrate evaporated

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

Procedure: To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (300 mg, 1.47 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (396 mg, 1.62 mmol, Bioorg. Med. Chem., 2002, 10, 1399-1415) in N,N-dimethylformamide (15 mL) were added diethyl cyanophosphonate (0.27 mL, 1.76 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.76 mmol) at room temperature. The resulting mixture was stirred for 14 h at the same temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), and the solution was washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (3:1) to give 618 mg (98%) of the title compound as a white amorphous solid. concentrated under reduced pressure The resulting residue was diluted with ethyl acetate (200 mL) the solution was washed with water (50 mL×2), brine (50 mL) dried over sodium sulfate concentrated under reduced pressure The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (3:1)

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

Procedure: (2S,4S)-4-Aminopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (7.3 g, 30 mmol) was dissolved in DCM (100 mL) and cooled in an ice bath. DIPEA (3 equiv) was added, followed by benzyl chloroformate (1 equiv). The mixture was stirred at room temperature for 3 hours and then diluted with DCM (200 mL). The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (10.4 g, 28 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C12H21NO7S, 323.4. found 324.3. cooled in an ice bath The solution was washed with 1M HCl (100 mL), saturated aqueous NaHCO3 (100 mL) and saturated aqueous NaCl (100 mL) dried over Na2SO4 The solvent was evaporated

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

Procedure: (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H20N2O4, 244.3. found 245.3. The mixture was filtered the filtrate evaporated

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

Procedure: (2S,4S)-4-azidopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (8.5 g, 31 mmol) and Pd/C (10% w/w, 2.0 g) were stirred in MeOH (150 mL) at room temperature under an atmosphere of hydrogen for 48 hours. The mixture was filtered and the filtrate evaporated to afford the title compound (7.34 g, 30 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H20N2O4, 244.3. found 245.3. The mixture was filtered the filtrate evaporated

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

Procedure: Triethylamine (1.13 mL), 1-hydroxybenzotriazole (1.04 g), and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.56 g) were added to a solution of cis-4-amino-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D102 (C), 1.65 g) and N-tert-butoxycarbonylglycine (1.42 g) in dichloromethane (100 mL) at 0° C. The mixture was stirred at room temperature for 19 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (2.84 g) as a colorless foam. evaporated in vacuo The residue was diluted with ethyl acetate washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine The organic layer was dried over anhydrous sodium sulfate evaporated in vacuo

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

Procedure: Methyl (2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [product of Reference Example 5(3), 2.4 g] and triethylamine (2.0 mL) were dissolved in tetrahydrofuran (20 mL), and benzoyl chloride (1.1 mL) was added thereto. The mixture was stirred for 1 hr. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give methyl (2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (1.63 g) as a white solid. extracted with ethyl acetate The extract was washed with saturated aqueous sodium hydrogencarbonate solution dried The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography

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

Procedure: Methyl (2S,4S)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [product of Reference Example 5(3), 2.4 g] and triethylamine (2.0 mL) were dissolved in tetrahydrofuran (20 mL), and benzoyl chloride (1.1 mL) was added thereto. The mixture was stirred for 1 hr. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give methyl (2S,4S)-4-benzoylamino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (1.63 g) as a white solid. extracted with ethyl acetate The extract was washed with saturated aqueous sodium hydrogencarbonate solution dried The solvent was evaporated under reduced pressure the residue was purified by silica gel chromatography