1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide

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A solution of 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (as prepared in Example 40, 200 mg, 0.54 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (85 mg, 0.55 mmol) and 1-hydroxybenzotriazole (80 mg, 0.57 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 101 mg, 0.65 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium 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 10% methanol/dichloromethane) to afford 2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide (186 mg, 68%) as a white solid: LR-ES-MS m/z calculated for C25H30F2N4O5 [M]+ 504, observed [M+H]+ 505; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H) 1.06 (s, 3H) 1.11-1.52 (m, 3H) 1.52-1.74 (m, 3H) 1.74-1.88 (m, 1H) 3.07-3.32 (m, 2H) 3.75-3.87 (m, 2H) 3.89 (s, 2H) 4.33 (d, J=19.0 Hz, 1H) 4.65 (d, J=19.0 Hz, 1H) 4.68 (s, 1H) 4.91 (dd, J=10.6, 4.5 Hz, 1H) 5.04 (s, 1H) 6.45 (d, J=2.2 Hz, 1H) 7.26-7.51 (m, 3H) 7.54 (d, J=2.2 Hz, 1H) 10.83 (s, 1H).

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