N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.15 g, 0.29 mmol, see: Example 1) was combined with pivalamide (0.12 g, 1.16 mmol), Xantphos (0.02 g, 0.033 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) in dioxane (5 mL). The mixture was sparged with argon for several min, treated with Pd2(dba)3 (0.015 g, 0.016 mmol), and heated at 100° C. overnight. The mixture was cooled to RT and filtered, washing with dioxane. The filtrate was concentrated to dryness and the residue was purified by reverse-phase chromatography [10%-45% CH3CN/H2O with 0.1% TFA]. The pure fractions were combined and co-evaporated with MeOH. The aqueous layer was neutralized with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain N-(2,5-difluoro-4-((2-pivalamidopyridin-4-yl)oxy)phenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (50 mg, 29.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 9.89 (s, 1H), 8.34 (dd, J=12.6, 7.2 Hz, 1H), 8.21 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H,) 7.51-7.48 (m, 3H), 7.36 (t, J=8.7 Hz, 2H), 6.76 (dd, J=5.7, 2.5 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28-4.27 (m, 2H), 1.34 (t, J=6.98 Hz, 3H), 1.05 (s, 9H); MS (ESI) m/z: 581.2 (M+H+).
