Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[C@H:9]2[CH3:20])[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH3:43])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:21]([C:3]1[C:2]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3([CH3:43])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]([N:16]([CH3:18])[CH3:17])=[O:19])[C@H:9]2[CH3:20])=[CH:5][N:4]=1)#[N:22]
Reactant: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](NC(=O)N(C)C)CCCN1c1cnc(C#N)c(Nc2ccc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
The mixture of 3-((2R,3R)-1-(6-chloro-5-cyanopyrazin-2-yl)-2-methylpiperidin-3-yl)-1,1-dimethylurea (326) (300 mg, 0.93 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (325 mg, 1.12 mmol), fine-powder cesium carbonate (1300 mg, 4.00 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), BINAP (190 mg, 0.30 mmol) in 45 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 3 hours. The mixture was cooled to RT, diluted with 150 mL EtOAc, and filtered using ChemGlass OP-6602-12 disposable funnel. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate tert-butyl 4-(4-(3-cyano-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (337). It was dissolved in 20 mL MeOH and 4 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water (×2), dried, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate tert-butyl 4-(4-(3-carbamoyl-6-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (338). It was treated with 2:1 DCM and TFA (10 mL/5 mL) at RT for 30 min and concentrated to dryness to give crude 5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (339) as TFA salt. Half of this salt was dissolved in 10 mL 1,2-dichloroethane (DCE) and 2 mL NMP. To it were added DIEA (700 μL, 4.0 mmol) and cyclopentanone (1.06 mL, 12.0 mmol). The mixture was stirred at RT for 2 hours. To it were then added acetic acid (450 μL, 8.0 mmol) and then NaBH(OAc)3 (510 mg, 2.4 mmol). The mixture was stirred at RT for overnight, diluted with 20 mL MeOH, concentrated in vacuo, acidified with TFA (1 mL). and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentyl-4-methylpiperidin-4-yl)phenylamino)-5-((2R,3R)-3-(3,3-dimethylureido)-2-methylpiperidin-1-yl)pyrazine-2-carboxamide (340) as HCl salt (142 mg, 54% overall yield for 4 steps). LC-MS (ESI): m/z (M+1) 564.0. UV: λ=268, 278, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.73-7.63 (3H, m), 7.34 (2H, m), 5.05 (1H, m), 4.33 (1H, m), 3.87 (1H, m), 3.64-3.50 (2H, m), 3.06 (1H, m), 2.96 (6H, s), 2.89-2.63 (3H, m), 2.23-2.09 (4H, m), 2.01-1.91 (4H, m), 1.89-1.62 (8H, m), 1.41-1.27 (3H, s), 1.17 (3H, d, J=7.0 Hz) ppm.