Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][C:15]([N+:23]([O-])=O)=[C:16]([CH:22]=1)[CH:17]=[CH:18][N+]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Fe].C(O)(=O)C>[CH2:4]([O:11][C:12]1[CH:22]=[C:16]2[C:15](=[CH:14][C:13]=1[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:23][CH:18]=[CH:17]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCOc1cc([N+](=O)[O-])c(C=C[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCOc1cc2[nH]ccc2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
8.6 g of activated iron are added at 60° C. to a solution of 28 ml of absolute ethanol and 14 ml of acetic acid. The mixture is kept for 15 minutes at 80° C. and 5-benzyloxy-4-butoxy-2,β-dinitrostyrene (1.6 g; 0.0043 mole) is added. The mixture is left at 80° C. for 1 hour, and the ferric sludge is filtered off and rinsed with 40 ml of ethanol and 40 ml of acetic acid. The filtrate is diluted with 100 ml of ice-cold water. After extraction of the solution with methylene chloride and drying of the organic phase over sodium sulphate, the organic phase is concentrated and chromatographed on silica 60 (eluent: toluene/CH2Cl2, 50:50). 0.5 g (40% yield) of the derivative 22 is obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:8]([C:9](O)=[O:10])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:8]([C:9]([NH:19][C:20]2[NH:24][N:23]=[N:22][N:21]=2)=[O:10])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCOc1cc(C(=O)O)nc2ccccc12
Solvent: CN(C)C=O
Product: CCCCOc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Reaction time: 3 h

Procedure:
4-Butyloxyquinaldic acid (0.83 g) in dry dimethylformamide (25 ml) was treated with N,N'-carbonyldiimidazole (0.55 g) and the mixture stirred at 60° for 3 hours. 5-Aminotetrazole (0.35 g) was added and the solution kept 72 hours and evaporated to a volume of 5 ml. Dilute hydrochloric acid was added and the 4-butyloxy-N(1H-tetrazol-5-yl)quinaldamide formed was crystallised from aqueous dimethylformamide, m.p. 282° (d).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)oc2c(N)cccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(C(C)=O)c(C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-acetyl-7-amino-2-methylbenzo[b]furan (2.4 g) in dichloromethane (30 ml) was added acetic anhydride (1.6 g) dropwise. The solution was stirred at ambient temperature for 1 hour and evaporated in vacuo. Toluene was added to the residue and the solution was evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-acetyl-7-acetylamino-2-methylbenzo[b]furan (2.92 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>>[CH3:15][N:16]([O:17][CH3:18])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 1793.6 %

Procedure:
2-Nitrobenzenesulfonyl chloride (5 g, 22.5 mmol) was allowed to react with N-methyl-N-methoxyamine hydrochloride (2.42 g, 22.5×1.2 mmol) in the presence of triethylamine (5.47 g, 22.5×2.4 mmol) to obtain 5.3 g (percent yield: 95.3%) of N-methyl-N-methoxy-2-nitrophenylsulfonamide.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15](=[N:18][C:19]#[N:20])SC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:21][N:22]([CH2:24][C:25]1[O:29][C:28]([CH2:30][S:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1)[CH3:23]>C(#N)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]([NH:34][CH2:33][CH2:32][S:31][CH2:30][C:28]2[O:29][C:25]([CH2:24][N:22]([CH3:23])[CH3:21])=[CH:26][CH:27]=2)=[N:18][C:19]#[N:20])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=NC#N)NCCSCc2csc(NC(=N)N)n2)o1
Yield: 19.9 %

Procedure:
A solution of 2-guanidino-4-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]thiazole (0.5 g) and 2-[5-dimethylaminomethylfuran-2-ylmethylthio]ethylamine (0.33 g) in acetonitrile (10 ml) was heated under reflux for 48 hours. A further portion of 2-[5-dimethylaminomethylfuran-2-ylmethylthio]ethylamine (0.5 g) was added and the mixture was heated under reflux for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was dried with anhydrous magnesium sulphate and evaporated. The residual gum was triturated four times with warm diethyl ether (10 ml). The residue was further purified by applying to Merck 60 F254 preparative plates and eluting with acetonitrile/ammonia (s.g. 0.880) 7:1 v/v. The product was redissolved in acetonitrile (5 ml), and the solution filtered and evaporated to give 2-guanidino-4-[2-(2-cyano-3-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]guanidino)-ethylthiomethyl]thiazole as pale brown gum (0.15 g).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(Nc2ccccc2OC)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1Nc1cccc(C(=O)O)c1C(=O)O
Yield: 91 %

Procedure:
A mixture of 3-(2-methoxyphenylamino)phthalic acid dimethyl ester (0.74 g, 2.4 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.61 g in 91% yield: 1H NMR (DMSO-d6) δ 3.83 (s, 3H), 6.89-7.11 (m, 4H), 7.24 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 7.33-7.41 (m, 2H), 7.96 (s, 1H).
Reaction SMILES: COC1CCC(OC)O1.C[O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)=[O:13].[K].[OH-].[Na+]>>[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)([OH:13])=[O:11]
Reactant: COC(=O)c1ccccc1-n1cccc1
Agent: COC1CCC(OC)O1
Agent: [K]
Agent: [Na+]
Product: O=C(O)c1ccccc1-n1cccc1

Procedure:
Synthesis substrates 9H-pyrrolol[1,2-a]indole and 9H-pyrrolol[1,2-a]indol-9-one and their derivatives are prepared in accordance with the general methods of Josey and Jenner, J. Org. Chem., 27 (1962) 2466 and Mazzola et al., J. Org. Chem., 32 (1967) 486. The process involves condensation of a substituted or unsubstituted methyl anthranilate (Aldrich Chemical, Inc.) with 2,5-dimethoxytetrahydrofuran (Aldrich Chemical, Inc.) in glacial acetic acid. Ester hydrolysis of the resulting 1-(2-methoxycarbonylphenyl)pyrrole with 10-15% potassium or sodium hydroxide in aqueous alcohol (e.g., 50% methanol) yields after acidification and subsequent work-up yields the corresponding 1-(2-carboxyphenyl)pyrrole. This acid is then converted into the corresponding acyl chloride to facilitate a Friedel-Crafts cyclization to the ketone. The preferred method of preparing the acyl chloride is with phosphorus pentachloride followed with stannic chloride as the Friedel-Crafts catalyst to cyclize the acyl chloride to the desired ketone. ##STR61## R=CH3,OCH3,H Z=Cl,H
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([O:15]CC)=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn(-c2cccc(F)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of ethyl 1-(3-fluorophenyl)pyrazole-3-carboxylate (234 mg, 1 mmol) in THF was added 3.0 mL of 1.0M of LiOH (3.0 mmol). The resulting mixture was stirred at room temperature for 3 h and then 1.0 M of HCl was added to adjust pH to 1.0. The organics were extracted with EtOAc (2×100 mL), followed by drying over MgSO4 and concentrated under reduced pressure to give a white solid (198 mg, 96%), which was used for next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]([N:24]([CH2:32][C@@H:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[O:34][Si](CC)(CC)CC)C(=O)OC(C)(C)C)[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@H:14]([CH3:23])[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:1][C@@H:2]([NH:24][CH2:32][C@@H:33]([C:42]1[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=1)[OH:34])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][C@H:14]([CH3:23])[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN(C(=O)OC(C)(C)C)[C@H](C)Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(O[C@H](C)C(=O)N3CCOCC3)cccc12)NC[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
Further, to a solution of tert-butyl (1R)-1-methyl-2-(7-(((1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl)oxy)-1H-indol-3-yl)ethyl((2R)-2-pyridin-3-yl-2-((triethylsilyl)oxy)ethyl)carbamate (190 mg, 0.285 mmol) in ethanol (2.0 mL) is added a 4N hydrochloric acid/dioxane (2.0 mL, 8.0 mmol), and the mixture is stirred at room temperature for 14 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and the mixture is extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (a saturated ammonia solution in chloroform/methanol=100/1→100/4) to give the title compound (107 mg, yield: 83%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([CH2:16][C:15]#[CH:14])[CH2:9][C:10]#[CH:11])([CH3:5])([CH3:6])[CH3:7]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN(CC#C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-Boc-propargylamine (2.63 g, 16.9 mmol) and DMF (35 mL) was prepared under argon and cooled to 0° C. for 20 min. Sodium hydride (60%, 0.714 g, 17.9 mmol) was added and the reaction stirred at 0° C. for 30 min. Propargyl bromide (80% in toluene, 2.7 mL, 24.2 mmol) in DMF (5 mL) was added slowly and the reaction stirred at 0° C. for 15 min then warmed to room temperature and stirred for additional 17 hr. The reaction mixture was quenched with water and extracted two times with EtOAc. The combined organic layers were washed with water (3×) and brine, dried over Na2SO4, filtered, and concentrated. The crude product was carried to the next reaction without purification. ESI-MS m/z 194 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7]C[C:5](=O)[CH2:4][CH2:3]1.[C:9](=[O:12])(O)[O-:10].[Na+].ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[CH3:1][CH:2]1[CH2:7][O:10][C:9](=[O:12])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1CCC(=O)CC1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC1CCCC(=O)OC1

Procedure:
This was prepared in similar manner to Lactone 1 except using 4-methyl cyclohexanone (50 parts; 0.445m ex. Aldrich) in place of the 3-methylcyclohexanone with appropriate increase in the dichloromethane (1500 ml), sodium bicarbonate (8.1 parts, 1.0M) and 3-chloroperoxybenzoic acid (123 parts; 0.5M). The reaction temperature was maintained below 10° C. throughout. The 5-methyl ε-caprolactone was obtained as a clear yellow oil (49 parts).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CCN(CC)CC>CCO>[CH3:37][C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][NH:24][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:9][C:10]([F:12])([F:13])[F:11])[CH2:14][C:15]([F:16])([F:18])[F:17])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22])=[O:32])([CH3:35])[CH3:36]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccc(C(=O)N(CC(F)(F)F)CC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (130 mg, 0.373 mmol) and (S)-2-aminomethyl-1-Boc-pyrrolidine (82 mg, 0.410 mmol) in 3 mL of EtOH containing Et3N (0.080 mL, 0.559 mmol). The product was purified by flash chromatography on silica gel using 3:1/hexanes:EtOAc as eluent. Yield: 165 mg (84%); 1H NMR (CDCl3) 1.47 (brs, 9H), 1.83 (m, 1H), 1.90 (m, 2H), 2.03 (m, 1H), 3.31 (m, 1H), 3.37 (m, 2H), 3.62 (m, 1H), 4.09 (m, 2H), 4.24 (m, 6H), 7.26 (m, 1H), 7.50 (m, 1H), 8.27 (s, 1H), 8.55 (brs, 1H); MS (ESI) 529.38 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([C:20](=[O:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C@@H:10]([C@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanone (0.38 g, 1.27 mmol) in THF (15 mL) at 0° C. were added portion wise LiAlH4 (43 mg, 1.13 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-13) 0.16 g (41%) as a white solid ES-MS m/e: 300.2 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethanol (X-A-13) 0.15 g (39%) as a white solid ES-MS m/e: 300.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([O:22][Si:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])(=[O:21])[CH2:12][C:13]([O:15][Si:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[O:14].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]([C:11]([O:22][Si:23]([CH3:27])([CH3:26])[CH2:24][CH3:25])=[O:21])[C:13]([O:15][Si:16]([CH3:19])([CH3:20])[CH2:17][CH3:18])=[O:14])=[CH:5][CH:4]=1
Reactant: CC[Si](C)(C)OC(=O)CC(=O)O[Si](C)(C)CC
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC[Si](C)(C)OC(=O)C(=Cc1ccc(OC)cc1)C(=O)O[Si](C)(C)CC
Yield: 71 %

Procedure:
4-Methoxybenzaldehyde (12.3 g, 0.03 mol) and di(methyltrimethylsilyl) malonate (25 g, 0.09 mol) in 40 ml of dry toluene in the presence of 0.9 ml of piperidine and 0.5 ml of acetic acid are refluxed for 4 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the toluene is removed by distillation. The reaction mixture is taken up in diisopropyl ether. The organic phase is washed 3 times with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. The solid obtained is recrystallized from isopropanol to give 25.1 g (yield: 71%) of the derivative of Example 13 in the form of a white powder:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:32])[C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13].N1CCCCC1.C([OH:41])C>CCOCC>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:19](=[O:41])[CH2:18][C:17]([NH:16][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[C:2]([Cl:1])[CH:3]=2)=[O:32])=[CH:25][CH:24]=1
Reactant: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(-c3ccccc3)cc2)cc1Cl
Reactant: CCO
Solvent: C1CCNCC1
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(NC(=O)CC(=O)c2ccc(-c3ccccc3)cc2)cc1Cl
Reaction time: 8 h

Procedure:
0.16 g (0.36 mmol) of 3-biphenyl-4-ylpropynoic acid-[3-chloro-4-(2-diethylaminoethoxy)phenyl]amide (educt XII.1) is dissolved in 10 mL of aqueous ethanol and 0.10 mL (1.0 mmol) of piperidine is added. The mixture is stirred for 8 hours at reflux temperature. After cooling, the solvent is eliminated, and the residue is suspended in ether and filtered off. The residue is dried in vacuo at 50° C. Yield: 75 mg (45% of theory); Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); m.p. 148° C.-151° C.; C27H29ClN2O3; EII mass spectrum: m/z=465/467 [M+H]+.
Reaction SMILES: FC(F)(F)C1C=CC(NS([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16]3)(=O)=O)=CC=1.[CH3:25][OH:26]>[Pd]>[CH3:25][O:26][C:13]1[CH:21]=[C:20]([C:21]2[CH:20]=[C:19]3[C:15]([CH2:16][C:17](=[O:22])[NH:18]3)=[CH:14][CH:13]=2)[CH:19]=[CH:15][CH:14]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccc(C(F)(F)F)cc3)ccc2N1
Reactant: CO
Agent: [Pd]
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 75 %

Procedure:
3′-Methoxy-3-nitrobiphenyl-4-acetic acid (5:2 g) was dissolved in methanol and hydrogenated over 0.8 g 10% palladium on carbon for 3 hours at room temperature. The catalyst was removed by filtration, washed with methanol and the filtrates combined and concentrated to give a brown solid. The solid was chromatographed on silica gel in ethyl acetate:hexane:acetic acid 33:66:1 to give 3.0 g (75% yield based on 4-fluoro-3′-methoxy-3-nitrobiphenyl) of 6-(3-methoxypheny)-2-oxindole as a pink solid.
Reaction SMILES: C(Cl)[Cl:2].[F:4][C:5]([F:23])([F:22])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:7].Cl>O1CCOCC1>[ClH:2].[F:23][C:5]([F:4])([F:22])[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)C(F)(F)F)CC1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)C(F)(F)F
Reaction time: 6 h
Yield: 96 %

Procedure:
To a stirred DCM solution of the title compound of Example 1 (100 mL) was added dropwise a solution of hydrogen chloride (250 mL, 1.0 mol) in 1,4-dioxane (4 M). Stirring was continued for 6 hours, then the suspension was filtered, and the solid washed with diethyl ether (500 mL) to afford the title compound (54.2 g, 96% yield) as a white solid. APCI/MS calcd. for C7H11F3N2O 196.1. found m/z=196.9 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([NH2:17])[CH3:16]>>[N:17]12[CH2:8][CH2:9][CH2:10][C:11]1([CH2:6][CH2:5][NH:12][C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:2][CH2:16][CH2:15]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Reactant: CCN
Product: O=[N+]([O-])c1ccc(NCCC23CCCN2CCC3)c2ccccc12
Yield: 65.6 %

Procedure:
1-Chloro-4-nitronaphthalene and 2-(1-azabicyclo-3.3.0]octan-5-yl)ethylamine were reacted in the same manner as in Example 1 to obtain the titled compound in a yield of 65.6%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][N:8]2[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)[CH2:2]1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCc1ccccc1N2CC1CNCCO1
Solvent: c1ccccc1
Product: CC(=O)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1
Reaction time: 4 h

Procedure:
To a solution of 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (0.34 g) in anhydrous benzene was added excess acetyl chloride under ice cooling. After stirring for 4 hours, the reaction mixture was washed with aqueous 2N sodium hydroxide and then with water, dried and evaporated to afford 5-(4-acetyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][N:6]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:1][NH:2][C:3](=[O:4])[O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([N:6]([CH3:5])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[CH:8]=[CH:9]2
Reactant: CN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1ccc2c(ccn2N(C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
Methyl isocyanate (0.72 g) was added to a solution of 1-(methyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 75 mL tetrahydrofuran containing milled potassium carbonate (2 g). After stirring three hours at ambient temperature the mixture was filtered and concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield a solid 3.1 g. This was eluted through silica with 5% methanol in dichloromethane via HPLC to yield 2.6 g solid, m.p. 186°-188° C. This was recrystallized from 20% methanol in ether to yield 1.6 g of product, m.p. 186°-188° C.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@H:16]([C@H:27]([CH2:29][CH3:30])[CH3:28])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].Cl>CO.O.[C].[Pd].C(Cl)Cl>[C:21]1([S:18]([NH:17][C@H:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[C@H:27]([CH2:29][CH3:30])[CH3:28])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: CC[C@H](C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 73.2 %

Procedure:
N-benzenesulfonyl-L-isoleucyl-L-proline benzylester (1.96 g, 4.3 mmole) was dissolved in methanol 40 ml ), and water (5 ml) solution of sodium bicarbonate (0.42 g, 5 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and the residue thus obtained was dissolved in water (20 ml), methylene chloride (100 ml) was added thereto, and at least 1N aqueous hydrochloric acid (10 ml) was added thereto while vigorous stirring. The methylene chloride layer was taken and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was recrystallized from ethyl acetate and petroleum ether to give N-benzenesulfonyl-L-isoleucyl-L-proline (yield: 1.16 g, 73.7%).