Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:60][O:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2([CH2:71]O)[CH2:70][CH2:69]2)=[CH:64][CH:63]=1>O1CCCC1>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:71][C:68]3([C:65]4[CH:64]=[CH:63][C:62]([O:61][CH3:60])=[CH:67][CH:66]=4)[CH2:70][CH2:69]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccc(C2(CO)CC2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC3(c4ccc(OC)cc4)CC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), [1-(4-methoxyphenyl)cyclopropyl]methanol (0.46 g) and tetrahydrofuran (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, to the residue was added diisopropyl ether (50 mL), and the mixture was stirred at room temperature for 1 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.71 g, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24].O>ClC1C=CC=CC=1Cl>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(O)c(Br)c1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Temperature: 160 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (1.33 g) and 2-bromo-4-methylphenol (2.5 ml) were dissolved in o-dichlorobenzene (3 ml), and the solution was stirred at 160° C. for 5 hr. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with aqueous sodium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel using acetone-chloroform to give the title compound (1.83 g, yield 82%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1.O>C1(C)C=CC=CC=1.O1CCCC1>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1
Reactant: CCOC(=O)c1c(N)nc(C(C)C)c(C(=O)OC)c1-c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C(C)C)nc(N)c(CO)c1-c1ccc(F)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
100 ml (0.35 mol) of a 3.5M solution of sodium bis-(2-methoxy-ethoxy)-dihydroaluminate in toluene are initially introduced under argon into 100 ml of tetrahydrofuran p.a. 63 g (175 mmol) of the compound from Example III dissolved in 700 ml of tetrahydrofuran are added dropwise and the mixture is subsequently stirred at 30° C. for 1 h. 2 l of water are cautiously added dropwise. The phases are separated and the aqueous phase is washed twice with 700 ml of ethyl acetate. The combined organic phases are washed with 500 ml of saturated sodium chloride solution and dried using sodium sulphate. The solution is filtered and concentrated in vacuo. The residue is chromatographed in a column (φ 6 cm) on 400 g of silica gel 230-400 mesh using petroleum ether/ethyl acetate (1:1). The eluate is concentrated in vacuo and the residue is thoroughly stirred in ether/petroleum ether.
Reaction SMILES: [OH-].[Na+].C([O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][C@@H:15]([OH:28])[C@@H:16]2[NH:26][CH3:27])[CH2:8]1)(=O)C.O>C(O)C>[CH3:27][NH:26][C@H:16]1[C@H:15]([OH:28])[CH2:14][C@H:13]2[C@H:12]3[C@H:21]([CH2:20][CH2:19][C@:17]12[CH3:18])[C@:22]1([CH3:25])[C:9]([CH2:8][C@@H:7]([OH:6])[CH2:24][CH2:23]1)=[CH:10][CH2:11]3
Reactant: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Sodium hydroxide solution (1.63 ml; 4 N) was added to a solution of 17β-methylamino-androst-5-ene-3β,16α-diol 3-acetate (1.63 g) in ethanol (32.6 ml) and the resultant solution was refluxed for 1 h. Water (350 ml) was added and the precipitated crude product was filtered off and washed with water. The product was dissolved in a mixture of dichloromethane-methanol (≈1:1) and treated with charcoal. After filtration through dicalite, the filtrates were evaporated to dryness and the resultant offwhite solid was crystallised from methanol-dichloromethane-ether to give pure 17β-methylamino-androst-5-ene-3β,16α-diol as needles (1.25 g; 86.8%), m.p. 241°-246° C. (decomp.), [α]D -100.2° (c 0.93 in pyridine).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][N:12]=[N+]=[N-])=[O:8])=[CH:5][CH:4]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][NH2:12])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)N[C@@H](CN=[N+]=[N-])c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N[C@@H](CN)c2ccccc2)cc1

Procedure:
Using Deprotection Method A, (R)-2-(4-methoxybenzoylamino)-2-phenylethyl azide (46.3 g) in THF (400 mL) afforded, after recrystallization with ethyl acetate, 35.4 g (84%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([OH:27])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8])[CH3:2].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([C@@H:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]([O:27][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:21]1)[S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN([C@@H]1CCCCC(O)C1)S(=O)(=O)c1ccc2ccccc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN([C@@H]1CCCCC(OS(C)(=O)=O)C1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (R)—N-naphthalene-2-sulfonyl (3-hydroxy-cyclohepty)glycine ethyl ester (0.90 g, 2.22 mmol) in dichloromethane (30 mL) at 0° C. is added triethylamine (0.463 mL, 3.3 mmol), methane sulfonyl chloride (0.269 g, 2.35 mmol), 4-dimethylaminopyridine (0.015 g, 0.12 mmol), and the reaction is allowed to warm to ambient temperature and stirred for 2 hours. The reaction is diluted with dichloromethane, washed with water and brine, and dried over magnesium sulfate. The solvents are removed in vacuo, and the residue is purified by column chromatography (35% hexanes-ethyl acetate) to afford the title compound as a colorless oil (0.95 g, 88% yield). LCMS (m/z): 484.17 (M+1), 482.16 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>CO.C1COCC1.[Zn].[Cu]>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[CH:2][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: Fc1ccccc1-c1c(Cl)nc2nccn2c1Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccccc1-c1cn2ccnc2nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.86 g (3.05 mmol) 5,7-Dichloro-6-(2-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 1.5 mL methanol and 8.6 mL THF. After addition of 0.589 g (4.6 mmol) zinc/copper pair the mixture is stirred at rt for 18 hours. The reaction mixture is filtered via a glass microfibre filter and washed with plenty of methanol. The solvent is evaporated and the residue is treated and evaporated three times with toluene. After chromatography on silicagel (eluents dichloromethane/methanol) 672.4 mg (89%) of the desired product containing bisdeschloro compound are obtained which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:21])[C@@H:7]1[CH2:11][C@H:10]([CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9][N:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](COS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (4S)-1-(tert-butyloxycarbonyl)-4-hydroxymethyl-L-proline tert-butyl ester (364 mg, 1.21 mmol) in pyridine (2 mL) cooled to 0° C. was added methanesulfonyl chloride (0.19 mL, 2.42 mmol). The reaction mixture was stirred for 2 hours at ice temperature, diluted with ethyl acetate (100 mL), washed with 1M sodium hydrogencarbonate solution, 1M citric acid, water, saturated brine solution, dried (Na2 SO4), and evaporated. The crude product was purified by flash silica gel chromatography eluting with 20% acetone/hexane; yield 437 mg (95%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]
Reactant: [N-]=[N+]=NCCCNC(=O)OCCNC(=O)c1ccccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NCCCNC(=O)OCCNC(=O)c1ccccc1O
Yield: 75.1 %

Procedure:
2-(2-Hydroxybenzoylamino)ethyl N-(3-azidopropyl)carbamate (128 mg) was dissolved in methanol (15 ml), 10% Pd/C (140 mg) was added and the reaction mixture was vigorously stirred while hydrogen was bubbled at r.t. for 3 hrs. The catalyst was filtered off and the methanol removed under vacuum to provide 2-(2-hydroxybenzoylamino)ethyl N-(3-aminopropyl)carbamate (88 mg) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH2:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:35])=[N-].C(OCC)C.CN(N=O)C(N)=O>C(OCC)C.C1(C)C=CC=CC=1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]([C:11]([C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[C:14]=2[F:26])=[CH:12][CH3:35])=[O:10])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC=C(C(=O)OC(c1ccccc1)c1ccccc1)c1c(F)cc(C(=O)OCC)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.2 %

Procedure:
In 30 ml of diethyl ether was dissolved 3.08 g of ethyl 4-(1-diphenylmethoxycarbonylvinyl)-2,3,5-trifluorobenzoate. To the resulting solution was added, with ice-cooling, a diazomethane-diethyl ether solution prepared from 2.00 g of N-methyl-N-nitrosourea. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of toluene. The resulting solution was stirred at 60° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by a column chromatography (eluant: toluene) to obtain 2.90 g (yield: 91.2%) of ethyl 4-(1-diphenylmethoxycarbonyl-2-methylvinyl)-2,3,5-trifluorobenzoate.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:9])[CH3:8])[C:4](=O)[CH3:5])O.[NH2:10][CH:11]([CH2:16][CH3:17])C(OC)=O.C(O)C.[OH-].[Na+]>C(#N)C>[C:7]([C:3]1[NH:1][C:11]([CH2:16][CH3:17])=[N:10][C:4]=1[CH3:5])(=[O:9])[CH3:8]
Reactant: CCC(N)C(=O)OC
Reactant: CC(=O)C(=NO)C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CCc1nc(C)c(C(C)=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To 4.99 g (0.039 moles) of 3-oximino-2,4-pentanedione dissolved in acetonitrile (40 ml) was added 4.59 ml (0.039 moles) of methyl 2-aminobutyrate. After stirring for two hours at room temperature, then at reflux for 2.5 h, the reaction mixture was cooled and treated with 15 ml of ethanol and 15 ml of 10% aqueous sodium hydroxide. The resulting mixture was refluxed for 3.8 h, cooled, then extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo to give 0.024 moles (62% yield) of 5-acetyl-2-ethyl-4-methylimidazole.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)=[O:4].Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:19][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:2])=[O:4])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Product: O=C(O)c1cc2ccc(C(F)(F)F)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-trifluoromethyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as white solid. MS: 368.0 ([M−H]−).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:38]1[O:49][C:48]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:44][NH2:45])=[CH:41][C:40]=2[O:39]1.C(N(CC)CC)C>>[O:49]1[C:48]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:44][NH:45][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([CH3:34])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:41][C:40]=2[O:39][CH2:38]1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6, 3,4-methylenedioxyphenethylamine hydrochloride and triethylamine (2.2 eq.), m.p. 154-157° C. MS [(+)ESI, m/z]: 582 [M+H]+
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[CH3:17].O>C1COCC1>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cccc(Cl)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1CO
Reaction time: 1 h
Yield: 103.9 %

Procedure:
LAH (61.00 mL, 1.0 M in THF, 61.00 mmol) was added to a solution of 3-chloro-2-methyl-benzoic acid methyl ester (4.50 g, 24.40 mmol) in THF at 0° C. The reaction mixture was stirred for 1 hour, water was added to quench the reaction. The aqueous layer was extracted with Et2O (3×150 mL), and the combined organic phases were washed with brine (1×150 mL) and dried over MgSO4. Purification by column chromatography using hex:EtOAc (4:1) as the eluant afforded 3.97 g of the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3.) δ 1.94 (br s, 1H), 2.36 (s, 3H), 4.67 (br s, 2H), 7.11 (t, J=7.765 Hz, 1H), 7.245 (d, J=7.03 Hz, 1H), 7.30 (d, J=7.91 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].[F:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:32])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(F)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-fluoro-1H-indol-3-yl)acetic acid in step 12 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 12 (B), the title compound was prepared. MS (ESI) (M+H)+=449.95 1H-NMR (500 MHz, CD3OD) δ 7.45 (s, 2 H), 7.32-7.41 (m, 2 H), 7.24 (dd, J=9.77, 2.44 Hz, 1 H), 6.84-7.02 (m, 1 H), 4.54 (s, 2 H), 3.95 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:8]([CH3:16])([CH3:15])[CH2:7][CH2:6][CH2:5]2.C([O:21]O)(C)(C)C>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([CH3:15])([CH3:16])[CH2:7][CH2:6][C:5]2=[O:21])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14]
Reactant: CCOc1cc2c(cc1Br)CCCC2(C)C
Reactant: CC(C)(C)OO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCOc1cc2c(cc1Br)C(=O)CCC2(C)C
Reaction time: 8 h

Procedure:
To 6-bromo-7-ethoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound A-3, 5.83 g, 20.6 mmol) in dichloromethane (25 mL) and tert-butyl hydroperoxide (25 mL) at room temperature was added a catalytic amount of chromium (VI) oxide. The reaction was stirred overnight. Quenched the reaction with water and followed by extraction with diethylether. The organic layers were washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (silica gel, 2% ethyl acetate/hexane) yielded the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1>O1CCOCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([S:2][CH3:1])[CH:4]=2)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: CSc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CSc1cccc(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
A solution of 3-(methylsulfanyl)aniline (658 mg, 4.73 mmol) and pyridine (995 uL, 18.9 mmol) was cooled to 0° C. under N2 before the dropwise addition of bis(trimethylsilyl)trifluorocetamide (1.76 mL, 9.45 mmol) over 5 min. After stirring for 5 min at 0° C., a solution of 4-fluoro-2-nitrobenzenesulfonyl chloride (1.19 g, 4.97 mmol) in 1,4-dioxane (7 mL) was added dropwise over 15 min. The mixture was stirred at rt for 1 h, then at 100° C. for 30 min. After cooling to rt, the mixture was concentrated in vacuo and partitioned between DCM and 1M aqueous HCl (25 mL each). The phases were separated and the aqueous layer extracted with DCM (2×25 mL). The combined organic layers were concentrated in vacuo and purified by gradient flash chromatography, eluting with 5-50% EtOAc in heptane to yield the title compound (865 mg, 2.53 mmol).
Reaction SMILES: [N:1]([CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15](=[O:32])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:18][CH:17]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N=[N+]=[N-])c3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N)c3ccccc32)cc1
Yield: 57.5 %

Procedure:
5-Azido-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.63 g) is dissolved in ethanol and thereto is added 10% Pd-C (0.1 g). The mixture is subjected to catalytic hydrogenation at room temperature under 1 atm. of hydrogen. Pd-C is removed by filtration and the filtrate is evaporated. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1), and recrystallized from diethyl ether to give 5-amino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.34 g) as white powder, m.p. 198.5°-199.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]([NH2:10])=[C:8]([C:11]2[C:15](=[NH:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:13](=[O:26])[N:12]=2)[N:7]=[CH:6]1.[CH:31](OCC)(OCC)OCC>CC#N.S(=O)(=O)(O)O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:14]2[C:15]3=[N:16][CH:31]=[N:10][C:9]4[N:5]([CH2:4][C:3]5[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=5[Cl:1])[CH:6]=[N:7][C:8]=4[C:11]3=[N:12][C:13]2=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(CN2C(=N)C(c3ncn(Cc4ccccc4Cl)c3N)=NC2=O)cc1
Reactant: CCOC(OCC)OCC
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: COc1ccc(Cn2c3ncnc4c(ncn4Cc4ccccc4Cl)c-3nc2=O)cc1
Yield: 83.6 %

Procedure:
To a suspension of 20 (3.5 g, 8.29 mmol, 1 equiv) in MeCN (30 mL), triethyl orthoformate (6.2 mL, 41.46 mmol, 5 equiv) was added followed by 4 drops of sulfuric acid. The reaction mixture was heated at reflux for 1.5 h until starting material was disappeared (TLC). The precipitated product was filtered, washed with diethyl ether and dried under vacuum to afford the pure product 21 (RK-12) as a pale yellow solid (3 g, 85%). IR: 1745 (C═O str.), 1621, 1586, 1248, 1171, 759 (C—Cl str.) cm−1. 1H NMR (400 MHz, d6-DMSO): δ=3.71 (s, 3H, OCH3), 5.09 (s, 2H, CH2), 5.68 (s, 2H, CH2), 6.86 (d, J=8.7 Hz, 2H, Ar—H), 6.98-6.99 (m, 1H, Ar—H), 7.25-7.27 (m, 1H, Ar—H), 7.30 (d, J=8.7 Hz, 2H, Ar—H), 7.34-7.38 (m, 1H, Ar—H), 7.53-7.55 (m, 1H, Ar—H), 8.70 (s, 1H, Ar—C═N—H), 8.86 (s, 1H, Imid-H). MS (ESI+ve) m/z: 433.2 (M+H)+, 455.1 (M+Na)+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:25])[O:17][CH2:18]C3CCCCO3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([N:25]=[C:16]([N:7]1[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[O:17][CH:18]1[CH2:29][CH2:28][CH2:27][CH2:26][O:33]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(OCC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1
Product: O=C(N=C(OC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1)c1ccccc1

Procedure:
starting from 2-tetrahydro-2H-pyranylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and benzoyl chloride, there is obtained tetrahydro-2H-pyran-2-yl N-(benzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6 carboximidate, m.p, 114.5°-117° C.;