tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 130° C. for 30 minutes. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. overnight, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.36-2.19 (m, 3H), 2.57-2.47 (m, 1H), 3.53-3.41 (m, 2H), 4.69-4.62 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.51 (m, 5H), 7.72-7.66 (m, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.97-7.92 (m, 2H), 9.19 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+. washed with saturated aqueous NaHCO3 The organic layer was dried over MgSO4 filtered concentrated The residue was dissolved in CH2Cl2 (2 mL) concentrated purified by HPLC (see protocol in Example 1F)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of Example 1E (0.048 g, 0.133 mmol) and tert-butyl 2-(4-aminophenyl)pyrrolidine-1-carboxylate (0.056 g, 0.213 mmol) was heated in a capped vial at 130° C. for 30 minutes. The reaction mixture was treated with ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid (0.103 ml, 1.334 mmol). The mixture was stirred at 35° C. overnight, concentrated, and purified by HPLC (see protocol in Example 1F) to provide the title compound as a trifluoroacetic acid salt. 1H NMR (500 MHz, CD3OD) δ 2.36-2.19 (m, 3H), 2.57-2.47 (m, 1H), 3.53-3.41 (m, 2H), 4.69-4.62 (m, 1H), 7.08 (d, J=1.9 Hz, 1H), 7.62-7.51 (m, 5H), 7.72-7.66 (m, 1H), 7.88 (d, J=1.9 Hz, 1H), 7.97-7.92 (m, 2H), 9.19 (s, 1H). MS (ESI+) m/z 458.2 (M+H)+. washed with saturated aqueous NaHCO3 The organic layer was dried over MgSO4 filtered concentrated The residue was dissolved in CH2Cl2 (2 mL) concentrated purified by HPLC (see protocol in Example 1F)

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Nitro-benzyl)-2-vinyl-pyrrolidine (220 mg, 0.95 mmol) in 44% yield.

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-Allyl-2-(4-bromo-phenyl)-pyrrolidine (470 mg, 1.77 mmol) in 87% yield.

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-Allyl-2-(4-bromo-phenyl)-pyrrolidine (470 mg, 1.77 mmol) in 87% yield.

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-Allyl-2-(4-bromo-phenyl)-pyrrolidine (470 mg, 1.77 mmol) in 87% yield.

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Bromo-benzyl)-2-ethoxymethyl-pyrrolidine (using the crude product obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%). obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%)

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

Procedure: Using the same procedure described for the preparation of 2-(4-Amino-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound is prepared from 1-(4-Bromo-benzyl)-2-ethoxymethyl-pyrrolidine (using the crude product obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%). obtained in the previous step) in 47% yield (two steps, based on crude residue, ˜85%)

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

Procedure: LiHMDS (1.6 g, 9.6 mmol) is added to a 100 mL round bottom flask. Toluene (20 mL) is added followed by addition of Pd2(dba)3.CHCl3 (50 mg, 0.05 mmol) and P(tBu)3.HBF4 (40 mg, 0.14 mmol). 2-(4-Bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.6 mmol) is added to the flask. After degasing, the mixture is stirred at room temperature overnight. After TLC suggested no starting bromide is left, the reaction mixture is diluted with ether and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with EtOAc. The EtOAc layer is dried and concentrated to provide the desired product (1.0 g, 83%). 1H NMR (300 MHz, CDCl3) ∂ 6.94-6.96 (2H, m), 6.60-6.67 (2H, m), 4.67-4.85 (1H, m), 3.58 (4H, br), 2.24 (1H, m), 1.73-1.97 (3H, m), 1.44 (3H, s), 1.21 (6H, s). After degasing is left the reaction mixture is diluted with ether poured into dilute HCl (aq) extracted with EtOAc The EtOAc layer is dried concentrated