Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:51]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][C:60]([O:62][CH3:63])=[O:61])#[CH:52]>CN(C=O)C.CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Pd]>[CH3:63][O:62][C:60](=[O:61])[CH2:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[CH2:51][CH2:52][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Temperature: 120 °C
Reaction time: 44 h

Procedure:
A suspension of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A44) (340 mg, 0.74 mmol), CuI (7 mg, 0.04 mmol), PPh3 (10 mg, 0.04 mmol) and Et3N (207 μL, 1.49 mmol) in DMF (2.5 mL) was sonicated for 5 minutes. PdCl2(PPh3)2 (26 mg, 0.04 mmol) and methyl 2-(2-ethynylphenyl)acetate (K1) (194 mg, 1.11 mmol) in DMF (1 mL) were added and the resulting mixture degassed with nitrogen for 5 minutes before heating under microwave irradiation at 120° C. for 20 minutes. The resulting mixture was adsorbed on silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in hexanes) to give a brown oil that was taken up in DMF (25 mL) and Et3N (2 mL) before 10% Pd/C (53% water; 75 mg) was added. The resulting mixture was stirred at room temperature for 44 hours under a hydrogen atmosphere then filtered through Celite, washing with EtOAc (200 mL). Activated charcoal (ca. 2.5 g) was added to the filtrate and the resulting suspension stirred at room temperature for 4 hours before filtration through Celite, washing with EtOAc (100 mL). The filtrate was washed with water (100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give a brown oil. A suspension of 10% Pd/C (53% water; 200 mg) in DMF (100 mL) and Et3N (10 mL) was added and the resulting mixture stirred under a hydrogen atmosphere at room temperature for 4.5 days. The resulting mixture was filtered through Celite, washing with EtOAc (250 mL) then the combined filtrates were washed with water (3×100 mL) then brine (3×100 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A45 as a yellow oil (96 mg, 21%); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J=2.4 Hz, 1H), 8.55 (d, J=0.5 Hz, 1H), 8.14 (dd, J=8.5, 2.7 Hz, 1H), 7.55 (s, 1H), 7.25-7.18 (m, 4H), 7.16 (d, J=8.5 Hz, 1H), 4.26 (s, 2H), 3.74 (s, 2H), 3.68 (s, 3H), 3.11 (s, 4H), 2.88-2.79 (m, 3H), 1.92 (d, J=12.0 Hz, 2H), 1.77-1.64 (m, 2H), 1.47 (s, 9H). LCMS-A: rt 6.137 min; m/z 600 [M+H]+.