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0 °C

To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.214 g, 0.71 mmol) in N,N-dimethylformamide (4.5 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.142 g, 0.91 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.618 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.142 g, 1.40 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.112 g, 36%) as a tan solid: HR-ES-MS m/z calculated for C24H32N4O4 [M+H]+ 441.2497, observed 441.2496, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.37-1.64 (m, 2H), 1.66-1.85 (m, 1H), 2.19 (s, 3H), 3.89 (br. s., 2H), 4.20 (d, J=18.1 Hz, 1H), 4.59 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.68 (s, 1H), 4.88 (dd, J=10.4, 4.4 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.11-7.32 (m, 3H), 7.35 (d, J=6.6 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 10.79 (br. s., 1H).

1. stirringThe mixture was stirred at room temperature for 4 h
2. customthe solvents were evaporated
3. additionThe residue was treated with ethyl acetate and ammonium chloride solution
4. customthe organic layer separated
5. washThe organic layer was washed with brine
6. dry with materialdried over sodium sulfate
7. customThe solvents were evaporated
8. customthe residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which