Reaction SMILES: Cl[C:2]1[C:3]([C:22]#[N:23])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:18][CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[C@H:9]2[CH3:21])[N:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([CH3:44])[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=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:22]([C:3]1[C:2]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([CH3:44])[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[N:7][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:18][CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[C@H:9]2[CH3:21])=[CH:5][N:4]=1)#[N:23]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Reactant: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](N2CCN(C)C2=O)CCCN1c1cnc(C#N)c(Nc2ccc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 1.17 h

Procedure:
The mixture of 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (357) (100 mg, 0.60 mmol), tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (175 mg, 0.60 mmol), fine-powder cesium carbonate (590 mg, 1.80 mmol), Pd(OAc)2 (45 mg, 0.2 mmol), BINAP (125 mg, 0.2 mmol) in 30 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 70 min. The mixture was cooled to RT, diluted with 120 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 4% MeOH in chloroform to isolate tert-butyl 4-(4-(3-cyano-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (358). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added fine-powder Cs2CO3 (50 mg) and then 1 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, and subjected to silica flash column using 0 to 4% MeOH in DCM to isolate tert-butyl 4-(4-(3-carbamoyl-6-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-ylamino)phenyl)-4-methylpiperidine-1-carboxylate (359). It was treated with 2:1 DCM/TFA (12 mL/6 mL) at RT for 30 min. The mixture was concentrated in vacuo. One third of the residue was dissolved in MeOH/water and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 5-((2R,3R)-2-methyl-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(4-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide (360) as HCl salt (65 mg). LC-MS (ESI): m/z (M+1) 507.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.68 (2H, d, J=9.0 Hz), 7.62 (1H, s), 7.35 (2H, d, J=8.5 Hz), 5.11 (1H, m), 4.28 (1H, m), 3.89 (1H, m), 3.53 (2H, m), 3.38 (2H, m), 3.30 (2H, m), 3.06 (3H, m), 2.81 (3H, s), 2.42 (2H, m), 2.03 (1H, m), 1.95 (3H, m), 1.83 (1H, m), 1.68 (1H, m), 1.31 (3H, s), 1.21 (3H, d, J=7.0 Hz) ppm.