Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].C(N(CC)CC)C.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].O>C(#N)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14])(=[O:31])=[O:30]
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(I)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
4-Hydroxy-5-methoxy-7-iodoisoindolinone (0.465 g, 1.52 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was added with triethylamine (0.850 mL, 6.09 mmol) and 2-pyridinesulfonyl chloride hydrochloride (0.488 g, 2.28 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was added with water (8.0 mL) and stirred at room temperature for 30 minutes. The precipitated crystal was collected by filtration to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-iodoisoindolinone (0.468 g, yield 69%).
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.[CH2:22]([C:25]1[C:35]([OH:36])=[C:34]([C:37](=[O:39])[CH3:38])[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][CH:29]1[O:31][CH2:30]1)[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>>[C:37]([C:34]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][CH:29]([OH:31])[CH2:30][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:35]=1[OH:36])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCC2CO2)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCc1c(OCC(O)CSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 2 using the mercaptan produced in Example 1 (2.0 g, 0.0066 mol), 3-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1,2-epoxypropane (described in U.S. Pat. No. 4,565,882) (1.5 g, 0.006 mol) and anhydrous potassium carbonate (3.0 g). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 3.22 g (92%) of the product as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].[C:28](=[O:30])=O>O1CCCCC1CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH:4]3[CH:3]=[CH:2][CH:1]=[CH:28][O:30]3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: O=C=O
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: OCC1CCCCO1
Agent: [K+]
Agent: [OH-]
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCC4C=CC=CO4)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 46 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of tetrahydropyran-2-methanol was stirred at room temperature and under nitrogen for 45 minutes with 240 mg of a 1.6% solution of KOH in tetrahydropyran-2-methanol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction mixture was chromatographed on a silica gel column using CHCl3 and then CHCl3 -MeOH 9.5:0.5. The product was further purified by preparative thin layer chromatography (silica gel, CHCl3 -MeOH 9.5:0.5). Thus, there was obtained 57 mg (46%) of the desired product having a melting point of 135°-138° C. (decomposition) and providing the following analysis:
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:23])[C@@H:17]3[C@H:20]([OH:22])[CH3:21])[C:14]=2[C:24]([O:26]CC=C)=[O:25])[CH2:9][CH2:8]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[OH:22][C@@H:20]([C@H:17]1[C:16](=[O:23])[N:15]2[C@@H:18]1[CH2:19][C:13]([C:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH:9]=1)=[C:14]2[C:24]([OH:26])=[O:25])[CH3:21]
Reactant: C=CCOC(=O)C1=C(C2=CCN(C(=O)OCC=C)CC2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3=CCNCC3)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.280 g) in tetrahydrofuran (9 ml) were added successively triphenylphosphine (0.094 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (0.201 g) and tetrakis(triphenylphosphine) palladium(0) (41.5 mg). After stirring at ambient temperature for 1 hour, the mixture was poured into a mixture of cold water (50 ml) and ethyl acetate (30 ml). The separated aqueous layer was washed with ethyl acetate (30 ml×2) and concentrated in vacuo to remove the organic solvent. The residue was chromatographed on acid aluminum oxide (3 ml) eluting with water. The fractions containing the desired compound were collected and chromatographed on nonionic adsorption resin, "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting with water. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-6-[ (1R)-1-hydroxyethyl]-7-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (68 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1.O.Cl>[Fe].C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[CH:4][C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1cc(-n2ccc(=O)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)c(-n2ccc(=O)cc2)cc1N

Procedure:
First, a mixture containing 3.0 g of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 3.78 g of iron powder, 10 ml of water, 90 ml of ethanol, and 1.15 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 3 hours. Then, 135 ml of ethanol was added to the mixture, and insoluble substances were filtered with Hyflo Super-Cel (trade name) and the solvent was removed.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CC(C)COC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C
Yield: 7 %

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalent) of triethylamine and 78 μl (2 molar equivalent) of isobutyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5) to provide 92 mg (yield=7%) of the desired product (formula shown hereinabove) as an orange powder which was characterized as follows:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].[OH-:25].[Na+].Cl>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:25])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a test tube (outside diameter: 21 mm Φ×overall length: 160 mm), 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazine-3-one ((2-34)-(1)-39) (62.8 mg), dimethylsulfoxide (0.5 ml), and 3.8% by weight of aqueous sodium hydroxide solution (0.5 ml) were added under a nitrogen atmosphere at room temperature, and stirred at 70° C. for 4 hours. Then, to the reaction mixture was added 3.5% by weight of hydrochloric acid (4 ml) at room temperature, and extracted with tert-butyl methyl ether. The organic layer was concentrated under reduced pressure to give 37.5 mg of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1>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.C1COCC1>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:35]([C:2]3[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=4)[C:3]=3[CH3:23])=[CH:34][CH:33]=[N:32]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccnn2-c2ccc(Cl)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 61.6 %

Procedure:
Methyl 6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (SM1, 0.133 g, 0.304 mmol), 1-(4-chlorophenyl)-5-tributylstannyl-1H-pyrazole (0.16 g, 0.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.011 g, 0.015 mmol) and anhydrous THF (1.5 mL) in a vial were heated three consecutive times (for 55 minutes in total) in a microwave reactor (Biotage) at 130° C. until most of the iodo SM was consumed. The dark solution was concentrated to dryness with silica and applied to a silica column. Flash chromatography with ethyl acetate/n-heptane (1:4 through 2:1) gave methyl 6-[2-(4-chlorophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate (0.0915 g, 62%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[CH2:20]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:29][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:20][CH3:21])=[CH:31][CH:30]=1
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
In a reaction vessel were placed 0.29 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.12 g of 4-ethoxybenzoic acid, 0.12 g of potassium carbonate and 10 ml of N,N-dimethylformamide, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water, and extracted twice with 50 ml of diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.30 g of 3,5-dichloro-4-(3-(4-ethoxybenzoyloxy)propyloxy)-1-(3,3-dichloro-2-propenyloxy)-benzene (86% yield), nD24.0 1.5715.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:17]2[C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:25].O1CCOCC1>CO.[Pd]>[NH2:22][C:18]1[C:17]2[N:12]([CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:13](=[O:25])[CH2:14][O:15][C:16]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C1COc2cccc([N+](=O)[O-])c2N1Cc1ccc2ccccc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2

Procedure:
A solution of 4-naphthalen-2-ylmethyl-5-nitro-4H-benzo[1,4]oxazin-3-one, I-59 (0.65 g) in methanol (30 mL) and dioxane (7.0 mL) was hydrogenated in presence of 10% Pd—C at 45 psi for 22 h. Reaction mixture was filtered and the filtrate was concentrated to give 5-Amino-4-naphthalen-2-ylmethyl-4H-benzo[1,4]oxazin-3-one, I-60 (620 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)=[O:4]>CO.C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc2ccc(N)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-Nitro-1H-indole-2-carboxylic acid methyl ester (108) 200 mg (0.91 mmole) in a mixture of methanol/ethylacetate 1:1 10% Pd/C (40 mg) was added. The flask was rinsed 3 times with hydrogen and filled with hydrogen at 30 to 35 psi. The suspension was stirred vigorously at room temperature for 30 minutes. The catalyst was filtered off, the filtrate was evaporated in vacuo to dryness. The resulted 6-amino-1H-indole-2-carboxylic acid methyl ester gave a single spot on TLC (Silica, toluene-ethylacetate 7:3, Rf:0.31) and was used for the next step without purification
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9].O>CN(C)C=O>[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:3]=[N:2][N:1]=3)=[CH:20][CH:21]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 140° C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride +6% ethanol).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.[C:19]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>C1COCC1>[CH3:19][N:2]1[N:3]=[N:4][C:5]([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[N:1]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nn[nH]n2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnc(C2CCNCC2)n1
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
To a solution of tert-butyl 4-(2H-tetrazol-5-yl)piperidine-1-carboxylate (CAS 91419-58-8) (0.98 g, 3.89 mmol) and triphenylphosphine (3.06 g) in THF under a blanket of Ar was added the diisopropyl azodicarboxylate (2.30 ml) and the mixture stirred for 10 minutes. Methanol (473 μl) was added and the reaction was stirred for 18 hours and then the solution was concentrated in vacuo. The residue was purified on silica using a 90 g Biotage cartridge and a gradient elution of 25 to 35% ethyl acetate in hexanes. This semi-pure mixture was partially dissolved in a 4M HCl in dioxane solution and stirred for 1 hour, then concentrated in vacuo. The residue was partially dissolved in DCM (40 ml) and triethylamine (162 μl) and MP-Carbonate (4.17 g, loading 2.8 mmol/g) added and slurry stirred for 64 hours. The resin was filtered off and washed with a 10% solution of methanol in DCM and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SCX-2 stationary phase using methanol and then a 1M ammonia in methanol solution. Evaporation of the solvent under reduced pressure gave the title compound as a yellow solid (0.502 g); NMR (CDCl3): 1.78 (2H, m), 2.06 (2H, d), 2.77 (2H, m), 3.08 (1H, m), 3.19 (2H, d), 3.08 (3H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[C:24]([CH2:31][C:32]#[C:33][CH3:34])=[CH:23][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13](CN2CCOCC2)=[CH:12][CH:11]=1)=S)[CH:2]=[CH2:3].[OH2:35].[NH2:36][NH2:37]>C(O)C>[CH2:1]([O:4][C:5]1[CH:26]=[C:25]([O:27][CH2:28][CH:29]=[CH2:30])[C:24]([CH2:31][C:32]#[C:33][CH3:34])=[CH:23][C:6]=1[C:7](=[N:36][NH2:37])[NH:9][C:10]1[CH:11]=[CH:12][C:13]([N:9]2[CH2:10][CH2:11][O:35][CH2:6][CH2:7]2)=[CH:14][CH:15]=1)[CH:2]=[CH2:3]
Reactant: NN
Reactant: O
Reactant: C=CCOc1cc(OCC=C)c(C(=S)Nc2ccc(CN3CCOCC3)cc2)cc1CC#CC
Solvent: CCO
Product: C=CCOc1cc(OCC=C)c(C(=NN)Nc2ccc(N3CCOCC3)cc2)cc1CC#CC
Yield: 122.7 %

Procedure:
Crude 2,4-bis-allyloxy 5-(but-2-ynyl)-N-[4-(morpholin-4-ylmethyl)-phenyl]-thiobenzamide (F470-IM10: 240 mg, 0.86 mmol) and hydrazine monohydrate (700 mg, 14 mmol) were dissolved in ethanol (6 mL) and the mixture was heated under reflux for 1 hour and then concentrated to obtain the crude title compound (F470-IM11: 243 mg).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[N:11]1([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+]>O>[OH:23][C:19]1[CH:18]=[C:17]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:22]=[CH:21][C:20]=1[CH:4]=[O:5]
Reactant: CN(C)C=O
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23 %

Procedure:
DMF (10 mL) was treated dropwise with phosphorus oxychloride (2.3 g, 15 mmol). The reaction was kept at 25° C. by cooling on ice. The reaction mixture was treated with 3-(4-morpholinyl)phenol (2.5 g, 14 mmol) in small portions, stirred for 30 min at room temperature, then stirred at 100° C. for 8 h. After cooling, the mixture was poured into aqueous sodium acetate (1 M, 40 mL) and 10 mL of water was added. The resulting precipitate was collected by filtration, washed with water (10 mL), air dried, and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 90/10 CHCl3/ether) to yield the product as a light gray solid (0.66 g, 23%). See U.S. Pat. No. 4,147,552.
Reaction SMILES: Cl.Cl.ClC1C=CC(C2C3C4CCNCCC4NC=3C=CC=2)=CC=1.[Cl:24][C:25]1[CH:48]=[CH:47][CH:46]=[CH:45][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32]2[C:33]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40][C:34]=3[NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1>>[Cl:24][C:25]1[CH:48]=[CH:47][CH:46]=[CH:45][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32]2[C@@H:33]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40][C@@H:34]3[NH:35][C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: Clc1ccccc1OCCCc1cccc2[nH]c3c(c12)CCNCC3
Agent: Cl
Agent: Clc1ccc(-c2cccc3c2C2CCNCCC2N3)cc1
Product: Clc1ccccc1OCCCc1cccc2c1[C@@H]1CCNCC[C@@H]1N2

Procedure:
Following the procedure for the preparation of 10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole dihydrochloride, making non-critical variations, starting from 10-[3-(2-chlorophenoxy)propyl]-1,2,3,4, 5,6-hexahydroazepino[4,5-b]indole the title compound was prepared: 1H NMR (CDCl3) δ 1.99-2.20, 2.27, 2.78, 2.93-3.05, 3.51, 4.11, 6.48, 6.62, 6.92, 7.03, 7.19, 7.38, 7.40. HRMS (FAB) calcd for C21H25ClN2O1 (MH+) 357.1733, found 357.1749.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:21][CH:20]=1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (345 mg, 1.0 mmol) in ethyl acetate (100 mL) was treated with 10% palladium on activated carbon (34.5 mg). The reaction mixture was stirred under 60 psi hydrogen gas at 25° C. for 6 h. The catalyst was then removed by filtration through a pad of celite and was washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg, 91.4%) as a yellow solid: mp 102-107° C.; EI-HRMS m/e calcd for C17H21N3OS (M+) 315.1405, found 315.1401.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C1C[O:21]CC1.[C:23]1([Li])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1CCCCC1.C(OCC)C.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]([OH:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: C1CCOC1
Reactant: [Li]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: O
Product: OC1CN(Cc2ccccc2)CC1c1ccccc1
Yield: 76.2 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, and 60.0 g of THF in a quartz round flask reactor, 45.6 g (0.20 mol) of (NH4)2S2O8 (ammonium peroxydisulfate produced by Mitsubishi Gas Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 5 days at room temperature with irradiation by 500 W Xe lamps (UXL-500D xenon lamp produced by Ushio). 300 mL (0.30 mol) of 1 mol/L phenyllithium (PhLi) in cyclohexane-diethyl ether solution (produced by Kanto Chemical Co., Inc.) was continuously added to the reaction mixture and stirred for 5 hours at about 5° C. using an ice-bath. After completion, water was added to destroy excess PhLi at about 5° C. using an ice-bath. Acetone and diethyl ether were evaporated under reduced pressure, and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 19.3 g of 1-benzyl-4-phenyl-3-pyrrolidinol (yield 76.3%) was obtained.