Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:44][N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54](B3OC(C)(C)C(C)(C)O3)[CH:53]=2)[CH2:47][CH2:46]1.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]>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:56]5[CH:55]=[CH:54][CH:53]=[C:52]([CH2:51][CH:48]6[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]6)[CH:57]=5)[C:7]([O:8][CH3:9])=[CH:6][CH:5]=4)=[O:13])[N:15]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
Reactant: CN1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CC4CCN(C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 12.8 %

Procedure:
A mixture of N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.077 mmol), 1-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}piperidine (30.8 mg, 0.077 mmol), Na2CO3 (24.44 mg, 0.231 mmol) and PdCl2(dppf) (5.62 mg, 7.69 μmol) 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 10 to 70% 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 the basified solution was 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-(methyloxy)-3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)-2,6-pyridinedicarboxamide as a solid (7.5 mg, 12.9%). LC-MS m/z 759 (M+H)+, 0.77 min (ret time); 1H NMR (400 MHz, CD3OD) δ 1.22-1.29 (m, 5H) 1.39 (t, J=7.15 Hz, 3H) 1.49-1.76 (m, 5H) 1.90-1.97 (m, 2H) 1.99-2.05 (m, 2H) 2.23 (s, 3H) 2.51 (d, J=7.03 Hz, 2H) 2.78-2.84 (m, 2H) 2.99 (q, J=7.53 Hz, 2H) 3.61 (td, J=11.42, 2.51 Hz, 2H) 3.74 (s, 3H) 3.90-4.02 (m, 2H) 4.12-4.19 (m, 1H) 4.40 (q, J=7.19 Hz, 2H) 4.58 (s, 2H) 4.74 (s, 2H) 6.97 (d, J=8.53 Hz, 1H) 7.01-7.08 (m, 1H) 7.16-7.32 (m, 5H) 7.98 (s, 1H) 8.15 (t, J=7.78 Hz, 1H) 8.28 (dd, J=7.91, 1.13 Hz, 1H) 8.36 (dd, J=7.78, 1.25 Hz, 1H).