(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]-2,5-dihydropyrrole-2-carboxylic acid

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G (yield=86%). 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9H).

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G. 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9).

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G (yield=86%). 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9H).

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G (yield=86%). 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9H).

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G. 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9).

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S)-2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (372 mg, 42%, slightly impure) was prepared according to the procedure in Example 25 from (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 1-tert-butyl ester (557.8 mg, 2.62 mmol) with isobutyl chloroformate (0.36 mL, 2.77 mmol) and triethylamine (0.73 mL, 5.2 mmol) in THF (7.5 mL). Then 3-cyano-N-hydroxy-benzamidine (424 mg, 2.6 mmol) and DMF (7 mL) were added and the mixture was heated at 120° C. for 16 h. 1H-NMR (CDCl3) was consistent with the expected product and showing a mixture of rotomers due to the Boc protecting group.

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

Procedure: To a solution of (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (10 g, 46.9 mmol) in DMF (249 mL) cooled at 0° C. were added cesium carbonate (16.8 g, 51.6 mmol) then benzyl bromide (6.69 mL, 56.3 mmol) and the mixture was allowed to warm up to RT overnight. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3×200 mL). The organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.25; MS (UPLC): 326 [M+Na]+, 204 [MH−Boc]+; tR (HPLC conditions f): 2.35 min. The reaction mixture was quenched with water (500 mL) extracted with ethyl acetate (3×200 mL) washed with brine dried (Na2SO4) filtered concentrated The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:1)

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G (yield=86%). 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9H).

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

Procedure: (S)-tert-Butyl 2-(benzyloxycarbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate is prepared from (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (Boc-3,4-dehydro-proline) and O-benzylhydroxylamine following Method G. 1H NMR (300 MHz, CHCl3) δ 9.38 (s, 0.5H), 8.46 (s, 0.5H), 7.52-7.22 (m, 5H), 6.01-5.77 (m, 2H), 5.04-4.79 (m, 3H), 4.38-3.99 (m, 2H), 1.43 (s, 9).