Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:9](=O)(=[O:12])([OH:11])[OH:10]>>[NH2:7][C:2]1[CH:3]=[C:4]([S:9]([OH:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(O)O
Product: Nc1ccc(S(=O)(=O)O)cc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To concentrated sulfuric acid (200 mL) at −40° C. was added benzene-1,2-diamine (20 g, 184.95 mmol, 1.00 equiv). The resulting solution was stirred for 30 min at room temperature. Then the resulting solution was stirred overnight at 140° C. in an oil bath. The reaction mixture was cooled to room temperature, quenched by the addition of 500 g of ice, and the solids collected by filtration. The crude product was purified by recrystallization from water, resulting in 9.8 g (28%) of 3,4-diaminobenzenesulfonic acid as a white solid.
Reaction SMILES: [C:1](=[S:11])([S:3][CH2:4][CH2:5][C:6]([F:10])=[C:7]([F:9])[F:8])[NH2:2].[CH2:12](OC(OCC)CCl)[CH3:13].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[F:10][C:6](=[C:7]([F:9])[F:8])[CH2:5][CH2:4][S:3][C:1]1[S:11][CH:12]=[CH:13][N:2]=1
Reactant: NC(=S)SCCC(F)=C(F)F
Reactant: CCOC(CCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)=C(F)CCSc1nccs1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
3 g (14.9 mmol) of 3,4,4-trifluoro-3-butenyl dithiocarbamate in 15 ml of glacial acetic acid are admixed with 2.3 g (15.1 mmol) of chloroacetaldehyde diethyl acetal and 40 mg of p-toluenesulphonic acid monohydrate. The mixture is stirred at 95° C. for 1.5 h and, after cooling to room temperature, is then concentrated by evaporation under reduced pressure. The evaporation residue is taken up in dichloromethane and washed with 1 N sodium hydroxide solution, and the organic phase is removed, dried over Na2SO4 and concentrated by evaporation under reduced pressure. 2.8 g (81.5% of theory; purity by GC/MS: 97.7 area %) of an oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](CCN)[CH:6]=[CH:7][CH:8]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH:21]([N:24](C(C)C)CC)(C)[CH3:22]>>[CH2:21]([N:24]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:22]
Reactant: COc1cccc(CCN)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCN(CC)c1cccc(OC)c1
Yield: 95.2 %

Procedure:
(3-Methoxyphenyl)ethylamine 14 (5.73 gm, 0.038 moles), ethyl 4-bromobutyrate (9.60 gm, 0.049 moles) and diisopropylethylamine (6.40 gm, 0.050 moles) were heated at 110-120° C. overnight, cooled, and partitioned between 100 ml DCM and 100 ml water. The aqueous layer was extracted twice with 50 ml portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a gradient mixture of ethyl acetate and hexane. Ethyl 4-[ethyl(3-methoxyphenyl)amino]butanoate 15 (9.6 gm, 95% yield) was isolated as a slightly yellow oil after removing the solvent. 1H NMR (CDCl3) δ 7.12, 1H, t; 6.31, 1H, d; 6.22, 2H, m; 4.12, 2H, q; 3.79, 3H, s; 3.3, 4H, m; 2.35, 2H, t; 1.9, 2H, m; 1.26, 3H, t; 1.14, 3H, t.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH3:34])([CH3:33])[C:13](=[O:32])[N:14]([CH:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:25]=4[CH3:31])=[O:23])[CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH2:36][C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44].COC1C=C(C2C(C)(C)C(=O)N(C3CCN(S(C4C=C(OC)C=CC=4OC)(=O)=O)CC3)N=2)C=CC=1OC.[OH-].[Na+]>C(O)C>[Cl:43][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:44])[C:37]=1[CH2:36][O:30][C:28]1[CH:27]=[CH:26][C:25]([CH3:31])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:32])[C:12]([CH3:34])([CH3:33])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:23])[CH:29]=1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(O)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Reactant: Clc1cccc(Cl)c1CBr
Agent: COc1ccc(OC)c(S(=O)(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)C(C)(C)C3=O)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(OCc5c(Cl)cccc5Cl)ccc4C)CC3)C(=O)C2(C)C)cc1OC
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 0.40 g of 5-(3,4-dimethoxyphenyl)-2-{1-[(5-hydroxy-2-methylphenyl)carbonyl]piperidin-4-yl}-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound described in example 85) and 0.41 g 2-(bromomethyl)-1,3-dichlorobenzene in 5 ml ethanol is treated with 0.17 ml 10 n aqueous sodium hydroxide solution and stirred under a blanket of nitrogen for about 6 h at 80° C. until the reaction is completed largely according to TLC analysis. The solvent is evaporated under reduced pressure, and the resulting crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH3:2].C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:3]([CH2:4][C:5]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[CH2:1][CH3:2])=[O:29]
Reactant: CCNCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC1(O)CCN(C(=O)OC(C)(C)C)CC1)C(=O)CCl
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a 100 mL round bottom flask containing tert-butyl 4-((ethylamino)methyl)-4-hydroxypiperidine-1-carboxylate (2.4 g) was added dichloromethane (30 mL) and triethylamine (3 mL, 21.52 mmol). An addition funnel was attached to the flask. The vessel was placed under nitrogen and the solution was cooled to 0° C. with an ice bath. In a separate vial, chloroacetyl chloride (1 mL, 12.48 mmol) was diluted with dichloromethane (20 mL) and transferred to the addition funnel. This mixture was added dropwise to the cold starting material over 10 min. The reaction mixture was then allowed to stir under nitrogen for 3 h while slowly allowing the ice bath to warm to room temperature. The reaction mixture was diluted with dichloromethane (100 mL) and was washed with water (2×50 mL) and brine (1×50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (3.23 g) which was carried forward without further purification. MS(ES)+ m/e 335.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][OH:23])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][C:11]([N:13]([CH3:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Yield: 100 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-methyl-N-phenylbenzenepropanamide (0.9 g) in CH2Cl2 (25 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.332 g), and methanesulfonyl chloride (0.365 g). After two hours the reaction mixture was washed with water (3×20 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (1.1 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].C(O)(=O)C(C(C(O)=O)O)O>CO.CC(C)=O>[CH3:1][CH2:2][O:3][C:4]([C@H:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)C(N)c1ccccc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CCOC(=O)[C@H](N)c1ccccc1

Procedure:
A solution of ethyl DL-phenylglycinate (5.051 g., contains 0.05 mole methylene chloride i.e. 27.5 mmole) and (+)-tartaric acid (4.264 g., 28.4 mmole, 1.03 equiv.) in methanol: acetone (1:1, 50 ml.) was stirred at 20° to 25°; crystallisation began immediately. After 231/2 hours the mixture was filtered and the product washed with solvent (2 × 12 ml.) and dried at 24°/2 mm. for 31/2 hours giving ethyl D-phenylglycinate (+)-hemitartrate solvated with 1.0 mole methanol (7.265g., 73%), [α]D24 - 47.4° (c 2.519, H2O).
Reaction SMILES: CN([C:4]([O:8]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][N:24]1[CH2:29][CH2:28]OC[CH2:25]1.[NH2:30][C:31]1[N:40]=[C:39]([C:41]([N:43]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:52]3[CH:57]=[C:56]([F:58])[C:55]([F:59])=[CH:54][C:53]=3[CH2:60][NH2:61])[CH:37]=2)[N:32]=1.Cl>CN(C=O)C>[NH2:30][C:31]1[N:40]=[C:39]([C:41]([N:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51]2)=[O:42])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:52]3[CH:57]=[C:56]([F:58])[C:55]([F:59])=[CH:54][C:53]=3[CH2:60][NH:61][C:4](=[O:8])[CH2:28][CH2:29][N:24]([CH3:23])[CH3:25])[CH:37]=2)[N:32]=1
Reactant: NCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CN1CCOCC1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)CCC(=O)NCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
85 mg of TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate), 112 μl of 4-methylmorpholine and 100 mg of [2-amino-6-(2-aminomethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are added to a solution of 43 mg of 3-dimethylaminopropionocarboxylic acid hydrochloride in 1 ml of DMF. The mixture is stirred at 22° C. for 16 h, and the product is isolated directly by column chromatography.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][CH:20]([F:35])[CH2:21][NH:22][CH2:23][C:24]1[NH:25][C:26](=[O:34])[C:27]2[CH2:33][O:32][CH2:31][CH2:30][C:28]=2[N:29]=1.CC#N.O>C(O)=O>[C:1]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([N:22]([CH2:21][CH:20]([F:35])[F:19])[CH2:23][C:24]2[NH:25][C:26](=[O:34])[C:27]3[CH2:33][O:32][CH2:31][CH2:30][C:28]=3[N:29]=2)=[O:18])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccccc2)CC1
Reactant: O=c1[nH]c(CNCC(F)F)nc2c1COCC2
Solvent: CC#N
Solvent: O
Solvent: O=CO
Product: O=C(c1ccccc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)F)CC1

Procedure:
The title compound (0.07 g) was prepared following the general procedure of Example 1 from 2-(4-benzoylpiperidin-1-yl)acetic acid and 2-((2,2-difluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one. 1H NMR (400 MHz, MeOD) δ ppm 7.89-8.03 (m, 2H), 7.44-7.66 (m, 3H), 5.88-6.43 (m, 1H), 4.61-4.69 (m, 1H), 4.53-4.60 (m, 1H), 4.40-4.48 (m, 1H), 3.78-4.23 (m, 5H), 3.36-3.59 (m, 2H), 3.02-3.18 (m, 1H), 2.83-2.93 (m, 1H), 2.54-2.69 (m, 3H), 2.13-2.36 (m, 2H), 1.65-1.97 (m, 3H), 1.37-1.54 (m, 1H). HRMS calculated for C24H29F2N4O4 475.2157. found (ESI, [M+H]+) 475.2180. MS (ESI) m/z 475.2. (M+H)+. Retention time: 3.04 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:12]=[CH:13][N:14]=1)([O-])=O.[H][H]>[Ni].C(O)C>[O:11]1[CH:12]=[CH:13][N:14]=[C:10]1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1-c1ncco1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1-c1ncco1
Yield: 108.7 %

Procedure:
To 19.0 g of 2-(2-nitrophenyl)oxazole, (prepared by the procedure of W. E. Cass, J. Am. Chem. Soc., 64, 785 [1942]) 3.0 g of Raney-Nickel catalyst (purchased from Aldrich Chemical Company, Milwaukee, Wis. 53201) and 200 ml ethanol were combined and reduced at ambient temperature and at a H2 pressure of 5-50 psi on a Paar Hydrogenator until the hydrogen uptake ceased. The catalyst was filtered through celite under a blanket of nitrogen. The solvent was removed on a rotary evaporator. 17.4 g of crude product with m.p. 31°-32° was obtained and used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[F:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37](=[O:47])[C:38](=[O:46])[N:39]2[CH2:42][C:43](O)=[O:44])=[CH:35][CH:34]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:43](=[O:44])[CH2:42][N:39]1[C:40]2[C:36](=[CH:35][CH:34]=[C:33]([F:32])[CH:41]=2)[C:37](=[O:47])[C:38]1=[O:46]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)CN1C(=O)C(=O)c2ccc(F)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CN1C(=O)C(=O)c2ccc(F)cc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol) in DCM (15 ml), DMAP (0.058. g, 0.476 mmol), EDC (0.274 g, 1.428 mmol) and 2-(6-fluoro-2,3-dioxoindolin-1-yl)acetic acid (0.127 g, 0.571 mmol) were added in one portion at room temperature. The resulting solution was stirred at room temperature for 24 hours; the solvent was removed under vacuum and the residue was dissolved in ethyl acetate (40 ml), washed with a saturated solution of NaHCO3 (20 ml), with 1N HCl (20 ml) and finally with brine (20 ml). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude was purified by preparative HPLC (Method 1) and two pure fractions were isolated:
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:35])[C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:29])[CH3:30])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C

Procedure:
A mixture of Z-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.17 g) and 20% palladium hydroxide on carbon (0.24 g) in methanol (20 ml) was stirred at room temperature in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered and washed with methanol. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 100:10:1) to give N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 609 mg (71%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[Mn]([O-])(=O)(=O)=O.[K+].OO>ClCCl.C(O)(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: OO
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Reaction time: 4 h
Yield: 60 %

Procedure:
A 1.75 g (5 mmols) quantity of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate was dissolved in 8.5 ml of dichloromethane and 4 ml of acetic acid, then 0.79 g of potassium permanganate was slowly added to the solution at room temperature, and the mixture was stirred for 4 hours. After the completion of reaction, a hydrogen peroxide solution was added to the reaction mixture until the mixture became transparent. The mixture was diluted with 10 ml of dichloromethane, subsequently washed with water, with sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride successively, and dried over anhydrous magnesium sulfate. The dried product was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) for separation and purification, affording 10.2 g (yield 60%) of the above-identified compound as a white solid product.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][C:4]1=[O:10])[CH3:2].[CH:11]([O-])([O-])[O:12][CH3:13]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[C:5](=[CH:11][O:12][CH3:13])[C:4]1=[O:10])[CH3:2]
Reactant: COC([O-])[O-]
Reactant: CCN1CCC(=O)CC1=O
Solvent: CC(=O)OC(C)=O
Product: CCN1CCC(=O)C(=COC)C1=O
Yield: 25.1 %

Procedure:
Added to 8.3 g of 1-ethylpiperidine-2,4-dione were 11 g of methyl orthoformate and 20 ml of acetic anhydride. The resultant mixture was refluxed for 7 hours. After allowing the reaction mixture to cool down, excess methyl orthoformate and acetic anydride were distilled off under reduced pressure. The brown residue was distilled under reduced pressure in a Kugelroll apparatus (0.5 mmHg; bath temperature: 200°-250° C.) to obtain 2.7 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione as crystals (yield: 25%). The crystals were recrystallized from a mixed solvent of ethyl acetate and hexane to obtain needles.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Sn](CCCC)(CCCC)CCCC)=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[C:32]#[N:33]>C1COCC1.CCOCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Reactant: N#Cc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccccc2C#N)nc1
Yield: 68.6 %

Procedure:
A mixture of [5-(tert-Butyldimethylsilyloxymethyl)pyridin-2-yl]tri-n-butylstannane (11.5 g, 0.022 mol), 2-iodobenzonitrile (5.1 g, 0.022 mol), CuI (0.43 g, 0.002 mol), and bis(triphenylphosphine)palladium(II) chloride (0.80 g, 0.001 mol) in THF (40 mL) was heated under reflux for 48 h. The mixture was diluted with ether and washed with saturated aqueous NH4Cl, aqueous NH4OH, water, and brine, dried (MgSO4), and concentrated to give 4.9 g (67%) of product as a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[H-].[Na+].Cl[CH2:32][CH2:33][CH2:34][CH:35]1[O:39][CH2:38][CH2:37][O:36]1.[OH-].[Na+]>CN(C=O)C.C(O)C>[O:36]1[CH2:37][CH2:38][O:39][CH:35]1[CH2:34][CH2:33][CH2:32][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([CH:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][O:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:28])=[O:2])[CH2:14][CH2:15]2)=[CH:20]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: ClCCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCCC3OCCO3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.75 g (7 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared as in Example 1, part D) in 10 mL of anhydrous DMF was added to a suspension of 0.36 g (9.1 mmol) of a NaH (60% dispersion in mineral oil) in 5 mL of anhydrous DMF under an inert atmosphere. After stirring for 30 minutes at room temperature, a solution of 1.1 mL (8.4 mmol) of 2-(3-chloro-propyl)-[1,3]dioxolane in 3 mL of DMF was added. The crude mixture was stirred at room temperature for 16 hours and the solvent was removed under reduced pressure. The residue obtained was dissolved with 150 mL of ethanol and 6 mL of a 2N NaOH aqueous solution were added. After 12 h at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved with 50 mL of water and neutralised with a 2N HCl aqueous solution. The crude mixture was purified by flash chromatography over silica gel affording 0.83 g (29% of yield) of the expected product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][C:27](Br)=[C:20]3[C:21]=2[C:16](=[CH:17][CH:18]=[CH:19]3)[C:15]1=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCN2C(=NCCC2)CC1>O>[CH2:6]([O:13][N:14]1[C:15](=[O:29])[C:16]2[CH:17]=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]3[C:21]=2[C:22](=[CH:25][CH:26]=[CH:27]3)[C:23]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2cccc3c(N4CCCC4)ccc(c23)C(=O)N1OCc1ccccc1

Procedure:
Pyrrolidine (3 mL) was added to 2-benzyloxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.8 g, 2.1 mmol, from Example M) in the presence of DBU (0.05 mL). The mixture was refluxed for 2 hours and poured into water (50 mL). The precipitate formed was filtered and dried to give 0.8 g of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.4 g, 1.1 mmol) in the presence of 10% Pd/C (0.2 g) in DMA (30 mL) gave 0.27 g of the title compound, mp 268-270° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH3:18])=[O:5].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:43])OC2C=CC=CC=2)[CH:29]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH2:19][CH2:20][N:21]([CH3:22])[C:35]([NH:34][C:30]1[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=1)=[O:43])[CH3:18])=[O:5]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: CNCCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CCN(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12)C(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-[N-(2-methylaminoethyl)-N-methylamino]quinoline (130 mg), phenyl 3-pyridylcarbamate (76 mg) and triethylamine (97.9 mg) in dimethylformamide (1.5 ml) was stirred for 1 hour at ambient temperature. The mixture was diluted with ethyl acetate, washed with 1N sodium hydroxide solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) to give 8-(2,6-dichlorobenzoylamino)-4-[N-[2-[l-methyl-3-(3-pyridyl)ureido)ethyl]-N-methylamino]quinoline (168 mg).