Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[N:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)C(C)(C)OB([C:51]2[CH:52]=[C:53]([CH2:57][CH:58]3[CH2:63][CH2:62][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:60][CH2:59]3)[CH:54]=[CH:55][CH:56]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[N:14]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:55]5[CH:56]=[CH:51][CH:52]=[C:53]([CH2:57][CH:58]6[CH2:59][CH2:60][N:61]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[CH2:62][CH2:63]6)[CH:54]=5)[CH:3]=4)=[O:12])[CH:18]=[CH:17][CH:16]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Temperature: 100 °C

Procedure:
A mixture of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (370 mg, 0.579 mmol), 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (233 mg, 0.579 mmol), Na2CO3 (184 mg, 1.738 mmol) and PdCl2(dppf) (42.4 mg, 0.058 mmol) was diluted in a mixture of 1,4-dioxane (3 mL) and water (1 mL) in a 2-5 mL biotage microwave reaction tube. The mixture was degassed by bubbling argon through it for 5 minutes and it was then heated in a Biotage microwave at normal absorption for 10 minutes at 100° C. The crude mixture was filtered through a PL-Thiol MP SPE+ and was then washed with ethyl acetate and water. The organic layer was concentrated under vacuum to obtain a crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 15 to 80% CH3CN in water at a flow rate of 20 mL/min. The product fractions were dried using a EZ2 GeneVac evaporator and then combined to give 1,1-dimethylethyl 4-[(5′-{[({6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-1-piperidinecarboxylate as a solid. It was re-dissolved in 25% TFA in DCM (2 mL) and stirred at room temperature for 2 h. Solvent was evaporated under a stream of nitrogen and then the residue was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 60% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined and converted to the free base with 1 N NaOH and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[6-fluoro-3′-(4-piperidinylmethyl)-3-biphenylyl]methyl}-2,6-pyridinedicarboxamide as a solid (92 mg, 21.7%). LC-MS m/z 733 (M+H)+, 0.87 min (ret time); 1H NMR (400 MHz, DMSO-d6) δ 0.99-1.05 (m, 2H) 1.20 (t, J=7.40 Hz, 3H) 1.32 (t, J=7.15 Hz, 3H) 1.42-1.61 (m, 5H) 1.83-1.96 (m, 2H) 2.32-2.36 (m, 2H) 2.45-2.50 (m, 2H) 2.82-2.89 (m, 2H) 2.97 (q, J=7.28 Hz, 2H) 3.50-3.58 (m, 2H) 3.81-3.88 (m, 2H) 4.06-4.17 (m, 1H) 4.31 (q, J=7.19 Hz, 2H) 4.59-4.65 (m, 4H) 6.92 (d, J=7.53 Hz, 1H) 7.17 (d, J=7.28 Hz, 1H) 7.20-7.39 (m, 5H) 7.42-7.46 (m, 1H) 8.01 (s, 1H) 8.15-8.33 (m, 3H) 9.50 (t, J=6.27 Hz, 1H) 9.74 (t, J=6.27 Hz, 1H).