Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[N:7]=[C:8]([S:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=[CH:14][N:13]=3)[NH:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[N:7]=[C:8]([S:10]([CH2:11][C:12]3[C:17]([O:18][CH3:19])=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=[CH:14][N:13]=3)=[O:36])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(SCc3nccc(OCC(F)(F)F)c3OC)[nH]c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(S(=O)Cc3nccc(OCC(F)(F)F)c3OC)[nH]c2c1
Yield: 69.2 %

Procedure:
5-Methoxy-2-[[3-methoxy-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (989 mg) was dissolved in chloroform (30 ml), to which a solution of m-chloroperbenzoic acid (503 mg) in chloroform (8 ml) was added dropwise under ice-cooling over 5 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and then a saturated saline, and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography, to give 5-methoxy-2-[[3-methoxy-4-(2,2,2-trifluoroethoxy)pyrid-2-yl)methylsulfinyl]benzimidazole (712 mg) as a light brownish yellow powder. m.p. 36°-46° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH3:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH2:2][N:27]([CH3:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(C)cc(CO)c1
Reactant: CCCCCNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirred solution of methyl 3-(hydroxymethyl)-5-methylbenzoate (200 mg, 1.1 mmol) in methylene chloride (2.2 mL) is added triethylamine (0.304 mL, 2.2 mmol) followed by methanesulfonyl chloride (0.116 mL, 1.5 mmol). The reaction mixture is stirred for 15 min and filtered. N-Methylpentylamine (333 mg, 3.3 mmol) is added to the filtrate, and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is diluted with methylene chloride (10 mL), washed with 1 N hydrochloric acid, and saturated sodium bicarbonate, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 15% ethyl acetate/hexanes) provides the title compound. 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=4 Hz, 2H), 7.36 (s, 1H), 3.90 (s, 3H), 3.47 (s, 2H), 3.13 (t, J=9 Hz, 3H), 2.39 (s, 2H), 2.34 (d, J=8 Hz, 2H), 2.18 (s, 3H), 1.45 (m, 5H), 1.32 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39](O)=[O:40]>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][C:39]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)=[O:40])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=C(O)c1ccccn1
Product: CS(=O)(=O)N(CCCNC(=O)c1ccccn1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with pyridine-2-carboxylic acid following procedure K. LC-MS showed the product had the expected M+H+ of 561. 1H NMR (Varian 300 MHz, DMSO-D6, shifts relative to the solvent peak at 2.49 ppm) δ 8.7 (d, 1H) 8.6 (t, 1H) 8.3 (d, 1H) 8.0 (s, 1H) 7.9 (t, 1H), 7.5 (m, 3H), 7.2 (t, 1H), 7.0 (m, 3H), 6.6 (d, 2H), 4.4 (s, 2H), δ 3.4 (t, 2H), 3.2 (m, 4H), 3.0 (s, 3H), 2.7 (t, 2H), δ 1.7 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[C:6]([O:18][CH3:19])[CH:5]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([O:18][CH3:19])[CH:7]=[C:8]([CH:21]2[CH2:23][CH2:22]2)[CH:9]=1
Reactant: COC(=O)c1cc(OC)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(OC)cc(C2CC2)c1
Yield: 96.5 %

Procedure:
The above prepared 3-methoxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (0.350 g, 1.11 mmol) was dissolved under Ar in 4.5 ml of abs. toluene and 0.49 ml of water and treated successively with cyclopropyl boronic acid (0.191 g, 2 eq.), K3PO4 (1.272 g, 5.4 eq.), tricyclohexylphosphine (0.069 g, 0.22 eq.), and finally Pd(OAc)2 (0.028 g, 0.11 eq.). The reaction flask was closed with a septum and the mixture was allowed to react for 16 h at 100° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=9/1), afforded 0.221 g of the title compound as yellow oil, 97% pure according to GC-analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cc(Cl)cc(Cl)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(NC(c1ccc(F)cc1)c1cccc(N)c1)c1cc(Cl)cc(Cl)c1

Procedure:
Following, a similar reaction, separation and purification procedure to that described in Example (59b), 3.39 g of N-[1-(3,5-dichlorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 3.86 g of nickel chloride hexahydrate and 1.23 g of sodium borohydride were reacted, to obtain 970 mg of isomer A and 567 mg of isomer B of the title compound as a pale yellow oil and a white solid, respectively.
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)CCN.C1(=O)CCCCC1>C(OC(=O)C)C>[CH:1]1([N:7]([CH2:21][CH2:22][CH:23]([CH3:28])[CH3:24])[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CCN
Solvent: O=C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)C1CCCCC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from 3-methyl-butylamine, cyclohexanone and 2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH:1](/[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][OH:16])=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH:1](/[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC/C=C/c1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCCCCCCCCC/C=C/c1ccccc1C=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of lithium aluminum hydride (22.2 mmoles) in tetrahydrofuran (30 ml) under argon, cooled to 0° C., was added 2-(1-dodecyn-1-yl) benzaldehyde (11.1 mmoles, prepared as in Example 4a) in tetrahydrofuran (10 ml), dropwise with stirring. After coming to room temperature, the reaction mixture was refluxed for 18 hours. The reaction mixture was then cooled to 0° C., ice was added, followed by ether and dilute hydrochloric acid, and the layers were separated. The organic layer was washed with water and brine. The dried solution was concentrated to give 2-(1-trans-dodecenyl)benzyl alcohol, after recrystallization from acetonitrile. The benzyl alcohol (0.080 mmoles) was dissolved in ethyl acetate (10 ml) under argon and manganese dioxide (12.6 mmoles) was added. The reaction mixture was stirred for 18 hours at room temperature, filtered and the filtrate concentrated to leave an oil which is the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Piperazine-1-carboxylic acid benzyl ester (500 mg) was dissolved in DCM (5 ml) and the mixture was cooled down to 0° C. Benzoyl chloride (290 μl) and NEt3 (379 μl) were added. The mixture was stirred for 48 h, diluted with DCM, washed with water, dried (Na2SO4) and evaporated off. After HV, 650 mg of the desired compound were obtained.
Reaction SMILES: CN.O.[C:4]1([CH:10]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:11]2[CH2:14][CH:13]([N:15]3C(=O)C4=CC=CC=C4C3=O)[CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[NH2:15][CH:13]1[CH2:14][N:11]([CH:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN
Solvent: CCO
Solvent: O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
572 ml of 40% aqueous methylamine solution and 300 ml of water were added successively to a suspension of 78.0 g (0.212 mol) of 1-(diphenylmethyl)-3-(phthalimido)-azetidine in 480 ml of ethanol. After 7 days' stirring at ambient temperature a clear solution had formed, which was freed from excess methylamine and ethanol in vacuo. The aqueous solution remaining was extracted exhaustively with ethyl acetate. The ethyl acetate extracts were dried over sodium sulphate and dried in vacuo. 45.0 g (89% of theoretical) of a colourless oil were obtained, which was further processed without any additional purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[OH:14].N[C@H:17]([C:25](O)=[O:26])CC1C=CC=CC=1.N1C=CC=CC=1.C(Cl)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[O:14][C:25](=[O:26])[CH3:17]
Reactant: COC(=O)NC1Cc2ccccc2C1O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: COC(=O)NC1Cc2ccccc2C1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The alcohol, (1-hydroxy-indan-2-yl)-carbamic acid methyl ester (1S-trans) prepared from L-phenylalanine (18.7 g, 0.09 mol) (J. Org. Chem. 1983, 48, 2675-2679) is suspended in methylene chloride and cooled to 0° C. Pyridine (10.7 g, 0.135 mol) is added followed by acetyl chloride (10.5 g, 0.135 mol). The mixture is stirred for 1 h. and then washed with sodium bicarbonate, 1N HCl and saturated sodium chloride. The organic layer is dried over Na2SO4, filtered and evaporated under reduced pressure to give (1-acetyloxy-indan-2-yl)-carbamic acid methyl ester (1S-trans).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: Clc1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(Nc2ccccn2)n1
Temperature: 95 °C
Reaction time: 12 h

Procedure:
To a N2 purged sealed tube, 2,4-dichloropyrimidine (1.0 g, 6.7 mmol, 1.2 eq.) and 2-aminopyridine (0.53 g, 5.6 mmol, 1.0 eq.) were added followed by 7 mL of anhydrous IPA. To the resulting suspension DIEA (0.98 mL, 5.6 mmol, 1.0 eq.) was added. The reaction was heated to 90-100° C. and stirred for 12 h. The reaction mixture was cooled to RT and the solvent was removed. The crude mixture was further purified by column chromatography (0-20% EtOAc in hexanes) providing pure (2-chloro-pyrimidin-4-yl)-pyridin-2-yl-amine.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21]Br)=[CH:20][C:14]=2[CH:13]=1)=[O:11]>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][C:4]3[NH:3][CH:7]=[CH:6][N:5]=3)=[CH:20][C:14]=2[CH:13]=1)=[O:11]
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc2cc(CBr)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(Cc3ncc[nH]3)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (0.34 g.:50% dispersion in oil) was added portion-wise to a stirred solution of imidazole (0.48 g.) in dry dimethylformamide (DMF) (20 ml.). After 1/2 hour a solution of 5-bromomethylbenzo[b]thiophene-2-carboxylic acid methyl ester (2.0 g.) in DMF (15 ml.) was added dropwise. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure and H2O (100 ml.) added to the residue. The aqueous solution was then extracted with EtOAc (3×50 ml.) and the combined organic extracts were washed (H2O), dried (MgSO4), filtered and evaporated to give a solid which was recrystallized from MeOH/H2O to give 5-(1-imidazolylmethyl)benzo[b]thiophene-2-carboxylic acid methyl ester, 0.7 g., m.p. 168°-169° C.
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[CH:10]=[O:11].[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1>>[F:13][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:17]=[CH:18][S:14][CH:15]=2)=[CH:12][C:9]=1[CH:10]=[O:11]
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: OBO
Product: O=Cc1cc(-c2ccsc2)ccc1F

Procedure:
2-fluoro-5-(thiophen-3-yl)benzaldehyde was prepared using the general boronic acid coupling procedure with 5-bromo-2-fluorobenzaldehyde and thiophen-3-ylboronic acid (27 mg, 102 mg theoretical, 26.5%). LC-MS m/z 207 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]2[CH:5]=[CH:6][C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:8][C:9]=2[CH2:10][CH2:11][CH:12]=1)#[N:2].CCO.[H][H]>[Pd].C(O)(=O)C>[C:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])[CH:6]=[CH:5][C:4]1=2)#[N:2]
Reactant: N#CC1=CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CC1CCCc2cc(NS(=O)(=O)c3ccccc3)ccc21
Yield: 90.1 %

Procedure:
N-(5-Cyano-7,8-dihydro-naphthalen-2-yl)-bezenesulfonamide (5.27 g, 17.2 mmol), 70 mL EtOH, and 50 mL acetic acid were placed in a Parr vessel, and 1.0 g of 10% Palladium on carbon (Fluka Chemica Co.) was added. The reaction mixture was shaken for 15 hours under 55 psi hydrogen. The Parr vessel was purged with nitrogen and the reaction mixture was filtered. The filtrate was added to 500 mL, water, and the aqueous mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated to yield 4.85 g (15.5 mmol, 90%) of N-(5-Cyano-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide as an oil. MS: 314 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C=O.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:16]1([NH:22][C:23]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]=2[OH:14])=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2C(C(=S)Nc2ccccc2)=C1O
Temperature: 0 °C
Reaction time: 5 h
Yield: 47.9 %

Procedure:
To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.37 g of phenyl isothio-cyanate, and 5 ml of dried N,N-dimethylformamide was added 0.31 g of potassium t-butoxide with under ice-cooling, followed by stirring for 5 hours under ice-cooling. Ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate, and the ether layer was removed by distillation. The residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.4 g of N-phenyl-6- cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.
Reaction SMILES: [CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:10][CH:9]=1)=[O:5].[ClH:42]>C(Cl)Cl>[ClH:42].[ClH:42].[CH3:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:28][NH2:29])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(C(=O)OCc2ccc(C(CN)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 9 h

Procedure:
To 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E145) in CH2Cl2 was added HCl (4 N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dihydrochloride (E146).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31](CO)[C:32]([CH3:37])=[C:33]2[OH:36])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([CH2:20][Cl:24])[C:32]([CH3:37])=[C:33]2[OH:36])=[CH:28][CH:27]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(CO)cc2ccc(Cl)cc2c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCl)cc2ccc(Cl)cc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of triphenylphosphine (20 g, 75.6 mmol) in anhydrous tetrahydrofuran (165 mL) was added carbon tetrachloride (50 mL). After the mixture was stirred at room temperature for 20 minutes, 7-chloro-3-hydroxymethyl-2-methyl-naphthalen-1-ol (8.4 g, 37.8 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 7-chloro-3-chloromethyl-2-methyl-naphthalen-1-ol (8.7 g, 96%) as a white solid.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([O:23]CC)=[O:22].CO.O>C1COCC1>[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:11]=2)[NH:6][C:5]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1[nH]c2ccc(NC(=O)OC(C)(C)C)cc2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)c(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
Lithium hydroxide (0.032 g, 1.344 mmol) was added to a solution of ethyl 3-chloro-5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-1H-indole-2-carboxylate (0.059, 0.17 mmol) in THF:methanol:water/3:1:1 (3 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in water, acidified with 1N aqueous HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the title compound (0.054 g, ˜75% pure).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:2]1([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccccc2)cc1
Yield: 86.3 %

Procedure:
According to general procedure B, chlorobenzene (57 mg, 0.50 mmol) reacted with aniline (48 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (59 mg, 0.60 mmol) in toluene at 70° C. to give the title compound (73 mg, 86%) as a white solid. The coupling reaction of bromobenzene (158 mg, 1.00 mmol) with aniline (93 mg, 1.00mmol) occurred at room temperature over 4 h using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 to give the title compound (166 mg, 98%): 1H-NMR (400 MHz, CDCl3): δ 7.34 (t, 4H, J=7.8 Hz and 7.5 Hz), 7.14 (d, 4H, J=8.7 Hz), 7.00 (t, 2H, J=7.2 and 7.5 Hz), 5.74 (bs, 1H). 13C{1H}-NMR (100 MHz, CDCl3): δ 143.09, 129.32, 120.97, 117.78. GC/MS(EI): m/z 169 (M+).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[CH2:26]([N:35]1[C:40](=[O:41])[C:39]([C:42]([O:44]C)=[O:43])=[CH:38][C:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[C:48]([CH3:53])[CH:47]=2)=[N:36]1)[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:42]([C:39]1[C:40](=[O:41])[N:35]([CH2:26][CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:36]=[C:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[C:48]([CH3:53])[CH:47]=2)[CH:38]=1)([OH:44])=[O:43]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC=Cc2ccccc2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 85.1 %

Procedure:
Following the procedure of Example 1 (7), 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as pale yellow needles (yield: 85.1%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])=[O:15]
Reactant: CC(C)(C)CCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CC(C)(C)CCOC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From 3,3-dimethyl-1-butanol (5.0 g; 49 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 4 h. The yield was 0.91 g (60%), mp146–148°.