Reaction SMILES: BrCC1C=CN2C=1C(Cl)=NC=N2.N#N.S1C=CC=C1CC(O)=O.CCN(C(C)C)C(C)C.Cl[C:34]1[C:39]2=[C:40]([CH2:43][S:44][C:45](=[O:47])[CH3:46])[CH:41]=[CH:42][N:38]2[N:37]=[CH:36][N:35]=1.[Cl:48][C:49]1[CH:50]=[C:51]([NH2:64])[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=1>C(Cl)Cl.ClCCCl.C(O)CCC>[Cl:48][C:49]1[CH:50]=[C:51]([NH:64][C:34]2[C:39]3=[C:40]([CH2:43][S:44][C:45](=[O:47])[CH3:46])[CH:41]=[CH:42][N:38]3[N:37]=[CH:36][N:35]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CC(=O)SCc1ccn2ncnc(Cl)c12
Agent: Clc1ncnn2ccc(CBr)c12
Agent: N#N
Agent: O=C(O)Cc1cccs1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)SCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 5-bromomethyl-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (1 gm, 4.05 mmole) in DCM (40 mL) was sparged with N2 for 15 min. The solution was cooled in an ice bath and thiolacetic acid (0.319 mL, 1.1 equiv) and DIPEA (0.71 mL, 1 equiv) were added. After 0.5 h, the reaction was removed from the bath and after an additional 0.5 h, it was washed with water (3×), dried (Na2SO4), and the solvent was removed. The crude thioacetic acid S-(4-chloro-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl) ester and 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine (0.915 mg, 0.9 equiv) were dissolved in a mixture of 1,2-dichloroethane (4 mL) and n-butanol (4 mL) and heated at 85° C. for 1 h. The solvents were removed and the residue was partitioned between DCM and sat. aq. NaHCO3 solution. The organic phase was separated, washed with water, dried (Na2SO4), and the solvent removed. Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1% MeOH) afforded thioacetic acid S-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl} ester (986 mg, 54%). A portion of this thioester (120 mg, 0.263 mmole) was dissolved in dry THF and sparged with N2 for 15 min. NaOMe (0.525 mL of a 0.5 M solution of NaOMe in MeOH, 1.1 equiv) and MeI (0.016 mL) were added with stirring. After 0.5 h, the solvents were removed and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na2SO4), and the solvent was removed. Purification by radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1% MeOH) afforded [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(5-methylsulfanyl-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-amine (91 mg, 81%): 1H NMR (CDCl3) δ 2.26 (s, 3H), 4.06 (s, 2H), 5.19 (s, 2H), 6.57 (d, 1H, J=2.6 Hz), 6.95–7.93 (m, 10H), 8.86 (s, 1H). Solid m-chloroperbenzoic acid (54 mg, 58 to 70%, 1 equiv) was added to an ice-cooled solution of the thioether (91 mg, 0.21 mmole) in CHCl3. After 1 h, this was removed from the bath and washed with a 6% aq. solution of NaHSO3 and sat. aq. NaHCO3 (3×) and then dried (Na2SO4). Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2, 3% MeOH) afforded the title compound (49 mg, 51%): MS: 445 (M+H)+; HPLC Ret Time: 1.70 min (YMC Xterra C18 S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).