Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1)([O-:6])=[O:5]>CO>[CH3:1][N:2]([CH3:3])[S:13]([C:10]1[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a stirring solution of dimethylamine (180 mL, 40% in water, 1.57 mol) in methanol (180 mL) at 0° C., was slowly added 4-nitrobenzenesulfonyl chloride (69.5 g, 314 mmol). After complete addition, the cold bath was removed; and, after stirring overnight, the mixture was filtered and the precipitate was washed with water and dried in vacuo to give 68 g (94%) of tan solid.
Reaction SMILES: [N:1]1([C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>[Ni].CO.C1COCC1>[N:1]1([C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1
Reaction time: 10 h

Procedure:
400 mg of 4-(2,3-dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (Example 6) are hydrogenated with 150 mg of Raney nickel in methanol/THF (35:20) at RT and normal pressure for 10 hours. The catalyst is filtered off and the solution is concentrated by evaporation. The residue is dissolved in THF and the product is precipitated by the addition of hexane. 4-(2,3-Dihydroindol-1-yl)-6-(4-amino-phenyl)-7H-pyrrolo[2,3-d]pyrimidine is obtained in the form of a colorless powder. M.p. >300° C.; FAB-MS: (M+H)+ =328 (corresponds to C20H17N5); Rf value (toluene-acetone--4:6)=0.21.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[N:14][NH:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]#[N:27])#[N:2].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[C:28]1([NH:34][C:35]([N:13]([C:4]2[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=2[C:1]#[N:2])[N:14]=[N:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=2[C:26]#[N:27])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Reactant: O=C=Nc1ccccc1
Solvent: CCOCC
Product: N#Cc1ccc(C(F)(F)F)cc1N=NN(C(=O)Nc1ccccc1)c1cc(C(F)(F)F)ccc1C#N

Procedure:
A mixture of 2.0 g. (5.2 mmol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene and 1.6 ml. of phenyl isocyanate in 20 ml. of ether is stirred at 25° for 48 hours. The precipitate is collected and recrystallized from ether to give 3-(N-phenylcarbamoyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)-triazene, m.p. 157°-158°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([OH:8])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(Cl)ccc1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(Cl)cc([N+](=O)[O-])c1O

Procedure:
4-Chloro-2-methoxyphenol (1.77 g) was dissolved in acetic acid (18 mL). To this solution, a separately prepared nitric acid solution (mixture of 70% nitric acid (1.88 mL) and acetic acid (5 mL)) was added under ice cooling with stirring. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, and washed with water. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain a crude product. This product was purified by silica gel chromatography (ethyl acetate:n-hexane=4:1 v/v) to obtain the title compound (1.8 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)=[C:25]([CH3:42])[CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[N:10]=2)=[N:7][C:2]([NH:22][C:23]2[N:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:31][CH2:30]3)=[C:25]([CH3:42])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)ncc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)nn1C1CCCCO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(Cl)c(Nc3cc(C)n(C4CCCCO4)n3)n2)ncc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a mixture of 2,5-dichloro-N-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (150 mg, 0.45 mmol), tert-butyl 4-(6-amino-4-methylpyridin-3-yl)piperidine-1-carboxylate (120 mg, 0.41 mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate (270 mg, 0.82 mmol) in THF (4 mL) was added palladium acetate (5 mg, 0.02 mmol). The mixture was purged with nitrogen and the tube was sealed. The mixture was heated in an oil bath at 100° C. for 5 h. The mixture was filtered and concentrated. The residue was purified with silica chromatography (70% ethyl acetate in hexanes) to afford tert-butyl 4-(6-(5-chloro-4-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-4-methylpyridin-3-yl)piperidine-1-carboxylate as a yellow solid; ESMS m/z 583 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=3[F:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: Oc1cccc(F)c1F
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3cccc(F)c3F)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (180 mg, 0.551 mmol) and 2,3-difluorophenol were reacted as starting materials at 150° C. for 19 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (203.3 mg, 90.0%). Melting point: 157.5-159.0° C. (chloroform-hexane).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].[OH:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])[CH:17]=[CH:18][C:19]=1OC>>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH:23]([CH3:29])[C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=1
Reactant: Clc1ccc(OCCBr)c(Cl)c1
Reactant: CCOC(=O)C(C)Cc1ccc(OC)c(O)c1
Product: CC(Cc1cccc(OCCOc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using 1-(2-bromoethoxy)-2,4-dichlorobenzene and ethyl 3-(3-hydroxy-4-methoxyphenyl)-2-methylpropanoate, the title compound was obtained in the same manner as described in Example 33c).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16].N1CCCCC1>C1C=CC=CC=1>[C:1]1([CH2:11][CH:14]([CH2:13][OH:20])[CH2:15][OH:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1cccc2ccccc12
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: OCC(CO)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
2 g of 1-naphthoaldehyde, 2.3 g of diethyl malonate and 0.2 ml of piperidine were dissolved in 10 ml of benzene, and the solution was refluxed under heating for 6 hours while removing water by azeotropic distillation. The reaction solution was diluted with benzene, washed sequentially with 1N hydrochloric acid, with a saturated sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in a mixture consisting of 55 ml of ethanol and 37 ml of THF, and 2.7 g of sodium borohydride and 3.0 g of lithium chloride were added thereto under cooling with ice. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Water was added to the residue, and the solution was neutralized with 6N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with a saturated sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, solvent was distilled off under reduced pressure. The residue was recrystallized from diethyl ether-n-hexane to obtain 2.5 g of 2-(1-naphthylmethyl)-1,3-propanediol.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].C(O[C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)C.Cl>O1CCCC1>[C:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)#[CH:2]
Reactant: CCOC1=CC(=O)CCC1
Reactant: C#C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C#CC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.5N ethynylmagnesium bromide in tetrahydrofuran (100 mL) was added under N2 and stirring 3-ethoxy-2-cyclohexen-1-one (3.75 g, 26.8 mmol) in tetrahydrofuran (12.5 mL). The mixture was stirred at RT for 20 h when it was acidified with 1N HCl (200 mL). After stirring for 15 min the acidic phase was extracted with dichloromethane (5×50 mL). The combined organic extracts were washed with water (2×50 mL) and dried (MgSO4). Evaporation of the solvent gave an oil that was purified by column chromatography (silica, ethyl acetate/hexane 1:9) to yield a yellow oil, 2.71 g, 22.6 mmol, 84%). Analysis were in agreement with literature data.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccncc1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccncc1
Yield: 44 %

Procedure:
Using the procedure described for Example 43 with isonicotinic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Upon addition of water a solid precipitated. The solid was collected by filtration and dried to provide N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]isonicotinamide (58 mg, 44%) as an off-white solid: mp 182-192° C.; 1H NMR (300 MHz, CD3OD) δ6.34 (1H, s), 6.67 (1H, s), 7.30-7.55 (7H, m), 7.84-7.87 (2H, m), 8.04 (1H, d, J=5.7 Hz), 8.63 (1H, s), 8.69-8.71 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=14.1 min.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:10]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCCCC
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: CCCCN(CCCC)c1ccc(C#N)cc1
Yield: 93.6 %

Procedure:
According to the general procedure B, 4-chlorobenzonitrile (70 mg, 0.51 mmol) reacted with N,N-di-n-butylamine (77 mg, 0.60 mmol) using 1 mol % Pd(dba)2, 2 mol % of ligand, and K3PO4 (254 mg, 1.20 mmol) at 100° C. in DME solvent to give the title compound (110 mg, 94%) as a colorless oil: 1H-NMR (300 MHz, CDCl3): δ 7.43 (d, 2H, J=8.7 Hz), 6.58 (d, 2H, J=9.0 Hz), 3.28 (t, 4H, J=7.5 and 8.1 Hz), 1.58 (m, 4H), 1.36 (m, 4H), 0.97 (t, 6H, J=7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 150.59, 133.52, 120.88, 111.01, 96.20, 50.64, 29.08, 20.20, 13.89. GC/MS(EI): m/z 230 (M+). Anal. Calcd for C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C, 78.22; H, 9.75; N, 12.29.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([C:23]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[O:39]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([C:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:38])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(C(=O)C3CCNCC3)c2c1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a solution of tert-butyl 4-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]carbonyl}piperidine-1-carboxylate (100 mg, 0.18 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The resulting mixture was stirred at room temperature until the reaction was complete monitoring by LC/MS and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 1-10% methanol in dichloromethane) to afford 60 mg of the desired product. MS (ESI+) [(M+H)+] 450, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (dd, J=7.83, 1.26 Hz, 1 H), 7.90 (d, J=7.07 Hz, 1 H), 7.68-7.56 (m, 2 H), 7.51-7.38 (m, 3 H), 7.34 (s, 1 H), 5.26 (brs, 2 H), 4.5 (brs, 2 H), 3.70-3.58 (m, 2 H), 3.37 (s, 2 H), 3.35-3.32 (m, 1 H), 3.14-3.03 (m, 2 H), 2.71 (td, J=12.25, 2.78 Hz, 2 H), 2.40 (s, 3 H), 1.79 (m, 2 H), 1.69-1.51 (m, 2 H).
Reaction SMILES: [Br-:1].[OH:2][CH2:3][CH2:4][N+:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH3:15])=[CH:7][CH:6]=1.C1(N(C2C=CC=CC=2)C=N)C=CC=CC=1.[Br-].[OH:32][CH2:33][CH2:34][N+:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=[CH:46]NC2C=CC=CC=2)=[CH:37][CH:36]=1>C(O)C>[Br-:1].[OH:2][CH2:3][CH2:4][N+:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]=[CH:46][CH:45]=[C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:35]([CH2:34][CH2:33][OH:32])[CH:36]=[CH:37]2)=[CH:7][CH:6]=1
Reactant: OCC[n+]1ccc(C=CNc2ccccc2)c2ccccc21
Reactant: Cc1cc[n+](CCO)c2ccccc12
Agent: N=CN(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCO
Product: OCCN1C=CC(=CC=Cc2cc[n+](CCO)c3ccccc23)c2ccccc21

Procedure:
On an oil bath, 2.7 g of 1-(2-hydroxyethyl)-4-methylquinolinium bromide and diphenylformamidine were heated for 5 minutes to melt them. Thereto was added 150 ml of ethanol, and the resulting mixture was boiled, upon which 1-(2-hydroxyethyl)-4-(2-anilinovinyl)-quinolinium bromide was crystallized. Then, 2.5 g of 1-hydroxyethyl-4-methylquinolinium bromide and 10 ml of triethylamine were added thereto and subjected to reaction under reflux for one hour. After completion of the reaction, the reaction product was cooled and the crude crystals thus obtained were recrystallized from methanol to obtain 2 g of the objective compound (melting point 262° C.) which was dark green. Its maximum absorption wavelength as measured in methanol was 707 nm.
Reaction SMILES: [CH3:1][C:2]1([C:10](=[O:12])[CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1.[C:13](O)(=O)C>>[CH3:1][C:2]1([C:10]([OH:12])([CH3:13])[CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1
Reactant: CC(=O)O
Reactant: CC(=O)C1(C)CC=C(C)CC1C
Product: CC1=CCC(C)(C(C)(C)O)C(C)C1
Temperature: 0 °C

Procedure:
0.4 moles (66.4 g) 1-(1,4,6-trimethylcyclohex-3-en-1-yl)-ethan-1-one (as per Example 1) was then added dosewise at 70° C. to the reaction mixture according to (a). Then stirring was continued for another hour at 70° C. The reaction mixture was then cooled, poured on 300 g ice, and the precipitated magnesium salt was dissolved with 30 ml glacial acetic acid. Finally the phases were separated, the organic phase neutralized with sodium bicarbonate solution, the solvent drawn off and the residue subjected to fractional distillation. 30 g of the desired end product were obtained, corresponding to 40% of the theoretical amount.
Reaction SMILES: P(Cl)(Cl)Cl.[NH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
2.8 G. of phosphorus trichloride in 20 ml. of pyridine are added to 5.2 g. of N-(2-aminoethyl)-morpholine in 80 ml. of pyridine at -5° C. over a period of 15 minutes, with stirring. The mixture is stirred for 30 minutes at -5° C. and 90 minutes at room temperature. Then, 3.1 g. of p-chlorobenzoic acid are added and the mixture is heated for 3 hours at 90° C. This mixture is evaporated to dryness and the residue is evaporated twice more with 100 ml. of toluene each time. The solid residue is taken up in 100 ml. of methylene chloride and 100 ml. of ice-water and the mixture is rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 1.3 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].CC(C(C(C(S)(C)C)(C)C)(C)C)C.[C:23](#[N:26])[CH:24]=[CH2:25].[O-]P(OP([O-])([O-])=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[O-]O.C1(C(C)C)C=CC=CC=1.C(C1C=C(CC)C=C(C(C)(C)C)C=1O)C1C=C(CC)C=C(C(C)(C)C)C=1O.S(=O)(=O)(O)O>O>[CH:1]([CH:25]=[CH:24][C:23]#[N:26])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC#N
Reactant: C=Cc1ccccc1
Agent: CC(C)C(C)(C)C(C)(C)C(C)(C)S
Agent: CCc1cc(Cc2cc(CC)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CC(C)c1ccccc1
Product: N#CC=CC=Cc1ccccc1
Reaction time: 1 h

Procedure:
A rubber-reinforced styrene-based resin (C8-6) was produced by the following method. That is, 80 parts of ion-exchanged water, 0.5 part of potassium rosinate, 0.1 part of tert-dodecyl mercaptan, 30 parts (solid content) of a polybutadiene latex (average particle diameter: 2000 Å; gel content: 90%), 10 parts (solid content) of a styrene-butadiene copolymer latex (styrene content: 25%; average particle diameter: 6000 Å), 15 parts of styrene and 5 parts of acrylonitrile were charged into a glass flask equipped with a stirrer under a nitrogen flow, and heated while stirring. When an inside temperature of the flask reached 45° C., a solution prepared by dissolving 0.2 part of sodium pyrophosphate, 0.01 part of ferrous sulfate heptahydrate and 0.2 part of glucose in 20 parts of ion-exchanged water were added thereto. Thereafter, 0.07 part of cumene hydroperoxide was added to the flask to initiate polymerization of the contents in the flask. After conducting the polymerization for 1 hr, 50 parts of ion-exchanged water, 0.7 part of potassium rosinate, 30 parts of styrene, 10 parts of acrylonitrile, 0.05 part of tert-dodecyl mercaptan and 0.01 part of cumene hydroperoxide were continuously added to the flask over 3 hr, and the polymerization of the contents in the flask was further continued for 1 hr, and then 0.2 part of 2,2′-methylene-bis(4-ethyl-6-tert-butyl phenol) was added to the flask to complete the polymerization. The obtained reaction product in the form of a latex was coagulated with an aqueous sulfuric acid solution, washed with water and then washed and neutralized with a potassium hydroxide aqueous solution. Further, the resulting product was washed with water and then dried to obtain a rubber-reinforced styrene-acrylonitrile graft copolymer. It was confirmed that the thus obtained copolymer had a graft percentage of 68%, and the intrinsic viscosity [η] of an acetone-soluble component therein was 0.45 dL/g.
Reaction SMILES: C(O)(=O)C=C.[C:6]([OH:11])(=[O:10])[C:7]([CH3:9])=[CH2:8].[CH3:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19](O)=[CH:20][CH:21]=1)=[O:14]>C(Cl)(=O)C(C)=C>[C:6]([O:11][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH3:12])=[CH:21][CH:20]=1)(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: C=C(C)C(=O)O
Agent: C=C(C)C(=O)Cl
Agent: C=CC(=O)O
Product: C=C(C)C(=O)Oc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In order to obtain the polymeric drug of the present invention, it is firstly required to obtain a monomer of acrylic acid or methacrylic acid derivatives by reacting a low molecular physiological active substance with acrylic acid or methacrylic acid. The above-mentioned monomer may be obtained in the manner as stated below, in case of using acetaminophen, for example. That is, acetaminophen is dissolved in an acetonitrile anhydride, and methacryloyl chloride is added drop by drop to the solution. The resulting reaction solution is stirred for 30 minutes at a room temperature, followed by the removal of a reaction solvent by distillation. The residue is dissolved in chloroform, and dried, followed by recrystallization from benzene to obtain p-methacryloyloxyacetanilide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[S:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[Li+].[OH-]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:28][CH2:29][CH2:30][C:31](=[O:35])[N:32]([CH3:34])[CH3:33])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CN(C)C(=O)CCSC(SCCC(=O)O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1

Procedure:
To a solution of (-)-methyl 5-(3-(2-(7-chloro-quinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 8) (640 mg, 1.21 mmol.) in peroxide-free 1,2-dimethoxyethane (15 mL) and water (1.5 mL) was added LiOH (1M, 1.8 mL, 1.8 mmol.). The solution was stirred for 3 hrs at room temperature Water was added and the mixture was washed with EtOAc. The aqueous layer was acidified with 1N HCl, extracted with EtOAc, the extracts were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness. The oily residue was coevaporated 3 or 4 times with EtOAc and finally was allowed to crystallize in this solvent overnight at 0° C. Filtration afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[CH:3][C:4]=1[CH3:9]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Cc1cc(N)ccc1O
Product: Cc1cc(N2CC(C(=O)O)CC2=O)ccc1O

Procedure:
In an analogous manner to that described in Example 2a), 4-amino-o-cresol is reacted with itaconic acid at 140° C. during 10 min to yield the (RS)-1-(4-hydroxy-3-methyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid as a light brown solid; MS: m/e=234 (M−H)+ which directly used in the next step.