[F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[Cl:26])[NH2:22])#[CH:18]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][C:25]=1[Cl:26])#[CH:18]A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 24 h to give a homogeneous mixture. It was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-ethynyl-4-chloroaniline (J. Org. Chem., 1981, 46, 2280-2286) (1.67 g, 11.0 mmol) and dry DMA (15 mL). The residue of 3-ethynyl-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 24 h. It was poured into water (300 mL) and the residue washed down with MeOH. The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (5×25 mL); ethyl acetate/petroleum ether (1:10) (4×25 mL) and dried to give N-(3-ethynyl-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (209) (3.0 g, 100%) as a pale brown solid, mp 218-222° C.; 1H NMR δ [(CD3)2SO] 10.13 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 8.32-8.22 (m, 2H), 7.95 (dd, J=8.8, 2.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 4.60 (s, 1H). Anal. Calcd for C15H8ClFN4.0.5H2O.0.5MeOH: C, 57.51; H, 3.43; N, 17.31. Found C, 57.33; H, 3.13; N, 17.10.
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