Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]([C:15]([OH:17])=O)[CH:6]=1)[CH3:3].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:60][C:59]([CH2:83][C:84]#[N:85])([N:61]3[CH:65]=[C:64]([C:66]4[C:67]5[CH:74]=[CH:73][N:72](COCC[Si](C)(C)C)[C:68]=5[N:69]=[CH:70][N:71]=4)[CH:63]=[N:62]3)[CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[N:8]=[C:7]([C:15]([N:51]2[CH2:52][CH2:53][CH:54]([N:57]3[CH2:58][C:59]([CH2:83][C:84]#[N:85])([N:61]4[CH:65]=[C:64]([C:66]5[C:67]6[CH:74]=[CH:73][NH:72][C:68]=6[N:69]=[CH:70][N:71]=5)[CH:63]=[N:62]4)[CH2:60]3)[CH2:55][CH2:56]2)=[O:17])[CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1cc(C(=O)O)nc(C(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.015 g, 0.060 mmol, from Step A) in N,N-dimethylformamide (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.028 g, 0.072 mmol, Aldrich) and N,N-diisopropylethylamine (0.042 mL, 0.24 mmol). This mixture was prestirred for 15 minutes, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.030 g, 0.061 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). The reaction was stirred overnight. Additional N,N-diisopropylethylamine (0.042 mL, 0.24 mmol), 4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridine-2-carboxylic acid (0.014 g, 0.056 mmol) in DMF (1 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.018 g, 0.048 mmol) were added and the reaction was stirred over an additional 48 hours. The reaction mixture was then partitioned between ethyl acetate and water and the layers were separated. Solid NaCl was added to saturate the aqueous layer and this was extracted with two further portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, decanted and concentrated. The crude product was deprotected by stirring with a 1:1 mixture of TFA:DCM for 1.5 hours, followed by evaporation and then stirring the resulting residue with ethylenediamine (0.2 mL) in methanol (4 mL). The mixture was filtered and purified by preparative HPLC-MS, (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing product were frozen and lyophilized. Yield: 0.015 g (42%); LC-MS: 593.2 (M+H)+. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.51 (d, 1H), 6.99 (d, 1H), 4.32 (ddd, 1H), 3.86-3.70 (m, 5H), 3.64 (s, 2H), 3.50 (s, 2H), 3.36-3.16 (m, 2H), 2.69-2.61 (m, 1H), 2.28 (s, 6H), 1.98-1.88 (m, 1H), 1.86-1.77 (m, 1H), 1.51-1.39 (m, 2H). 19F NMR (400 MHz, CD3OD): δ −69.82 (s, 3F).