In an oven-dried round bottom flask, (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) and 5-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (44.1 mg, 0.173 mmol) were dissolved in DMF (2 ml). To this solution was added DIEA (0.093 ml, 0.532 mmol) followed by PyBOP (69.3 mg, 0.133 mmol). The reaction mixture was allowed to stir at room temperature under a nitrogen atmosphere for 3 hours during which time it became dark red in color. The DMF was evaporated under high vacuum. The residue was subjected to column chromatography (silica, 20:1 CH2Cl2/2M NH3 in MeOH). The most pure fractions were collected, evaporated and again subjected to column chromatography (silica, 40:1 CH2Cl2/2M NH3 in MeOH). The fractions were collected, evaporated and dried overnight under vacuum to give (S)-5-chloro-2-(1-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,2,3,6-tetrahydropyridin-4-yl)benzonitrile (40 mg, 0.069 mmol, 52.1% yield) as a light tan solid. 1H NMR (500 MHz, MeOD) δ ppm 1.24-1.34 (m, 1H) 2.50-2.60 (m, 3H) 2.60-2.76 (m, 2H) 2.95-3.05 (m, 1H) 3.14-3.23 (m, 2H) 3.82-3.91 (m, 1H) 3.90-4.02 (m, 1H) 4.05-4.14 (m, 1H) 4.53-4.62 (m, 2H) 5.54 (d, J=17.4 Hz, 1H) 6.07 (d, J=13.7 Hz, 1H) 7.21 (s, 1H) 7.46 (d, J=8.3 Hz, 1H) 7.64 (d, J =8.5 Hz, 1H) 7.78 (s, 1H) 8.24 (s, 1H); MS (ESI): 575 (M-1H); Rf=1.90 (4 min run).
