8-Hydroxyquinoline → tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

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tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.15 g, 0.40 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.42 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copper iodide (98 mg, 0.51 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 21 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2(30 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes, then increased to 0:100 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (0.55 mg, 21%) as a clear film: 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84-7.79 (m, 2H), 7.67-7.60 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.18 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69-3.66 (m, 5H), 3.62-3.57 (m, 2H), 3.08-3.04 (m, 2H), 2.99-2.94 (m, 2H), 1.43-1.42 (m, 9H).

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