Reaction SMILES: Br.Br.[F:3][C:4]1[CH:5]=[C:6]([NH:33][C:34]([NH:36][C:37](=[O:45])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[S:35])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][CH:25]3[CH2:32][CH:28]4[CH2:29][NH:30][CH2:31][CH:27]4[CH2:26]3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1.C=O.[C:48]([O-])(O)=O.[Na+]>C(C#N)(C)=O.O.CC(O)=O>[F:3][C:4]1[CH:5]=[C:6]([NH:33][C:34]([NH:36][C:37](=[O:45])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[S:35])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][CH:25]3[CH2:32][CH:28]4[CH2:29][N:30]([CH3:48])[CH2:31][CH:27]4[CH2:26]3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=C([O-])O
Reactant: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CNCC2C1
Agent: Br
Agent: C=O
Agent: CC(=O)C#N
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CN(C)CC2C1
Reaction time: 1 h
Yield: 40 %

Procedure:
1-{3-Fluoro-4-[6-methoxy-7-(octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea, dihydrobromide salt (3.4 g, 4.5 mmol) was dissolved in a combination of AcCN (100 ml), H2O (30 ml), and AcOH (2.45 ml). Formaldehyde (37% in H2O, 855 ml, 10.5 mmol) was added and the mixture cooled in an ice bath. Na(OAC)3BH (2.99 g, 14.1 mmol) was added and the reaction mixture was stirred at 0 C for 1 hr, followed by stirring at room temperature for 2 hrs. The reaction mixture was neutralized with the addition of sat'd NaHCO3 and then concentrated in vacuo. The resulting aqueous mixture was extracted with CH2Cl2 (3×). The combined extractions were washed with sat'd NaHCO3 (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by flash chromatography (100% EtOAc, followed by 4% Et3N in EtOAc) to give the free base of 1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxyl]-phenyl}-3-phenylacetyl-thiourea (1.13 g, 40%). The free base was converted to the HCl salt by dissolving the free base in a mixture of 1:1 AcCN:H2O containing 2-3 equivalents of 1N HCl and lyophilizing to give the HCl salt of 1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea as a white solid. 1H-NMR (400 MHz, DMSO): 12.44 (s, 1H), 11.83 (s, 1H), 10.24 (br s, 1H), 8.59 (s, 1H), 7.93 (m, 1H), 7.59 (s, 1H), 7.50 (m, 2H), 7.42 (s, 1H), 7.36 (m, 4H), 7.30 (m, 1H), 4.20 (m, 2H), 3.95 (s, 3H), 3.73 (s, 2H), 3.39 (m, 2H), 3.06 (m, 2H), 2.95-2.77 (m, 5H), 2.35 (m, 1H), 2.15 (m, 2H), 1.45 (m, 2H). LC/MS Calcd for [M+H]+ 616.2. found 616.2. Alternatively, the free base was converted to the acetate salt by dissolving the free base in a mixture of MeOH and CH2Cl2 to which was added 3 equivalents of acetic acid. The resulting mixture was concentrated in vacuo and the resulting residue lyophilized from 1:1 AcCN:H2O to give the acetate salt of 1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinazolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea as a white solid. 1H-NMR (400 MHz, CDCl3): d 12.45 (s, 1H), 8.65 (s, 1H), 7.98 (dd, 1H), 7.50 (s, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 4.17 (d, 2H), 4.05 (s, 3H), 3.75 (s, 2H), 2.93 (m, 2H), 2.80 (m, 2H), 2.72 (m, 2H), 2.53 (s, 3H), 2.47 (m, 1H), 2.25 (m, 2H), 2.02 (s, 3H), 1.35 (m, 2H). LC/MS Calcd for [M+H]+ 616.2. found 616.2.