Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:10][CH:11]([N:15]1[CH:19]=[C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[N:16]1)[CH2:12][C:13]#[N:14].[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[C:41]([F:48])[CH:40]=1)#[N:38].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>C1COCC1.O.C(OCC)(=O)C>[C:13]([CH2:12][CH:11]([N:15]1[CH:19]=[C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[N:16]1)[CH2:10][N:5]1[CH2:6][CH2:7][N:8]([C:43]([C:42]2[CH:46]=[CH:47][C:39]([C:37]#[N:38])=[CH:40][C:41]=2[F:48])=[O:44])[CH2:9][CH:4]1[CH2:3][OH:2])#[N:14]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4CO)c3)ncnc21
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4CO)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
4-[2-(hydroxymethyl)piperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloric acid salt (0.26 g, 0.46 mmol, prepared as in Step 4) was added to a mixture of 4-cyano-2-fluorobenzoic acid (106 mg, 0.639 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (208 mg, 0.548 mmol) and triethylamine (382 μL, 2.74 mmol) in THF (5.4 mL) that was pre-stirred at RT for 15 min. After addition, the mixture was stirred for 1 h. Ethyl acetate and water were added. The organic layer was washed with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. Flash chromatography, using a 40 g silica gel cartridge and eluting with 0-5% MeOH in EtOAc afforded a viscous oil (200 mg, 68%). Chiral HPLC (Chiral Technologies ChiralPak IA-H column, 20×250 mm, 5 micron particle size, eluting with 45% ethanol in hexanes at a flow rate of 8 mL/minute) afforded separation of individual isomers. Retention times: peak 1: 2.148 min, peak 2: 6.074 min, peak 3: 9.283 min, peak 4: 16.879 min. Peak 1: (41 mg), 1H NMR (400 MHz, CDCl3, rotamers): δ 8.84 (s, 0.4H), 8.83 (s, 0.6H), 8.36 (s, 0.4H), 8.35 (s, 0.6H), 8.31 (s, 0.4H), 8.29 (s, 0.6H), 7.54-7.37 (m, 4H), 6.78 (d, 0.4H), 6.77 (d, 0.6H), 5.68, 5.67 (2s, 2H), 4.68 (dddd, 1H), 3.96-0.78 (m, 17H), −0.07 (s, 9H); LCMS (M+H)+: 644.3. Peak 2: (25 mg), 1H NMR (400 MHz, CDCl3, rotamers): δ 8.84 (s, 0.4H), 8.83 (s, 0.6H), 8.36 (s, 0.4H), 8.35 (s, 0.6H), 8.31 (s, 0.4H), 8.29 (s, 0.6H), 7.54-7.37 (m, 4H), 6.78 (d, 0.4H), 6.77 (d, 0.6H), 5.68, 5.67 (2s, 2H), 4.68 (dddd, 1H), 3.96-0.78 (m, 17H), −0.07 (s, 9H); LCMS (M+H)+: 644.1. Peak 3: (25 mg), 1H NMR (400 MHz, CDCl3, rotamers): δ 8.85 (s, 0.5H), 8.83 (s, 0.5H), 8.37-8.32 (m, 2H), 7.54-7.38 (m, 4H), 6.79 (d, 1H), 5.68 (s, 2H), 4.77-4.60 (m, 1H), 4.22-0.81 (m, 17H), −0.07 (s, 9H); LCMS (M+H)+: 644.2. Peak 4: (46 mg), 1H NMR (400 MHz, CDCl3, rotamers): δ 8.85 (s, 0.5H), 8.83 (s, 0.5H), 8.37-8.32 (m, 2H), 7.54-7.38 (m, 4H), 6.79 (d, 1H), 5.68 (s, 2H), 4.77-4.60 (m, 1H), 4.22-0.81 (m, 17H), −0.07 (s, 9H); LCMS (M+H)+: 644.3.