Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[C:25]3[C:24]([F:26])=[CH:23][C:22]([OH:27])=[C:21]([F:28])[C:20]=3[C:19]3[C:29]([CH3:36])=[N:30][N:31](C(C)(C)C)[C:18]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:48][CH:49]1[CH2:54][CH2:53][N:52]([C:55](OC(C)(C)C)=O)[CH2:51][CH2:50]1)(=O)=O.C=O.Cl.[F:65][C:66]([F:71])([F:70])[C:67]([OH:69])=[O:68]>CN(C)C=O.C(O)=O.CCO.O1CCOCC1>[F:65][C:66]([F:71])([F:70])[C:67]([OH:69])=[O:68].[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[C:25]3[C:24]([F:26])=[CH:23][C:22]([O:27][CH2:48][CH:49]4[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]4)=[C:21]([F:28])[C:20]=3[C:19]3[C:29]([CH3:36])=[N:30][NH:31][C:18]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)c(Cl)c3)c3c(F)cc(OCC4CCN(C)CC4)c(F)c3c12
Temperature: 70 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
5-{3-Chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol (0.030 g, 0.059 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (0.041 g, 0.296 mmol) was added followed by 1,1-dimethylethyl 4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (0.019 g, 0.065 mmol). The mixture was stirred at 70° C. for 15 h and then at 90° C. for 24 h. The mixture was partitioned between ethyl acetate and 1N NaOH. The organic portion was washed with 1 N NaOH. The aqueous portion was back-extracted with ethyl acetate. The combined organic portion was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was dissolved in trifluoroacetic acid (0.5 mL) and stirred at room temperature for 0.6 h, then at 50° C. for 0.2 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution. The combined aqueous portion was extracted with ethyl acetate and then 10% MeOH in ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by preparative HPLC to afford a yellow film which was dissolved in formic acid (0.5 mL) and heated at 95° C. for 17 h. Formaldehyde (37 wt. % solution in water; 0.015 mL, 0.200 mmol) was added and the mixture was stirred at 95° C. for 23 h. The mixture was concentrated in vacuo to afford a residue which was dissolved in EtOH and 4 N HCl in dioxan was added. The mixture was concentrated in vacuo to afford a yellow solid which was purified by preparative HPLC to afford 2-chloro-4-(6,9-difluoro-1-methyl-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol trifluoroacetate as a yellow oil (0.0054 g, 0.0092 mmol, 16% yield). 1H NMR (400 MHz, CD3OD): 7.48 (t, 1H), 7.29 (dt, 1H), 7.13 (dd, 1H), 7.00 (d, 1H), 4.14-4.09 (m, 2H), 3.64-3.57 (m, 2H), 3.12-3.03 (m, 2H), 2.89 (s, 3H), 2.76 (d, 3H), 2.26-2.13 (m, 3H), 1.81-1.66 (m, 2H); MS (EI) for C24H23ClF2N4O2: 473 (MH+).