[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[C:13]([OH:19])(=O)[CH2:14]C(O)=O.[N:20]1[CH:25]=CC=C[CH:21]=1.BrN1C2C(=CC=CC=2)C(=O)C1=O.C(=O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O.Cl>C(OCC)(=O)C.O.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:14][C:13]([N:20]([CH3:25])[CH3:21])=[O:19])[OH:12]A 2 L flask fitted with an inner thermometer, mechanical stirrer, and reflux condenser is charged with 5-bromo-isatin (100 g, 0,442 mol), malonic acid (55.2 g, 053 mol), pyridine (100.6 g, 1.274 mol), dimethyl formamide (80 g), and ethyl acetate (100 g). When the temperature of the mixture reaches 60° C., the bromo isatin starts to dissolve, and a deep red mixture forms, Carbon dioxide starts to evolve, and after about 45 minutes the precipitation of the intermediate pyridinium (5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-acetate starts. The reaction mixture is kept at 80° C. for another 3 hours. Then triethyl amine (49.2 g, 0.486 mol) is added, and the pyridinium salt dissolves to give a deep brown solution. This solution is allowed to cool to 50° C., and then a solution of dimethyl carbamoyl chloride (48 g, 0.442 mol, CAUTION: carcinogen) in 40 g of ethyl acetate is added dropwise during 30 minutes. Carbon dioxide evolves, and the temperature rises to 60° C. After about 45 minutes, the product starts to precipitate from the reaction mixture. The mixture is kept at 60° C. for another hour, and then water (500 mL) and 36% HCl (250 mL, 4 mol) are added in that order during 10 minutes. The product is filtered off, and reslurried in an mixture of acetone/water (500 mL, 1:1, v:v). The slurry is filtered again, and the product is finally dried to give the title compound as a gray powder which is of suitable purity for direct use in the further steps. Yield: 75.2 g (54.2%). An analytically pure sample is obtained by recrystallization from methanol, mp=245-246° C., dec. 1H-NMR (DMSO-D6, 300 MHz): δ 2.64 (s, 3, CH3), 2.93 (s, 3, CH3), 2.93, 3.27 (AB, 2, 2J=16.5 Hz, CH2), 6.01 (br s, 1, OH), 6.73 (d, 1, J=8.2 Hz, H-7), 7.30 (dd, 1, 3J=2.0 Hz, H-6), 7.42 (d, 1, H-4), 10.18 (br s, 1, NH). 13C-NMR (DMSO-D6, 75 MHz) δ 35.04, 37.45 (N(CH3)2), 40.78 (CH2), 73.90 (C-3), 111.85 (C-7), 113.29 (C-5), 127.03 (C-4), 131.83 (C-6), 135.78 (C-9), 143.18 (C-8), 168.93 (CONMe2), 178.68 (C-2).
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