N-(6-Chloropyrimidin-4-yl)-2-(4-fluorophenyl)quinolin-6-amine (22)

Compound 19 (300 mg, 1.26 mmol) was suspended in N-methylpyrrolidone (1 mL) and 4,6-dichloropyrimidine (210 mg, 1.39 mmol) was added, followed by careful addition of HCl in dioxane (0.17 mL, 4.0 M, 5.0 mmol). The reaction mixture was stirred at 110 °C for 24 h. The reaction was cooled to room temperature, and the yellow solid was filtered off. The solid was extracted with EtOAc and saturated NaHCO₃ solution, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude mixture was purified by column chromatography (5% MeOH in dichloromethane) to yield 22 as a yellow solid (440 mg, 71%). ¹H NMR (DMSO-d₆) δ 10.27 (s, 1H, exchanges with deuterium), 8.60 (d, J = 0.8 Hz, 1H), 8.47–8.40 (m, 2H), 8.35–8.26 (m, 2H), 8.12 (d, J = 8.7 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.93 (dd, J = 9.1, 2.4 Hz, 1H), 7.44–7.33 (m, 2H), 6.95 (d, J = 0.9 Hz, 1H). ¹³C NMR (DMSO-d₆) δ 163.2 (d, ¹J_CF = 247.1 Hz), 161.1, 158.5, 158.1, 153.4, 143.6, 137.2 (two peaks overlapping, detected by HSQC and HMBC), 134.7 (d, ⁴J_CF = 2.3 Hz), 129.4 (d, ³J_CF = 8.6 Hz), 129.2, 127.4, 125.0, 119.1, 115.8 (d, ²J_CF = 21.5 Hz), 115.4, 105.8. HRMS (ESI-TOF) calcd for C₁₉H₁₃N₄ClF [M + H]⁺ 351.0813 m/z, found 351.0808. LC purity (254 nm) >98%.