Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:16]([Li])[CH2:17][CH2:18][CH3:19].Cl.Cl.C1(C2C=[CH:32][CH:31]=[CH:30][NH:29]N=2)CCC1.[CH3:34][CH2:35][N:36]([CH:40](C)C)C(C)C.CC[O:45]CC>C(Cl)Cl>[CH:19]1([N:29]2[CH2:30][CH2:31][CH2:32][N:36]([C:40]([C:2]3[CH:7]=[N:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)=[CH:4][CH:3]=3)=[O:45])[CH2:35][CH2:34]2)[CH2:18][CH2:17][CH2:16]1
5-Bromo-2-(4-fluoro-phenoxy)-pyridine (27.2 mg, 0.102 mmol) was dissolved in Et2O (0.8 mL). The mixture was cooled to −78° C. n-Butyl lithium (0.040 mL, 2.5 M in hexanes) was added and the reaction mixture was stirred for 5 min at −78° C. CO2 gas (from dry ice, passed through 4 Å molecular sieves) was bubbled through the mixture and the reaction was allowed to warm to 23° C. over 3 min. The solvents were removed by distillation then DCM (0.5 mL), DMF (0.05 mL) and oxalyl chloride (0.070 mL, 2.0 M in DCM) were added. The mixture was stirred for 3 min then cyclobutyl diazepine bis-HCl salt (27.6 mg, 0.122 mmol) and iPr2NEt (0.1 mL) were added to the reaction following dissolution in DCM (0.5 mL). The mixture was stirred for 3 min at 23° C. and was concentrated. Analysis by HPLC indicated a yield of 80%. Chromatography on SiO2 gave 21.5 mg (57%) of the title compound that was >90% pure by NMR.
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