Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:20]=[O:21]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a mixture of 1-bromo-3,5-dimethoxybenzene (21.7 g, 100.0 mmol) in DMF (80 mL) was added POCl3 (15 mL, 150 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min and then heated to 100° C. for an additional 30 min. After cooling to room temperature, the mixture was poured onto ice (200 g). The precipitate was collected by filtration and dried under high vacuum to give the title compound as a yellow solid (19.4 g, Yield: 79%). 1H NMR (400 MHz, CDCl3) δ 12.33 (s, 1H), 10.11 (s, 1H), 6.47 (s, 1H), 6.39 (s, 1H), 5.49 (t, J=3.13 Hz, 1H), 3.78-3.90 (m, 1H), 3.52-3.72 (m, 1H), 2.54 (s, 3H), 1.77-2.03 (m, 3H), 1.53-1.70 (m, 3H); MS (ESI) m/z=285 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:31]([C:40]([F:43])([F:42])[F:41])[CH:30]=1>CN(C=O)C>[CH:35]1([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]3[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[CH:5]4)=[CH:30][C:31]=2[C:40]([F:41])([F:42])[F:43])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 73.2 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (107 mg, 0.391 mmol) and cesium carbonate (191 mg, 0.587 mmol) in DMF (2 mL)was added 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (123 mg, 0.47 mmol). The reaction was heated at 75° C. for 5 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (143 mg). LCMS m/z=500.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (t, J=7.1 Hz, 3H), 1.52-1.67 (m, 3H), 1.68-1.80 (m, 2H), 1.80-1.92 (m, 2H), 2.00-2.24 (m, 5H), 2.55 (dd, J=15.6 and 8.7 Hz, 1H), 2.95 (dd, J=15.6 and 5.4 Hz, 1H), 3.35-3.45 (m, 1H), 3.45-3.55 (m, 1H), 3.83-3.92 (m, 1H), 4.10-4.18 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 5.10 (s, 2H), 6.19 (s, 1H), 6.90 (dd, J=8.8 and 2.4 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.1 and 1.3 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[S:13].N[C:20]1[CH:25]=CC=CN=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:25]=[CH:20][CH:18]=[CH:17][N:16]=1)=[S:13]
Reactant: Nc1ccccn1
Reactant: COc1ccccc1CCNC(=S)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccccc1CCNC(=S)Nc1ccccn1
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A solution of 1-(2-[2-methoxyphenyl]ethyl)thiocarbamoyl imidazole (0.52 g, 2 mmol ) and 2-aminopyridine (0.19 g, 2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 90° C. for 4 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 0.25 g (44%) of the titled product: IR (KBr, cm-1) 3219, 3048, 1607, 1557, 1236, 1036, 756; 1H NMR (300 MHz, DMSO-d6) δ 11.65 (m, 1H), 10.55 (br s, 1H), 8.1 (m, 1H), 7.75 (m, 1H), 7.3-6.9 (m, 6H), 3.8 (m, 2H), 3.78 (s, 3H), 2.9 (t, J=7 Hz, 2H); MS (FD) m/e 287 (M+) ; UV (EtOH) 290 nm (ε=10141), 267 nm (ε=13121), 247 nm (ε=10959), 202 nm (ε=24078).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2].[C:12]([Si:16]([CH3:19])([CH3:18])Cl)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>CN(C)C=O>[Si:16]([N:10]1[CH:7]([CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:8][C:9]1=[O:11])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:19])[CH3:18]
Reactant: CC(=O)OCCC1CC(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OCCC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A solution of 4-(2'-acetoxyethyl)-2-azetidinone (50.2 g., 0.32 mole) and t-butyldimethylchlorosilane (50.6 g, 0.335 mole) in 250 ml anhydrous N,N-dimethylformamide is treated at 0° with triethylamine (35.6 g, 0.353 mole). A white precipitate appears immediately. The mixture is stirred for a period of five minutes. It is then partitioned between 1600 ml benzene and 600 ml water. The organic phase is washed an additional four times with water and finally with brine. The benzene solution is then dried over magnesium sulfate and filtered. Evaporation of the filtrate under reduced pressure gives 84.0 g of 1-(t-butyldimethylsilyl)-4-(2'-acetoxyethyl)-2-azetidinone. Recrystallization from pentane gives 68.9 g of product with m.p. 35°.
Reaction SMILES: [O:1]=[CH:2][CH2:3][N:4]([C:18]1[C:19]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:20]=2[N:21]=[CH:22][N:23]=1)[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1.[OH:37]O>CC#N.CCOC(C)=O>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:5]([N:4]([C:18]2[C:19]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][C:2]([OH:37])=[O:1])[CH2:6]1)=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: OO
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(CC(=O)O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((2-oxoethyl)(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (0.5 g, 0.97 mmol) in CH3CN (2 mL) at rt, was added an aq. solution of NaH2PO4 (3 mL, 0.21 g, 1.75 mmol), aq. NaO2Cl (2 mL, 0.16 g, 1.75 mmol) and 30% H2O2 (0.17 ml, 1.5 mmol) at 0° C. The reaction mixture was warmed to rt and stirred for overnight. The organic phase was concentrated in vacuo to afford a residue that was dissolved in EtOAc, filtered and dried over Na2SO4, concentrated in vacuo and purified by column chromatography (Silica gel, gradient MeOH: CH2Cl2) to afford the titled compound (0.105 g, 20.38%). LCMS [M+1]: 530.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([OH:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:13][C:8]1[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]2[O:3][C:2]([CH3:1])([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:18][CH2:17]3)[CH2:6][C:5]=2[C:7]=1[CH3:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(C)c2c(c(C)c1O)CC(C)(CN1CCN(c3ccccc3)CC1)O2
Reactant: BrCc1ccccc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(C)(CN1CCN(c3ccccc3)CC1)O2
Yield: 48 %

Procedure:
Using 2,4,6,7-tetramethyl-2-(4-phenyl-1-piperazinyl)methyl-2,3-dihydrobenzofuran-5-ol and benzyl bromide, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8](CS(C3C=CC(C)=CC=3)(=O)=O)=[N:7][C:6]=2[CH:30]=1.[NH2:31][CH2:32][CH2:33][N:34]([CH3:43])[CH2:35][CH2:36][CH2:37][N:38]([CH2:40][CH2:41][NH2:42])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8]([NH:42][CH2:41][CH2:40][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][NH:31][C:8]3[C:9]4[C:10](=[O:18])[C:11]5[CH:12]=[N:13][CH:14]=[CH:15][C:16]=5[C:17]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][C:6]=4[N:7]=3)[CH3:43])[CH3:39])=[N:7][C:6]=2[CH:30]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Cc2nc3cc(Cl)ccc3c3c2C(=O)c2cnccc2-3)cc1
Product: CN(CCCN(C)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1cnccc1-2)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1cnccc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from 3-chloro-6-(toluene-4-sulfonylmethyl)-5,9-diaza-benzo[c]fluoren-7-one (the compound of Reference Example 7c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH3:37])=[CH2:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[Pt](=O)=O>[Si:1]([O:8][CH2:9][CH:10]([C@@H:12]1[N:15]([CH:16]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14](=[O:35])[C@@H:13]1[C@H:36]([O:38][C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH3:37])[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]2C(C)CO[Si](C)(C)C(C)(C)C)cc1

Procedure:
A solution of (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2azetidinone (1.0 g) and triethylamine (0.06 ml) in ethyl acetate (50 ml) was hydrogenated under hydrogen atmosphere in the presence of platinum dioxide (0.05 g) at 0°-5° C. for 2 hours. After removal of the catalyst, the filtrate was washed successively with 2 N hydrochloric acid, brine, 5% sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. Filtration and concentration of the filtrate in vacuo gave (3S,4S)-4-(1-t-butyldimethylsilyloxymethylethyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[F:18][C:19]1[C:24](F)=[C:23]([F:26])[C:22]([F:27])=[C:21]([F:28])[C:20]=1[F:29].O>CN(C)C=O>[CH3:17][C:14]1[CH:13]=[CH:12][C:11]([C:4]2([O:3][C:24]3[C:23]([F:26])=[C:22]([F:27])[C:21]([F:28])=[C:20]([F:29])[C:19]=3[F:18])[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)=[CH:16][CH:15]=1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1ccc(C2(O)CCN(C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C2(Oc3c(F)c(F)c(F)c(F)c3F)CCN(C)CC2)cc1
Temperature: 85 °C

Procedure:
To a suspension of sodium hydride (2.2 g, 60% in oil) in 20 ml of dimethylformamide, was added a solution of 11.0 g of 4-hydroxy-4-(4-methylphenyl)-1-methylpiperidine in 50 ml of dimethylformamide. After heating to 85° C. for thirty minutes, the mixture was cooled with an ice-bath, and treated over a period of ten minutes with a solution of 7 ml of hexafluorobenzene in 20 ml of dimethylformamide. After stirring at ambient temperature for twenty hours, the mixture was poured into 200 ml water, stirred for five minutes, then extracted with ethyl acetate (2×). The organic layer was washed with water (2×), followed by a saturated solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% methanol/dichloromethane). The desired fractions were combined, and evaporated to yield 13 g of (4-(4-methylphenyl)-1-methyl-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13](O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:21][CH3:22])=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[N:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:12]=1
Reactant: COc1ccc2c(O)nc(-c3ccc(OC(C)C)nc3)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(-c3ccc(OC(C)C)nc3)cc2c1
Yield: 68.2 %

Procedure:
A solution of 3-(6-isopropoxypyridin-3-yl)-6-methoxyisoquinolin-1-ol (400 mg, 1.289 mmol) in POCl3 (5 mL, 53.6 mmol) was refluxed for 14 h. Concentrated the solvent. The residue was taken into a mixture of DCM and 4N NaOH solution. The solution was adjusted PH to 7. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 10% EtOAc/Hexanes as eluent to give 289 mg of the desired product 1-chloro-3-(6-isopropoxypyridin-3-yl)-6-methoxyisoquinoline as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (dd, J=2.6, 0.6 Hz, 1H), 8.32 (dd, J=8.5, 2.5 Hz, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.82 (s, 1H), 7.253 (dd, J=6.8, 2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 6.81 (dd, J=8.7, 0.6 Hz, 1H), 5.40 (quin, J=6.1 Hz, 1H), 4.00 (s, 3H), 1.41 (d, J=6.0 Hz, 6H). MS: MS m/z 329.02 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH:28]1([C:31]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 28.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopropanecarbonyl chloride (76.0 μL, 0.836 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (103 mg, 29%) as a white solid.
Reaction SMILES: [ClH:1].O1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.Cl.[CH3:14][NH:15][CH3:16].C=O>C(O)C>[ClH:1].[CH3:14][N:15]([CH3:16])[CH2:3][CH2:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: O=C1CCOc2ccccc21
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccccc1
Yield: 55 %

Procedure:
Concentrated hydrochloric acid (0.2 ml) was dropwise added to a solution of 4-chromanone (10 g), dimethylamine hydrochloride (7.1 g) and paraformaldehyde (2.6 g) dissolved in ethanol (20 ml). The mixture was refluxed for 2 hours with heating. The mixture was allowed to cool. The resulting crystals were collected by filtration, washed with acetone and dried to obtain 9 g of β-dimethylaminopropiophenone hydrochloride (yield: 55%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Br)=[O:13]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:12](=[O:13])[CH2:11][Br:10]
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1NC(=O)CBr

Procedure:
2,6-dimethylaniline and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:28]([O:35][C:36](=[O:39])[CH2:37]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:39])[CH2:37][N:14]([S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:12])=[O:13])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][C:24](=[O:27])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: O=C(CBr)OCc1ccccc1
Product: COc1ccc(S(=O)(=O)N(CC(=O)OCc2ccccc2)c2ccc(N3CCC(=O)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 242) and benzyl-2-bromoacetate according to the procedure of Example 251 as an orange gum; 1H NMR (300 MHz, CDCl3) δ 2.53 (t, J=6.06 Hz, 4H), 3.59 (t, J=6.00 Hz, 4H), 3.79 (s, 3H), 3.93 (s, 3H), 4.50 (s, 2H), 5.13 (s, 2H), 6.78-6.87 (m, 2H), 7.07-7.10 (m, 2H), 7.15 (d, J=2.1 Hz, 1H), 7.27-7.37 (m, 7H); MS (ES) m/z: 539.0 (MH+); HRMS found for C28H30N2O7S(MH+): 539.1842.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([Cl:20])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7].[CH2:21]([OH:23])[CH3:22]>>[ClH:20].[OH:2][C:3]1[CH:13]=[CH:12][C:11]([CH:14]([O:23][CH2:21][CH3:22])[CH2:15][NH:16][CH:17]([CH3:19])[CH3:18])=[CH:10][C:4]=1[NH:5][S:6]([CH3:9])(=[O:8])=[O:7]
Reactant: CCO
Reactant: CC(C)NCC(Cl)c1ccc(O)c(NS(C)(=O)=O)c1
Agent: Cl
Product: CCOC(CNC(C)C)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
A 1 g sample of 2'-hydroxy-5'-[1-chloro-2-(isopropylamino)ethyl]methanesulfonanilide hydrochloride is added to 10 ml of absolute ethanol and heated at reflux for 30 minutes. The mixture is evaporated to dryness and the residue is washed with ethyl ether thus yielding the product compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([F:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[F:19])[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])c(F)c1
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2F)c1[N+](=O)[O-]
Yield: 41.3 %

Procedure:
Method H3 was used with 4-(4-amino-2-fluorophenoxy)-3-nitropyridin-2-amine (0.25 g, 0.946 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.21 g, 0.946 mmol) to afford the title compound (0.19 g, 42%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 5.98 (dd, 1H, Ja=5.7 Hz, Jb=1.0 Hz), 7.21 (s, 2H), 7.26 (dd, 1H, Ja=9.1 Hz, Jb=2.3 Hz), 7.34 (t, 1H, J=8.8 Hz), 7.60-7.73 (m, 3H), 8.01 (d, 1H, J=5.7 Hz), 8.10 (d, 1H, J=2.1 Hz), 9.19 (s, 1H), 9.27 (s, 1H). m/z 486.1 [(M+H)+ calcd. for C19H12ClF4N5O4 485.1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].O.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][N:12]([C:24](=[O:27])[CH:25]=[CH2:26])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Clc1ccc(C2CNc3ccccc3S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1CC(c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.7 %

Procedure:
To a mixture of 2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (9.62 g), sodium hydrogen carbonate (6.0 g), methylene chloride (100 ml) and water (50 ml) is added dropwise with stirring a solution of acryloyl chloride (5.0 g) in methylene chloride (20 ml) under ice cooling over a period of about 30 minutes. The mixture is stirred at room temperature for 3 hours, and the organic layer is washed and dried. After the solvent is distilled off, the resulting crystals are washed with n-hexane to give 2-(4-chlorophenyl)-4-acryloyl-3,4-dihyro-2H-1,4-benzothiazine (10.76 g, yield 93%).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[OH:16]O>C(O)(=O)C.C(OC(=O)C)(=O)C>[NH:1]1[C:6](=[O:16])[C:5](=[O:7])[NH:4][C:3]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14](=[O:15])[C:2]1=2
Reactant: OO
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1c2ccccc2-c2[nH]c(=O)c(=O)[nH]c21
Yield: 79.6 %

Procedure:
9H-Indeno[1,2-b]pyrazine-3,9(4H)-dione (20 g, 100.9 mmol), recrystallized from acetic acid, was suspended in a mixture of 135 ml acetic acid and 135 ml acetic anhydride and hydrogen peroxide (9.8 ml, 35%) was added. After stirring overnight another portion (9.8 ml, 35%) of hydrogen peroxide was added. This was repeated five times over a week. The red precipitate was filtered off, washed with acetic acid and water and dried to give 18.5 g (79.6%) of the title compound, which could be further purified by dissolving in aqueous sodium hydroxide and precipitation by hydrochloric acid. M.p. >300° C. 1H-NMR (DMSO-d6, δ): 7.15-7.45 (m, 4H), 12 (s, 1H), 12.8 (s,1H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[N:16]1([CH2:21][CH2:22][O:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28]([CH:33]=O)=[CH:27]3)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:33][C:28]1[NH:29][C:30]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][CH2:22][CH2:21][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:32][CH:31]=2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.