Reaction SMILES: COC1C=CC(CN2C3=NC=CC(OC4C=CC(N(C5C=CC(F)=CC=5)C(C5(C(N)=O)CC5)=O)=CC=4F)=C3C(C3C=C(CN4CCN(C)CC4)OC=3)=N2)=CC=1.COC1C=CC(C[N:63]2[C:67]3=[N:68][CH:69]=[CH:70][C:71]([O:72][C:73]4[CH:78]=[CH:77][C:76]([N:79]([C:88]5[CH:93]=[CH:92][C:91]([F:94])=[CH:90][CH:89]=5)[C:80]([C:82]5([C:85]([NH2:87])=[O:86])[CH2:84][CH2:83]5)=[O:81])=[CH:75][C:74]=4[F:95])=[C:66]3[C:65]([C:96]3[O:97][C:98]([CH2:102][N:103]4[CH2:108][CH2:107][N:106]([CH3:109])[CH2:105][CH2:104]4)=[CH:99][C:100]=3[Br:101])=[N:64]2)=CC=1.C(O)(C(F)(F)F)=O>>[Br:101][C:100]1[CH:99]=[C:98]([CH2:102][N:103]2[CH2:108][CH2:107][N:106]([CH3:109])[CH2:105][CH2:104]2)[O:97][C:96]=1[C:65]1[C:66]2[C:67](=[N:68][CH:69]=[CH:70][C:71]=2[O:72][C:73]2[CH:78]=[CH:77][C:76]([N:79]([C:88]3[CH:89]=[CH:90][C:91]([F:94])=[CH:92][CH:93]=3)[C:80]([C:82]3([C:85]([NH2:87])=[O:86])[CH2:84][CH2:83]3)=[O:81])=[CH:75][C:74]=2[F:95])[NH:63][N:64]=1
Reactant: COc1ccc(Cn2nc(-c3oc(CN4CCN(C)CC4)cc3Br)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Agent: COc1ccc(Cn2nc(-c3coc(CN4CCN(C)CC4)c3)c3c(Oc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2cc(Br)c(-c3n[nH]c4nccc(Oc5ccc(N(C(=O)C6(C(N)=O)CC6)c6ccc(F)cc6)cc5F)c34)o2)CC1
Temperature: 25 °C

Procedure:
A 17:83 mixture of N-(4-(1-(4-methoxybenzyl)-3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and N-(4-(1-(4-methoxybenzyl)-3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide (26 mg, 0.035 mmol) were heated with TFA (0.5 mL) at 80° C. for 2 hours in a sealed vessel. After cooling to ambient temperature, the mixture was concentrated in vacuo, using toluene to azeotrope. The resulting solid was partitioned between EtOAc (5 mL) and 1:1 saturated aqueous NaHCO3/water (5 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude products were separated by preparative TLC (0.5 mm thickness; N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.33; N-(3-fluoro-4-(3-(5-((4-methylpiperazin-1-yl)methyl)furan-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide: Rf=0.25), eluting with 10% MeOH (containing 7N NH3) in CHCl3. The product, N-(4-(3-(3-bromo-5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, was obtained as a white powder (8 mg, 32%). HPLC: 98% purity (254 nm); LRMS (ESI+): 100% purity, 220 nm, 708, 606 (loss of piperazine) m/z (M+1) detected; 1H NMR (400 MHz, CDCl3+few drops CD3OD) δ 8.31 (d, J=5 Hz, 1H), 7.73 (m, 1H), 7.48 (m, 2H), 7.32 (m, 1H), 7.21 (t, J=9 Hz, 1H), 7.04 (t, J=9 Hz, 2H), 6.48 (s, 1H), 6.33 (d, J=5 Hz, 1H), 3.55 (s, 2H), 2.48 (m, 8H), 2.21 (s, 3H), 1.69 (m, 4H). 1H NMR/13C-NMR correlation spectroscopy was consistent with the depicted bromo-furan regioisomer.