Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][C:12]([O:15][CH3:16])([CH3:14])[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67]([O:71][C:72]([NH:74][C:75]1[S:79][C:78]([C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[F:87])=[N:77][C:76]=1[C:88](O)=[O:89])=[O:73])([CH3:70])([CH3:69])[CH3:68]>C(Cl)Cl>[C:67]([O:71][C:72]([NH:74][C:75]1[S:79][C:78]([C:80]2[C:85]([F:86])=[CH:84][CH:83]=[CH:82][C:81]=2[F:87])=[N:77][C:76]=1[C:88]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][C:12]([O:15][CH3:16])([CH3:14])[CH2:11][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:8]1)=[O:89])=[O:73])([CH3:70])([CH3:68])[CH3:69]
Reactant: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2c(N)cnn2C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1(C)CN(C(=O)OC(C)(C)C)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (ice-water bath) solution of Intermediate 44, tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.20 mmol) in DMF (1 mL) under nitrogen, was added sodium hydride (60% in mineral oil, 9.5 mg, 0.24 mmol) and the mixture stirred for 10 min. Iodomethane (0.04 mL, 0.6 mmol) was added and the mixture stirred at room temperature for 16 hr. Additional sodium hydride (60% in mineral oil, 9.5 mg, 0.24 mmol) was added and the mixture stirred for 30 min before the addition of more iodomethane (0.04 mL, 0.6 mmol). After 5 hr, water (30 mL) was added and the mixture extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford tert-butyl 6-methoxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate as an oil. A solution of this oil in MeOH (4 mL) was passed through the H-Cube® (full H2, 60° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as an oil. To a solution of this amine in DCM (10 mL) was added DIPEA (0.1 mL, 9.6 mmol), PyBOP (160 mg, 0.30 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (78 mg, 0.22 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-methoxy-6-methyl-1,4-diazepane-1-carboxylate as a beige solid (123 mg). This solid (120 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 2.3 mL, 9.1 mmol) in MeOH (1 mL) at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH and the residue was purified via silica gel column chromatography (0-10% MeOH/DCM, 1% 7 N ammonia in MeOH). Further purification by preparative HPLC gave 192 as the monoformate salt as an off-white solid (19 mg, 20% over four steps). 1H NMR (400 MHz, d6-DMSO) δ 9.38 (s, 1H), 8.21 (s, 1H), 7.66 (s, 1H), 7.60-7.48 (m, 3H), 7.33-7.23 (m, 2H), 3.67 (t, J=4.9 Hz, 3H), 3.29-2.69 (m, 11H), 0.97 (s, 3H). Alkyl NH not observed. LCMS (ES+) m/z 477 (M+1).