Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[O:29][C:7]1([CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]4[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=4)[N:16]=3)=[O:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:33].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:2]2[CH:3]=[C:4]3[C:30](=[CH:31][CH:32]=2)[O:29][C:7]2([CH2:12][CH2:11][N:10]([C:13]([C:15]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]5[C:17](=[C:18]([O:27][CH3:28])[CH:19]=[CH:20][CH:21]=5)[N:16]=4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][C:5]3=[O:33])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Br)ccc2O3)nc2c(OC)cccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc2O3)nc2c(OC)cccc12
Temperature: 110 °C
Reaction time: 20 h

Procedure:
6-Bromo-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one (1.00 g), 1-t-butoxycarbonylpiperazine (574 mg), palladium acetate (87.8 mg), 2-(di-t-butylphosphino)biphenyl (117 mg) and cesium carbonate (766 mg) were suspended in 1,4-dioxane (10 mL), and stirred at 110° C. for 20 hours. The reaction solution was filtered through Celite, the residue on Celite was washed with chloroform, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/5 to 0/10) to obtain a crude product of the compound, 6-(4-t-butoxycarbonylpiperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one. The resulting crude product was then dissolved in chloroform (8 mL), trifluoroacetic acid (8 mL) was added to it and stirred at room temperature for 3 hours. The reaction solution was partitioned between chloroform and aqueous 1 N sodium hydroxide solution, extracted with chloroform, and then dried with magnesium sulfate. The desiccant was removed through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified through thin-layer chromatography (chloroform/methanol/28% aqueous ammonia=85/15/1) to obtain 6-(piperazin-1-yl)-1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]spiro[chroman-2,4′-piperidin]-4-one. Trimethylsilyl isocyanate (100 mg, 0.870 mmol) was added to a solution of this compound (220 mg) in tetrahydrofuran (2 mL), and stirred at room temperature for 14 hours. The reaction solution was partitioned between chloroform and aqueous saturated sodium hydrogen carbonate solution, and the aqueous layer was extracted with chloroform, which was washed with saturated brine. The organic layer was dried over magnesium sulfate, the desiccant was removed through filtration, the filtrate was concentrated under a reduced pressure, and the resulting residue was purified through thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound. 1H-NMR (400 MHz, CDCl3) δ: 7.74 (1H, d, J=8.4 Hz), 7.44 (1H, dd, J=8.4, 7.6 Hz), 7.31 (1H, d, J=2.8 Hz), 7.17 (1H, dd, J=8.8, 2.8 Hz), 7.14 (1H, s), 7.05 (1H, d, J=7.6 Hz), 6.94 (1H, d, J=8.8 Hz), 4.72 (2H, br s), 4.50-4.60 (1H, m), 4.06 (3H, s), 4.01 (3H, s), 4.00-4.15 (1H, m), 3.50-3.65 (1H, m), 3.53 (4H, t, J=5.2 Hz), 3.30-3.40 (1H, m), 3.08 (4H, t, J=5.2 Hz), 2.77 (1H, d, J=16.4 Hz), 2.71 (1H, d, J=16.4 Hz), 2.10-2.25 (1H, m), 2.00-2.05 (1H, m), 1.75-1.90 (2H, m). MS [M+H]+=560.