Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)C=C1.Cl.CN(C)[CH2:16][CH2:17][CH2:18][N:19]=[C:20]=NCC.[CH3:25]O>ClCCl>[CH3:25][O:12][C:10]([C:7]1[C:6]2[CH:5]=[CH:20][NH:19][C:18]=2[CH:17]=[CH:16][CH:8]=1)=[O:11]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CCN=C=NCCCN(C)C
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
N,N-Dimethylaminopyridine (7.6 mg, 0.06 mmol) was added to a mixture of 1H-indole-6-carboxylic acid (100 mg, 0.62 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol) and methanol (1 mL, 24.7 mmol) in dichloromethane (2 mL). The mixture was allowed to stir at room temperature overnight, then the solvent was evaporated and ethyl acetate (20 mL) was added. The solution was washed with 1N hydrochloric acid solution (2×15 mL), saturated sodium bicarbonate solution (15 mL) and brine (10 mL), dried (MgSO4), filtered and evaporated in vacuo to give 1H-indole-4-carboxylic acid methyl ester (85.4 mg, 79% yield) as a pale yellow solid.
Reaction SMILES: S([O-])(=O)(=O)C.[N:6]1[C:15]2[CH:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:32][C:33]#[N:34]>CCN(C(C)C)C(C)C>[N:34]1[C:13]([CH2:14][N:16]([CH:14]2[C:15]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]2)[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])=[CH:12][CH:11]=[CH:32][C:33]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:15][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: CC#N
Agent: CS(=O)(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: NCCCCN(Cc1cccc(-c2ccccn2)n1)C1CCCc2cccnc21

Procedure:
Using the general alkylation procedure A: Reaction of the mesylate from above and 2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione in dry CH3CN and DIPEA gave the desired amine as a yellow oil. Deprotection with hydrazine following General Procedure E gave compound 361 as a colorless oil. 1H NMR (CDCl3) δ 1.42-1.58 (m, 4H), 1.63-1.72 (m, 1H), 1.86-2.04 (m, 2H), 2.14-2.19 (m, 1H), 2.08-2.19 (m, 2H), 2.60 (t, 2H, J=6.9 Hz), 2.65-2.90 (m, 4H), 3.83 (d, 1H, J=15.6 Hz), 3.99 (d, 1H, J=13.2 Hz), 4.18 (dd, 1H, J=9, 6 Hz), 7.03 (dd, 1H, J=7.8, 4.8 Hz), 7.25-7.33 (m, 2H), 7.74-7.82 (m, 3H), 8.15 (d, 1H, J=8.1 Hz), 8.34 (d, 1H, J=8.1 Hz), 8.51 (d, 1H, J=3.6 Hz), 8.66 (d, 1H, J=3.6 Hz); 13C NMR (CDCl3) δ 21.83, 26.64, 26.79, 29.72, 31.82, 42.40, 53.27, 58.48, 61.50, 119.30, 121.54, 121.86, 123.30, 123.82, 134.59, 136.81, 137.24, 137.52, 147.58, 149.56, 155.27, 156.91, 158.64, 162.20. ES-MS m/z 388 (M+H). Anal. Calcd. for C24H29N5.1.3CH2Cl2: C, 61.03; H, 6.40; N, 14.06. Found: C, 61.25; H, 6.36; N, 13.98.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.[Br:10][CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[BrH:10].[NH2:9][C:4]1[N:3]=[C:2]2[S:1][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:7]2[C:6](=[NH:8])[CH:5]=1
Reactant: BrCC(Br)c1ccccc1
Reactant: Nc1cc(N)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Br
Product: N=c1cc(N)nc2n1CC(c1ccccc1)S2
Temperature: 45 °C
Reaction time: 6 h
Yield: 79.9 %

Procedure:
A mixture of 14.2 g (0.1 mole) of 2-mercapto-4,6-diamino-pyrimidine, 30.4 g (0.115 mole) of (1,2-dibromo-ethyl)-benzene, 200 ml of dimethyl formamide and 13.8 g (0.1 mole) of potassium carbonate is stirred at 45° C. for 6 hours. The reaction mixture is cooled, the precipitate is filtered, washed with water and dried. Thus 26.0 g of the desired compound are obtained, yield 80%, m.p.: above 300° C.
Reaction SMILES: [CH3:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[C:19]([NH2:20])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[C:3]([C:4]2[NH:20][C:19]3[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=3[N:10]=2)=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: Cc1ncccc1C=O
Product: Cc1ncccc1-c1nc2c(C(=O)O)cccc2[nH]1

Procedure:
2-Methylnicotinaldehyde (149; 2.18 g, 18 mmol) was subjected to the standard conditions used to prepare substituted benzimidazoles by reaction with 2,3-diaminobenzoic acid 1. The desired product, 2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid 150, was obtained by purification using chromatography, followed by crystallization from EtOAc (0.43 g, 11%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[C:22]([O:24]C)=[O:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+]>C(O)CCC>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]5[C:22]([OH:24])=[O:23])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:28][C:29]=2[CH:35]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of cis-methyl 2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate (200 mg, 0.59 mmol) in n-butanol (8 mL) was added 2,6-dichloro-1,3-benzothiazole (241 mg, 1.19 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was combined with MeOH. Then 1 N NaOH (6.0 mL, 6.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated aqueous HCl was added to adjust the acidity to pH 1, and the precipitate was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid (45 mg, 15%). LC-MS m/z 491.1 (MH+), ret. time 3.90 min; 1H NMR (400 MHz, DMSO-d6) δ 1.13 (m, 1H), 1.28˜1.51 (m, 3H), 1.78 (m, 1H), 1.93 (m, 1H), 2.09 (m, 1H), 2.68 (m, 1H), 3.63 (m, 1H), 7.35 (m, 1H), 7.60 (m, 1H), 7.80 (m, 4H), 7.90 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 10.75 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32]>C(O)(=O)C>[C:1]([CH2:3][C:4]([NH:6][C:7]1[N:11]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:20])([F:22])[F:21])=[CH:14][C:13]=2[Cl:23])[N:10]=[CH:9][C:8]=1[N+:31]([O-:33])=[O:32])=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N#CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 36 %

Procedure:
7.26 g (0.02 mol) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole (Example 1) are taken in 70 ml of glacial acetic acid, and 2 ml of acetic anhydride and 2 ml of nitric acid are added dropwise in succession at about 10° C. A crystalline solid precipitates out of the initially clear solution after prolonged stirring. After filtration with suction, washing several times with diisopropyl ether and drying, 2.9 g (36% of theory) of 5-cyanoacetylamino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-nitro-pyrazole of melting point 221°-223° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([N:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]3)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(c1cccc2c(Cl)nccc12)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCN(S(=O)(=O)c2cccc3c(Cl)nccc23)C1

Procedure:
Substantially the same procedures as in Example 4 were repeated except that 1.8 g of 3-hydroxypyrrolidine was used in place of 2.1 g of 4-hydroxypiperidine to obtain 1-(1-chloro-5-isoquinolinesulfonyl)-3-hydroxypirrolidine. Then, in substantially the same manner as in Example 10, 2.5 g of the thus obtained 1-(1-chloro-5-isoquinolinesulfonyl)-3-hydroxypirrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride, 0.67 g of dimethylsulfoxide and 0.60 g of triethylamine to obtain 1-(1-chloro-5-isoquinolinesulfonyl)-3-pyrrolidone.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1>O1CCOCC1>[N:4]1[N:3]=[C:2]([N:1]2[C:7](=[O:8])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:16])[NH:6][CH:5]=1
Reactant: Nc1nc[nH]n1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1nnc[nH]1
Temperature: 120 °C

Procedure:
3-Amino-[1,2,4]triazole (8.40 g, 100 mmol) and isobenzofuran-1,3-dione (14.8 g, 100 mmol) were suspended in 1,4-dioxane (200 ml) and heated at 120° C. for 2 days. After the reaction mixture was cooled down at room temperature, the resulting precipitate was filtered, and the cake was washed with H2O then EtOAc to obtain the intended compound as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[C:6]([CH2:10][CH:11]=O)[C:5]([CH2:13][CH3:14])=[N:4]1)[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:53]>>[ClH:53].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([N:28]3[CH2:29][CH2:30][N:31]([CH2:11][CH2:10][C:6]4[C:5]([CH2:13][CH3:14])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=4[CH2:8][CH3:9])[CH2:32][CH2:33]3)=[N:24][CH:25]=[CH:26][N:27]=2)=[CH:18][CH:17]=1
Reactant: CCc1nn(CC)c(CC)c1CC=O
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nn(CC)c(CC)c1CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Product: Cl
Yield: 83 %

Procedure:
Combine (1,3,5-triethyl-1H-pyrazol-4-yl)-acetaldehyde (0.16 g, 0.82 mmol) and 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.24 g, 0.91 mmol) in DCM (10 mL) and stir at room temperature for 15 min. Then add glacial acetic acid (0.07 mL, 1.23 mmol) and sodium triacetoxyborohydride (0.26 g, 1.23 mmol) and stir for 3 hr. at room temperature. Purify using SCX chromatography and further purify using silica gel chromatography (5% 7 M ammonia in methanol/DCM). Dissolve the free base in methanol (5 mL) and treat with ammonium chloride (0.037 g). Concentrate the resulting solution to give the title compound (0.032 g, 83%). MS: m/z=437.3[M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([O:25]C)[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10][CH:11]([CH3:12])[CH3:13])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:20]=1
Reactant: COc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: Cc1c(OCC(=O)OC(C)C)ccc(F)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]-2-methyl-phenoxy]acetate (300 mg, 0.66 mmol, 1 eq) and AlCl3 (526 mg, 3.95 mmol, 6 eq) in CH2Cl2 (10 mL) was added ethanethiol (245 mg, 3.95 mmol, 5 eq) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 2 h and the resulting mixture was quenched by the addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was purified by column chromatography (petroleum ether:EtOAc, 15:1) to give the title compound as a colorless oil (120 mg, 41%).
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.CCOCC.C(N(CC)CC)C>C1COCC1>[NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[O:7][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: OCc1ccccc1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@H](CCC(=O)OCc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 78 %

Procedure:
To a solution of 29.1 g (1.0 eq) H-D-Glu-OH in 205.6 mL (10.0 eq) benzyl alcohol which was stirred at r.t, 47.7 mL (2.0 eq) boron trifluoride etherate solution was added slowly, and 10 min later, all of the substrate was dissolved. The reaction was completed in 15 h, 616.8 mL (3 times of the volume of benzyl alcohol) THF was added, stirred and 55.1 mL (2.0 eq) triethylamine was added slowly. A large number of white viscous precipitate precipitated. The THF was removed under reduced pressure; the residue was cooled, after adding the proper amount of the AcOEt, the viscous precipitate turned to powder. 36.6 g target compound was obtained with yield of 78% after filtration and drying. m.p.=174˜176° C.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[F:14])=[O:5].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:18]([C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=2)[CH:10]=[CH:9][C:8]=1[F:14])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 2-chloro-3-(1-cyanocyclopropyl)-N-(2-fluoro-5-hydroxyphenyl)benzamide (6.50 g, 19.7 mmol), 2-chloro-5-nitropyridine (3.17 g, 20 mmol) and potassium carbonate (2.76 g, 20 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (6.60 g, 74%) as a yellow powder.
Reaction SMILES: [Cl-].[NH4+:2].[C-:3]#[N:4].[K+].[CH3:6][O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH:10]=O>O.N>[NH2:2][CH:10]([C:9]([CH3:13])([CH3:12])[CH2:8][O:7][CH3:6])[C:3]#[N:4]
Reactant: COCC(C)(C)C=O
Reactant: [NH4+]
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: COCC(C)(C)C(N)C#N
Yield: 8.2 %

Procedure:
Ammonium chloride (2.9 g) and potassium cyanide (3.3 g) were dissolved in water (20 ml), a solution of 3-methoxy-2,2-dimethylpropanal (F. Effenberger et al., Tetrahedron: Asymmetry, 6, 271-282 (1995); 5.7 g) in aqueous ammonia (5 ml) was added dropwise at 0° C., and mixed at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diluted hydrochloric acid. The aqueous solution was washed with diethyl ether, alkalified with a 1 N aqueous sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.57 g, 8%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2.Cl[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[Br:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([CH2:14][C:15](=[O:17])[CH3:16])[CH2:8]2
Reactant: CC(=O)CCl
Reactant: Brc1cccc2c1CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CN1CCc2c(Br)cccc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture containing 5-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (1 g, 4 mmol), chloroacetone (407 mg, 4.4 mmol) and potassium carbonate (1.38 g, 10 mmol) in dimethyl formamide (DMF) (8 ml) is stirred at room temperature for 18 hours. To this mixture is added water (50 ml) and ethyl acetate (50 ml). The organic layer is separated, washed with brine, dried over MgSO4, and concentrated. The crude product is purified by flash column chromatography using 30% ethyl acetate in dichloromethane as eluent to give 1-(5-Bromo-3,4-dihydroisoquinolin-2(1H)-yl)propan-2-one as an orange oil. LC-MS m/z: 269.1 (M+1).
Reaction SMILES: Cl[CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C-:17]#[N:18].[Na+].O>CS(C)=O>[C:17]([CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[N:18]
Reactant: [C-]#N
Reactant: CCC(Cl)CCC#CCOC1CCCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C#N)CCC#CCOC1CCCCO1
Reaction time: 65 h
Yield: 65.8 %

Procedure:
A solution of chloride 35 (20.0 g, 92.3 mmol) in dry DMSO (75 mL) was added to a solution of NaCN (6.0 g, 122.0 mmol) in dry DMSO (100 mL). The reaction mixture was stirred at 50°-60° C. for 65 h. The dark brown mixture was cooled, poured into water (200 mL), and extracted with five 100-mL portions of CH2Cl2. The combined organic extracts were washed with water (3×150 mL), dried over Na2SO4, and concentrated by rotary evaporation. The black oil was dissolved in Et2O (200 mL) and filtered through a pad of silica gel (60-200 mesh, Baker Chemical Co.) to yield 36 as a yellow oil (14.3 g, 75%): IR (neat) 2940 (s), 2870, 2280 (w), 2250, 1440, 1345, 1200, 1130, 1115 (s), 1075, 1020 (s), 900, 865, 810 cm-1 ; 1H NMR (CDCl3)δ 4.80 (m, 1H), 4.23 (t, J=2 Hz, 2H), 3.66 (m, 2H), (m, 4H), 1.67 (m, 8H). Nitrile 36 was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.S([O-])([O-])(=O)=[O:11].[Al+3].S([O-])([O-])(=O)=[O:17].S([O-])([O-])(=O)=O.[Al+3]>>[C:1]1([C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:11])[OH:7].[C:1]1([CH:6]=[CH:5][C:4]([OH:17])=[CH:3][CH:2]=1)[OH:7]
Reactant: O=S(=O)([O-])[O-]
Reactant: Oc1ccccc1
Agent: OO
Agent: [Al+3]
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O

Procedure:
10 g. (106 m. moles) of phenol, 8.20 m. moles of the ketone indicated in Table 3, 0.300 g. (5.29 m. moles) of 60 percent hydrogen peroxide, 0.070 g. of aluminum sulfate (Al2 (SO4)3.18H2O) (miligramion 0.315 of SO4 --) were mixed together and the resulting mixture was reacted at 100° C. for 30 minutes in the same manner as in Example 1. Yields of catechol and hydroquinone are shown in Table 3.
Reaction SMILES: [H-].[Na+].C1([SH:9])C=CC=CC=1.Cl[CH2:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=O.Cl.[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C)C=O>[C:22]1([CH2:11][C:12](=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[S:9])[CH:21]=[CH:20][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCC
Reactant: Sc1ccccc1
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=S)CC(=O)Cc1ccccc1
Temperature: -5 °C
Reaction time: 1.5 h
Yield: 104 %

Procedure:
Sodium hydride (17.32 g, 0.433 mol) was washed with hexane (100 ml×2) then was suspended in dimethylformamide (300 ml). To the mixture was dropwise added thiophenol (44.5 ml, 0.433 mol) in DMF (50 ml) under ice-methanol bath cooling with controlling the inner temperature of 5-10° C. under nitrogen atmosphere. After 1.5 h stirring at -5° C., methyl 4-chloroacetoacetate (50 ml, 0.433 mol) was dropwise added to the reaction mixture under ice-methanol bath cooling with controlling the inner temperature of 5-10° C. under nitrogen atmosphere and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 1N HCl to pH 2 under ice bath cooling then partitioned between EtOAc (500 ml) and H2O (100 ml). The aqueous phase was extracted with EtOAc (250 ml×2). The combined extracts were concentrated to about 500 ml and then washed with aq. NaHCO3 solution (150 ml) and brine (100 ml×3). The organic solution was dried over MgSO4 and concentrated to afford 100.88 g of methyl 4-phenylthioacetoacetate as an orange color oil. (104% yield).(contained 1/6 eq of DMF) 1H NMR (CDCl3) 7.42-7.18 (m, 5H), 3.80 (s 2H), 3.71 (s, 3H), 3.65 (s, 2H).
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]([CH3:16])[CH:7]=1.Br[C:20]1[CH:21]=[CH:22][C:23]2[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[CH:37][CH:36]=3)=[O:33])=[CH:25][C:24]=2[CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:16][C:8]1[CH:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:23]3[S:29](=[O:31])(=[O:30])[CH2:28][CH2:27][C:26]([C:32]([NH:34][C:35]4[CH:40]=[CH:39][C:38]([CH2:41][N:42]([CH3:49])[CH:43]5[CH2:48][CH2:47][O:46][CH2:45][CH2:44]5)=[CH:37][CH:36]=4)=[O:33])=[CH:25][C:24]=3[CH:50]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1C
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
In toluene (23 ml), ethanol (2.3 ml) and water (2.3 ml) were suspended 3-methyl-4-propoxyphenyl borate (219 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (450 mg) and potassium carbonate (312 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (70 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate (twice). The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (125 ml) to give colorless crystals of 7-(3-methyl-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 137) (242 mg).