Reaction SMILES: [CH2:1]([C:3]1[C:28](=[O:29])[N:27]([C:30]2[CH:31]=[C:32]([NH:36]C(=O)OC(C)(C)C)[CH:33]=[CH:34][CH:35]=2)[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:25][CH3:26])[N:9]=[CH:10][C:5]=2[CH:4]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:32]1[CH:31]=[C:30]([N:27]2[C:6]3[N:7]=[C:8]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:14][C:13]=4[O:25][CH3:26])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:1][CH3:2])[C:28]2=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: CCc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc2n(-c2cccc(NC(=O)OC(C)(C)C)c2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc2n(-c2cccc(N)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
Steps 3 and 4. tert-Butyl (3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate from above was treated with DCM (10 mL) and TFA (10 mL) and stirred at RT for 30 min. The reaction mixture was concentrated under reduced pressure (rotary evaporator) and purified on silica gel on an ISCO Combiflash RF (40 g Redisep column, 5-20% 2M NH3/MeOH in DCM) affording 8-(3-aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (392 mg, 0.81 mmol, 51% yield) as a brown/yellow film. m/z (ESI, +ve ion) 486.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.67 (1H, s), 7.74 (1H, s), 7.68 (1H, d, J=8.6 Hz), 7.34 (1H, t, J=7.9 Hz), 6.92 (1H, dd, 1=8.1, 1.5 Hz), 6.61-6.67 (2H, m), 6.58 (1H, dd, J=7.6, 1.0 Hz), 6.26 (1H, d, J=7.2 Hz), 5.51 (2H, s), 3.90 (3H, s), 3.30 (4H, br. s), 3.18 (4H, br. s), 2.79 (3H, s), 2.63 (2H, q, J=7.4 Hz), 1.28 (3H, t, J=7.5 Hz). 8-(3-Aminophenyl)-6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (390 mg, 0.80 mmol) in a mixture of DCM (7 mL) and THF (7 mL) at 0° C. was treated with DIEA (0.35 mL, 2.01 mmol) followed by the slow dropwise addition of acryloyl chloride (0.078 mL, 0.964 mmol) over 5 min. The solution was stirred 0° C. for 15 min. LC-MS indicated ca. a 79:11 ratio of desired product m/z (ESI, +ve ion) 539.9 (M+H)+ and starting material m/z (ESI, +ve ion) 486.0 (M+H)+. 2 additional drops of acryloyl chloride were added and the mixture was stirred an additional 2 h at 0° C. The reaction mixture was treated with silica gel and concentrated on the rotovap to dryness. The material was purified on an ISCO Combiflash RF (40 g Redisep column, using a gradient of 0-20% MeOH in DCM) affording enriched product as a yellow powdery solid. It was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated on the rotovap to remove the CH3CN and treated with 1N NaOH and extracted with CHCl3 (3×50 mL), dried over Na2SO4, filtered and concentrated affording N-(3-(6-ethyl-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (6) (154 mg, 0.29 mmol, 35% yield) as a bright yellow solid. m/z (ESI, +ve ion) 540.0 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.68 (1H, s), 8.04 (1H, d, J=7.2 Hz), 7.77 (1H, s), 7.58-7.65 (2H, m), 7.49 (1H, d, J=8.4 Hz), 7.08 (1H, d, J=8.0 Hz), 6.58 (1H, d, J=2.5 Hz), 6.34-6.51 (2H, m), 6.14 (1H, d, J=7.0 Hz), 5.80 (1H, dd, J=9.6, 2.2 Hz), 3.88 (3H, s), 3.13 (4H, d, J=3.9 Hz), 2.58-2.69 (6H, m), 2.38 (3H, s), 1.30 (3H, t, J=7.4 Hz).