A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (154 mg, 0.40 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 75 mg, 0.48 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (424 mg, 0.96 mmol) and N,N-diisopropylethylamine (129 mg, 1.0 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (85 mg, 41%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75-1.32 (m, 6H) 1.04 (s, 3H) 1.06 (s, 3H) 1.51-1.84 (m, 7H) 3.89 (s, 2H) 4.24 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.91 (dd, J=10.7, 5.0 Hz, 1H) 4.96 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.36-7.53 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.81 (s, 1H). HR-ES-MS m/z calculated for C26H32ClFN4O4 [M+H]+ 519.2169, observed 519.2169.
