Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].N1CCCCC1.Cl>C(O)C>[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[C:20]2[S:16][C:17](=[O:22])[NH:18][C:19]2=[O:21])=[CH:10][CH:9]=1)=[O:12]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a mixture of terephthalaldehyde mono-(diethyl acetal) (3.96 mL, 20.0 mmol) and 2,4-thiazolidinedione (2.81 g, 24.0 mmol) in ethanol (40 mL) was added piperidine (2.0 mL, 20.0 mmol). The reaction mixture was heated to reflux for 4 h. After cooling on an ice-bath, hydrochloric acid (0.2 mol/L, 100 mL) was added and the precipitated products were collected by filtration. The cake was washed with water and dried. To a solution of this product (5.50 g) in tetrahydrofuran (180 mL) was added hydrochloric acid (1 mol/L, 18 mL) and the mixture was stirred at room temperature for 2 h. Water was added, and the precipitated products were collected by filtration to give 5-(4-formylbenzylidene)-2,4-thiazolidinedione (3.91 g, 94%).
Reaction SMILES: [CH2:1]([OH:12])[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].Cl[CH2:16][C:17]([O-])=[O:18].[Na+].O>C(OCC)C>[CH2:3]([CH:2]1[O:11][C:17](=[O:18])[CH2:16][O:12][CH2:1]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC(O)CO
Reactant: O=C([O-])CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCC1COCC(=O)O1
Temperature: 55 °C
Reaction time: 1.75 h
Yield: 63 %

Procedure:
Powdered decane-1,2-diol (0.25 moles) is stirred at room temperature and very well powdered sodium hydroxide (0.25 moles) is added in portions. Gentle heating of the mixture to 55° C. gives a viscous yellow paste. Sodium chloroacetate (0.25 moles) is now added in portions over 10 minutes. The white mobile paste produced is stirred at 70°-60° C. for 1.75 h. After cooling to 20° C., 100 ml of petroleum ether is added followed by water. After separation of phases (aided by acetone) the aqueous phase is run off and acidified to pH 1.5 using 98% sulphuric acid. The oil produced is taken up into 2×375 ml diethyl ether which is then dried and evaporated to leave the title product as a clear oil (63%).
Reaction SMILES: O=S(Cl)Cl.C(OC([N:12]1[CH2:17][CH2:16][C:15]2([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)[CH2:14][CH2:13]1)=O)(C)(C)C.[CH3:27]O>>[CH2:16]1[C:15]2([CH2:18][CH2:19][CH:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)[CH2:14][CH2:13][NH:12][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(CC(=O)O)CC2)CC1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCC2(CCNCC2)CC1
Reaction time: 0.25 h

Procedure:
Methanol (50 mL) was cooled in an ice bath and SOCl2 (2 mL) was added dropwise with stirring. After 15 min, 2-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (0.34 g, purchased from WuXi Pharmatech) was added. The mixture was stirred at rt for 2 d and concentrated to afford methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate as its hydrochloride salt.
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]1([C:25]2[CH:26]=[C:21]([Br:20])[CH:22]=[CH:23][CH:24]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: Brc1cccc(I)c1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
4.92 g (20 mmol) of pyrene-1-boronic acid, 5.94 g (21 mmol) of 3-bromoiodobenzene, and 0.46 g (0.4 mmol, 2 mol %) of tetrakis(triphenylphosphine)palladium(0) were loaded into a 300-ml three-necked flask, and air in the container was replaced with argon. Further, 10 ml of toluene and 30 ml (3 eq) of a 2M aqueous solution of sodium carbonate were added to the mixture, and the whole was refluxed under heat in an oil bath at 100° C. for 8 hours. After one night, the resultant was extracted with toluene/ion-exchanged water and purified by column chromatography, whereby 5.61 g of 3-pyrenylbromobenzene were obtained (79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31]Cl)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:31][CH2:30][CH2:29][CH2:28][C:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[O:33])[CH2:16][CH2:15]1
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Product: O=C(CCCCN1CCC(Nc2cc(=O)oc3ccc(Cl)cc23)CC1)c1ccc(F)cc1
Yield: 34.1 %

Procedure:
According to Procedure B above, 6-chloro-4-(piperidin-4-ylamino)-chromen-2-one (0.025 g, 0.05 mmol) and 1-(4-fluorophenyl)-5-chloro-1-oxopentane (0.024 g, 0.11 mmol) were allowed to react to give the title compound (0.0078 g, 27.4%, mono-TFA salt) as a off-white solid. 1H NMR (300 MHz, MeOH) δ ppm 8.05-8.15 (m, 3H), 7.62 (dd, J=3, 9, 1H), 7.35 (d, J=9, 1H), 7.20-7.28 (m, 2H), 5.47 (s, 1H), 3.82-3.92 (m, 1H), 3.67-3.75 (m, 2H), 3.11-3.25 (m, 5H), 2.32-2.43 (m, 2H), 2.15-2.25 (m, 1H), 1.87-2.03 (m, 2H), 1.79-1.87 (m, 4H); MS (ESI+Q1MS) m/z 457 [M]+
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7]O)[C:3]2[CH:9]=[CH:10][C:11]3[C:16]([C:2]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:36]I.N1C=CN=C1>C1COCC1>[I:36][CH2:7][CH2:6][C:4]1[C:3]2[CH:9]=[CH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:2]=2[O:1][CH:5]=1
Reactant: II
Reactant: OCCc1coc2c1ccc1ccccc12
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCc1coc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-naphtho[1,2-b]furan-3-yl ethanol (1.06 g, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was extracted with chloroform, washed well with 5% Na2S2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 3-(2-iodo-ethyl)-naphtho[1,2-b]furan, was obtained as brown liquid. Yield: 1.4 g (87%); 322 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1.[CH:22](OCC)(OCC)OCC.C(O)C.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:22][NH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH2:7][N:8]3[CH:19]=[CH:18][CH:17]=[C:9]3[C:10](=[CH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1ccc2c(c1)C(=CCCN(C)C)c1cccn1CC2
Reaction time: 2 h

Procedure:
A solution of 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine in triethyl orthoformate (2.8 g.; 10 mmoles in 80 ml.) was refluxed for 5 hours. The volatiles were removed under vacuum and the residue dissolved in 100 ml. of absolute ethanol was stirred in an ice bath as sodium borohydride (0.88 g., 0.024 moles) was added over a period of 10 minutes. The mixture was stirred for a period of 2 hours. After concentration of the ethanol, the residue was dissolved in ethyl acetate, washed with water, dried over Na2SO4 and concentrated to dryness to yield 9-methylamino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: Br[C:2]1([F:19])[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:18][CH2:17][CH2:16][O:15]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[F:19][CH:2]1[CH2:4][CH:3]1[O:5][N:6]=[C:7]([C:13]1([O:15][CH2:16][CH2:17][O:18]1)[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=NOC1CC1(F)Br)C1(C)OCCO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(=NOC1CC1F)C1(C)OCCO1
Yield: 44.3 %

Procedure:
A solution of ethyl 2-(2-bromo-2-fluorocyclopropyloxy- imino)-3,3-ethylenedioxybutyrate (syn isomer)(4 g) and tri-n-butyltinhydride (2.28 ml) in benzene (30 ml) was refluxed under nitrogen atmosphere in the presence of 2,2'-azobisisobutyronitrile (250 mg) for 2 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography on silica gel and eluted with benzene. The fractions containing the compound, which had higher Rf-value on TLC [development solvent system:benzene], were collected and concentrated in vacuo to give ethyl 2-(2-fluorocyclopropyloxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(1.36 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1>[Pd].O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2ccccc21
Agent: [Pd]
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)cc2ccccc21
Yield: 76.4 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 3.24 g of 5-[4-(1-methylindol-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 24), 4.86 g of 10% w/w palladium-on-charcoal and 100 ml of dioxane were used, to give 1.49 g of the title compound, melting at 174.3°-175.5° C.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[CH:27][C:26]=1[C:36]([NH:38][CH3:39])=O)#[N:24]>C1(C)C=CC=CC=1>[C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[CH:27][C:26]=1[C:36](=[S:10])[NH:38][CH3:39])#[N:24]
Reactant: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)c1cnn(-c2ccccc2)c1C#N
Yield: 7.8 %

Procedure:
Eight grams of Lawesson's Reagent was added to a stirring solution of 3 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide in 75 ml of toluene. The reaction mixture was refluxed for approximately 1 hour and the solution was evaporated to dryness. The residue was dissolved in methylene chloride and filtered. The filtrate was concentrated under reduced pressure and the residue was chromatographed employing high pressure liquid chromatography and methylene chloride as the eluent. Fractions containing the second spot were combined and the solvent was evaporated therefrom. The residue was recrystallized from toluene to provide 250 mg of 5-cyano-N-methyl-1-phenyl-1H-pyrazole-4-thiocarboxamide, MP=215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([OH:15])=[O:14]>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][O:8][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=C(O)CCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)COCCc1ccc(Cl)cc1
Yield: 105.4 %

Procedure:
3.15 g of 4-chlorophenethyl alcohol were reacted with 2.2 g of chloroacetic acid in a manner analogous to that described in Example 1(a) to give 4.55 g (91%) of 2-(4-chlorophenyl)ethoxyacetic acid of melting point 75°-77° C. (from ethyl acetate/hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][C:12]([NH:14][C:15](C)=O)=[O:13].C=O>S(=O)(=O)(O)O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:15][NH:14][C:12](=[O:13])[CH3:11]
Reactant: CC(=O)NC(C)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: O=S(=O)(O)O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Temperature: 55 °C
Reaction time: 19 h
Yield: 64.8 %

Procedure:
To a solution of p-nitrotoluene (2.74 g; 0.02 mol) and diacetamide (4.24 g; 0.04 mol) in concentrated sulfuric acid (20 ml) is added aqueous formaldehyde (37%; 1.6 g; 0.02 mol) dropwise with stirring. The reaction mixture is stirred at room temperature for 17 hours, heated to 55° C. for 8 hours and then to 85° C. for 19 hours. The mixture is then poured onto ice. The resulting colorless precipitate is removed by filtration and recrystallized from aqueous ethanol to give 2.7 g of product (65% yield) having a melting point of 133° to 137.5° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[CH:16][NH:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[CH:9][CH:10]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccnn1-c1ccccc1
Product: CCOC(=O)C(=CNc1ccnn1-c1ccccc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 15.9 g. (0.10 mole) of 1-phenyl-5-aminopyrazole and 21.6 g. (0.10 mole) of diethyl ethoxymethylenemalonate was heated at 115-120° in an oil bath for 2 hours. After cooling, the crystalline mass was recrystallized from hot hexane containing 1% of ethanol. Cooling to room temperature and filtering gave 24.8 g. (75%) of off-white crystals, m.p. 96-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3cccc(C(F)(F)F)c3)c(=O)n2Cc2ccccc2)c1O
Yield: 57 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(3-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (115 mg, 0.25 mmol) and N-bromosuccinimide (50 mg, 0.28 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M-1, 79/81Br).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:27])[CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cc(F)cc(F)c3)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 3,5-difluorobenzoyl chloride (29 μL, 0.229 mmol) and mixing for 24 h, 46.1 mg (>100%) of the title compound were recovered.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:17][CH2:18][CH2:19][SH:20])C=CC=CC=1>>[CH:1]1([NH:7][C:8]([S:20][CH2:19][CH2:18][NH2:17])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCC1
Reactant: SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: NCCSC(=S)NC1CCCCC1

Procedure:
Cyclohexylisothiocyanate (0.2 ml) and N-triphenylmethylcysteamine (150 mg) were subjected to the reaction described in Reference 5. From the reaction product, triphenylmethyl was removed by the method described in Reference 4 to obtain 2-cyclohexylaminothiocarbonylthioethylamine (crude formate: 92 mg). The product was dissolved in anhydrous methanol (2 ml). Triethylamine (0.24 ml) and mitomycin A (97 mg: 0.8 molar equivalent) were added to the reaction solution which was then treated in a similar manner to that described in Example 1 to obtain Compound 37 (54 mg) in the form of grayish blue powders with a yield of 36%.
Reaction SMILES: C([O:8][C:9](=[O:35])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:34])[C:18]([CH3:33])([CH3:32])[CH2:19][NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].O.CO>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH2:19][C:18]([CH3:33])([CH3:32])[C:17]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]([OH:35])=[O:8])[CH2:16][CH2:15]2)=[O:34])=[O:31])=[CH:27][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1ccc(C(=N)N)cc1)C(=O)N1CCC(CC(=O)O)CC1

Procedure:
N-(N-4-Amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid benzyl ester (0.10 g) was stirred under a hydrogen atmosphere in a 50% water/methanol mixed solution under the presence of palladium hydroxide catalyst at a room temperature for 6 hours. The catalyst was removed by filtration and the solvents were distilled off. The residue was dissolved in a 1N aqueous solution of acetic acid and the resulting solution was purified with a high performance liquid chromatography (HPLC) [column: ODS 5C18 (μ bondasphere, φ 19×150 mm), mobile phase: (A) 0.1% TFA, (B) 100% CH3CN/0.1% TFA, gradient: (A):(B)=80:20-70:30, 20 minutes, flow rate: 17 ml/min]. The desired fractions were collected and lyophilized to yield N-(N-4-amidinobenzoyl-α,α-dimethyl-β-alanyl)-4-piperidineacetic acid (15 ml).
Reaction SMILES: I.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([S:19][CH3:20])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[C:32]1([O:31][C:29]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=[C:10]2[S:19][CH3:20])=[O:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-(methylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydroiodide (42) (1.00 mg, 2.52 mmol), triethylamine (0.528 mL, 0.379 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (20 mL) is added phenyl chloroformate (0.379 mL, 3.02 mmol), and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.58 g of the product 548. 1H NMR (CDCl3) δ 7.25-6.95 (m, 11H), 6.95-6.80 (m, 2H), 6.80-6.70 (m, 2H), 5.80-5.65 (m, 2H), 2.62 (s, 3H). MS: m/z 389 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C@H:32]4[CH2:31][CH2:30][C@@H:29]([C:22]5[C:21]6[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=6)[N:24]([CH3:28])[CH:23]=5)[CH2:34][CH2:33]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(F)ccc21
Reactant: Brc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(Br)cc5cccnc45)CC3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-8-piperazin-1-yl-quinoline (610 mg, 2.09 mmol), 4-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclohexanone (510 mg, 2.09 mmol), and sodium triacetoxyborohydride (660 mg, 3.14 mmol) in dichloroethane (40 mL) was added acetic acid (0.24 mL, 4.18 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and H2O (100 mL) then extracted in CH2Cl2 (100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc). The majority of the cis compound precipitated out of 5% MeOH/EtOAc before application to the column and was purified by filtration affording 510 mg (47%) of the cis isomer as a pale yellow solid: mp 215-217° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:17][C:18](=[O:28])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH3:21])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]([NH:17][C:18](=[O:28])[CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH3:21])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: CCOC(=O)CC(NC(=O)C(CC)c1ccccc1)c1cccc(N)c1

Procedure:
Corresponding to Example 3b, 6.3 g of (7a) were reduced using tin-(II) dichloride. A white solid was obtained (yield: 3.9 g).
Reaction SMILES: [CH:1](=O)[C:2]([CH3:4])=[O:3].[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([NH2:13])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1>CC(OC)(C)C>[CH3:6][C:7]1([CH3:16])[CH2:12][CH:11]([N:13]=[CH:1][C:2](=[O:3])[CH3:4])[CH2:10][C:9]([CH3:15])([CH3:14])[NH:8]1
Reactant: CC(=O)C=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: COC(C)(C)C
Product: CC(=O)C=NC1CC(C)(C)NC(C)(C)C1
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a solution of pyruvaldehyde (40% w/w solution in water, 2.68 mL, 3.16 g, 17.5 mmol) in 30 mL of TBME at room temperature was added dropwise 2,2,6,6-tetramethyl-4-amino-piperidine (2.0 mL, 2.19 g, 14.0 mmol). After 30 min, the solution was diluted with 50 mL of TBME and washed with 3×25 mL of water and 25 mL of brine. The solution was concentrated in vacuo to yield 2.1 g (71%) of the imine product which was used as such in the subsequent step: 1H NMR (CDCl3) δ 7.64 (1H, s), 3.70 (1H, tt, J=3.9, 11.6 Hz), 2.34 (3H, s), 1.61 (2H, dd, J=3.9, 13.0 Hz), 1.32 (2H, t, J=12.2 Hz), 1.21 (6H, s), 1.14 (6H, s).