To a suspension of 7-chloro-8-(pyridin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (165 mg, 0.40 mmol), 4-chlorophenylboronic acid (190 mg, 1.20 mmol) in toluene (3.0 mL) and 2.0 M aqueous sodium carbonate (0.66 mL) was added (Ph3P)4Pd (70 mg, 0.06 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon in a 100° C. oil bath for 2 h. HPLC/MS analysis indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc phase was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, and concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (0-100%) in hexanes to provide the title compound as a light yellow foam (160 mg), which was crystallized from hot methanol to afford 60 mg of pure product. The mother liquor was concentrated, and the residue was purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 40% to 80% B over 8 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford an additional 88 mg of pure title compound as a light yellow powder. HPLC/MS: retention time=2.70 min, [M+H]+=482. 1H NMR (CDCl3, 400 MHz): δ 8.78 (s, 1H), 8.57 (d, J=6.2 Hz, 2H), 7.91 (dd, J=1.8, 7.9 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 6.65 (d, J=7.5 Hz, 1H), 5.25 (s, 2H).
