Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[N:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=2)=[CH:12][CH:11]=1>C(O)(=O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH:19]2[N:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=3)[CH2:20]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C2=NN(c3ccccc3)C(c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc(N)cc3)C2)cc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
15.8 g of reduced iron and 1.6 g of ammonium chloride were dispersed in a mixed solution of 140 ml of isopropyl alcohol and 14 ml of water, and, while stirring and refluxing under heating, 13.1 g of 3-(4-methoxyphenyl)-5-(4-nitrophenyl)-1 -phenyl-2-pyrazoline was added thereto. After refluxing for 2 hours, 10 ml of acetic acid was added thereto, and the reaction was thereafter continued for 30 minutes. Solids were removed by filtration using sellaite, and 150 ml of water was added to the filtrate. Crystals precipitated were collected by filtration to obtain 9.7 g of 5-(4-aminophenyl)-3-(4-methoxyphenyl)-1-phenyl-2-pyrazoline.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].[CH3:19][N:20]([CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH:30]([CH3:32])[CH3:31])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:36]1[CH:35]=[CH:34][C:33]([CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][N:20]([CH3:19])[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[CH:38][CH:37]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)C(CN(C)C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CN(C)C(=O)OC(C)(C)C)C(C)C)cc1
Yield: 14 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one) (440 mg, 1.4 mmol) was reacted with tert-butyl methyl(3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)carbamate (600 mg, 1.5 mmol) to afford the desired product (100 mg, 14%) as a yellow solid: ESI MS m/z 521 [C30H36N2O4S+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][C:14]1[CH:19]=[C:18]([OH:20])[C:17]2[O:21][C:22]3[C:27]([C:28]([O:30][CH2:31][C:16]=2[CH:15]=1)=[O:29])=[C:26]([O:32][CH3:33])[C:25]([C@@H:34]([OH:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:24][CH:23]=3>C(Cl)Cl>[OH:39][CH:34]([C:25]1[CH:24]=[CH:23][C:22]2[O:21][C:17]3[C:18]([O:20][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:19][C:14]([CH3:13])=[CH:15][C:16]=3[CH2:31][O:30][C:28](=[O:29])[C:27]=2[C:26]=1[O:32][CH3:33])[CH2:35][CH:36]([CH3:37])[CH3:38]
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(OS(C)(=O)=O)c1O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.14 ml (1.0 mmol) of triethylamine and 86 μl (1.1 mmol) of methanesulphonyl chloride are added at 0° C. under argon to 150 mg (0.4 mmol) of penicillide (Ib) in 3 ml of methylene chloride and the mixture is stirred at 25° C. for 12 h. Acidifying to pH 2, extracting with methylene chloride, washing, drying and evaporating yields, after chromatography on silica gel Si60 in ether/petroleum ether 2:1, 75 mg (41% of theory) of colorless solid
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH:33]1[C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][NH:32][CH:33]([C:38]([NH2:40])=[O:39])[CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: NC(=O)C1CNCCN1
Product: NC(=O)C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]piperazine-2-carboxamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperazine-2-carboxylic acid amide following General Procedure C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[O:42]1[C:46]([CH2:47][S:48][C:49]2[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=2)=[CH:45][CH:44]=[N:43]1>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:53][C:52]4[CH:54]=[CH:55][C:49]([S:48][CH2:47][C:46]5[O:42][N:43]=[CH:44][CH:45]=5)=[CH:50][CH:51]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(SCc2ccno2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccno4)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.15 ml) was added to the mixture at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[(isoxazol-5-ylmethyl)sulfanyl]aniline (429 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 1.5 hours at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(isoxazol-5-ylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (557 mg) (Compound 327) as yellow crystals.
Reaction SMILES: C(O)C.[C:4]([C:8]1[C:9](=[O:28])[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][C:12](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+]>[Pd].O>[C:4]([C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=1[OH:28])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
To a mixture of 200 ml of ethanol and 25.0 g (0.0736 mole) of 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-l-one and 12 g (0.087 mole) of potassium carbonate warmed on a steam bath was added 1.0 g of palladium on charcoal. The mixture was reduced using a Paar apparatus for 2 hours. The mixture was diluted with 300 ml of water, filtered through celite, and the filtrate acidified with 6N hydrochloric acid. The yellow solid precipitate was collected by filtration to provide 4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p. 241°-242° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31][NH2:32])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31]/[N:32]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])=[CH:28][CH:27]=1
Reactant: COc1ccc(CON)cc1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: COc1ccc(CO/N=C(\C)c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Yield: 37 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-(4-methoxybenzyl)hydroxylamine (intermediate G) in 37% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CDCl3), δ ppm 9.44 (s, 1H), 8.93 (s, 1H), 8.13 (m, 2H), 7.91 (s, 1H), 7.84 (d, 1H), 7.47 (dd, 1H), 7.44 (d, 2H), 6.92 (d, 2H), 6.10 (s, 2H), 5.28 (s, 2H), 3.82 (s, 3H), 2.37 (s, 3H). LCMS (method A): [MH]+=440, tR=5.94 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](O)([CH2:9][CH3:10])[CH2:7][CH3:8])=[C:2]1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.Cl>C(O)(=O)C>[CH3:8][CH:7]=[C:6]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][CH3:10]
Reactant: CCC(O)(CC)c1ccsc1-c1cccs1
Agent: Cl
Solvent: CC(=O)O
Product: CC=C(CC)c1ccsc1-c1cccs1

Procedure:
3-(2,2′-bithiophene-3-yl)pentan-3-ol (IIa) (0.100 g, 0.40 mmol) was dissolved in acetic acid (69 mL). A solution of concentrated HCl (0.28 mL) in acetic acid (15 mL) was added via syringe to the reaction mixture. The solution was refluxed for 4 h followed by an extraction with chloroform, washing and drying over MgSO4. The solvent was removed in vacuo. The residue was purified by column chromatography on silica (n-Hexane). (0.070 g, 75%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[O:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C=O)cc1

Procedure:
A solution containing 3.053 g (25 mmol) of 4-formylphenol, 6.48 ml (3705 mmol) of 1-bromooctane and 6.9 mg (50 mmol) of potassium carbonate in 100 ml of acetone was refluxed overnight. When the reaction was substantially complete, as indicated by thin layer chromatagraphy (TLC), the reaction was quenched by the addition of 100 ml of water. The desired compound was extracted from the reaction mixture using two 100 ml portions of diethyl ether. The resultant solution was dried over magnesium sulfate, filtered and then concentrated in vacuo to provide a liquid which was purified using HPLC (eluent of 10 ethyl acetate in hexane) to provide the desired compound.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:25][CH:26]=1
Reactant: CCCSc1ncc(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1ncc(CO)n1Cc1ccc(O)cc1
Yield: 26.5 %

Procedure:
A solution of 1.40 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole in 15 mL of trifluoroacetic acid was refluxed for 0.25 hour. After cooling, the reaction was poured into water containing an excess of sodium bicarbonate, and the resulting emulsion was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-5% methanol/chloroform) afforded 0.28 g of 1-(4-hydroxybenzyl)-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ9.41 (s, 1h); 6.88 (s, 1h); 6.79 (A2B2, 4H); 5.14 (t, 1h); 5.07 (s, 2H); 4.33 (d, 2H); 2.89 (t, 2H); 1.54 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=3[N+:26]([O-:28])=[O:27])[S:3][C:4]=2[C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1sc(Nc2ccc(C=O)cc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a mixture of 0.10 g (0.39 mmole) of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18), 0.07 g (0.39 mmole) of 4-fluoro-3-nitrobenzaldehyde and 2 mL of dimethylformamide was added 0.19 g (0.59 mmole) of cesium carbonate. The mixture was heated at 120 degrees for 6 hours and then cooled. Water was then added and the suspension stirred at room temperature for one hour. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.16 g of 4-(4-chloro-phenyl)-2-(4-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.18a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:35][CH2:36][CH3:37])[C:31]=1[O:32][CH2:33][CH3:34])[C:26](Cl)=[O:27])[CH3:21].[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH2:36]([O:35][C:30]1[CH:29]=[C:25]([CH:24]=[C:23]([O:22][CH2:20][CH3:21])[C:31]=1[O:32][CH2:33][CH3:34])[C:26]([C:10]1[C:11]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=2[S:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:27])[CH3:37]
Reactant: CCOc1cc(C(=O)Cl)cc(OCC)c1OCC
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc(OCC)c1OCC
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a well stirred solution of 2-(4'-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.501g, 1.85 mmol) and 3,4,5-triethoxybenzoyl chloride (1.00 g, 3.66 mmol) in CH2Cl2 (45 ml) was added AlCl3 (0.870 g, 6.52 mmol) portion-wise over a 15 minute period. After 30 minutes, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexanes) afforded the title compound (0.827 g, 1.63 mmol, 88%) as a pale yellow solid. Recrystallization (EtOAc/hexanes) afforded a highly pure, crystalline sample with mp 108°-110° C. 1H-NMR (CDCl3, 360 Mhz): δ=7.64 (d,J=8.9 Hz, 1H, ArH), 7.32 (d,J=2.3 Hz, 1H, ArH), 7.29 (d,J=8.7 Hz, 2H, ArH), 7.02(s,2H, ArH), 6.99 (dd,J=9.0,2.4 Hz, 1H, ArH), 6.73 (d,J=8.7 Hz, 1H, ArH), 4.06 (q,J=7.1 Hz, 2H, CH2), 3.91 (q,J=7.0, 4H, CH2), 3.89 (s,3H, --OCH3), 3.74 (s,3H, --OCH3), 1.34 (t,J=7.0 Hz, 6H, CH3), 1.28 (t,J=7.1 Hz, 3H, CH3 ; 13C-NMR (CDCl3, 90 MHz): δ=193.2 , 159.8, 157.7, 152.5, 143.6, 142.6, 140.0, 133.9, 132.3, 130.3, 130.1, 126.0, 124.2, 114.8, 114.0, 108.9, 104.4, 68.8, 64.6, 55.6, 55.2, 15.4, 14.7. HRMS (EI) M+ calcd for C29H30O6S 506.1763, found 506.1777. Anal. Calcd for C29H30O6S: C, 68.75; H, 5.97; S, 6.33. Found: C, 68.67; H, 5.97; S, 6.27.
Reaction SMILES: S(=O)(=O)(O)O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:17]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:39]([F:69])([F:68])[CH:40]([OH:67])[CH:41]([NH:49][C:50](=[O:66])[C@H:51]([CH:63]([CH3:65])[CH3:64])[NH:52][C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)[CH:36]([CH3:38])[CH3:37])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C(O)(=O)C>[C:17]([NH:27][C@H:28]([C:32]([NH:34][CH:35]([C:39]([F:68])([F:69])[C:40](=[O:67])[CH:41]([NH:49][C:50](=[O:66])[C@H:51]([CH:63]([CH3:65])[CH3:64])[NH:52][C:53]([O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:54])[CH2:42][CH:43]1[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1)[CH:36]([CH3:38])[CH3:37])=[O:33])[CH:29]([CH3:31])[CH3:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: CC(C)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)C(NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(F)(F)C(=O)C(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A solution of oxidant was prepared as follows: to 392 mg of sulfuric acid was added 5 ml of acetic acid and 298 mg of sodium dichromate. To a solution of 150 mg of the resultant compound of Example 182 in 10 ml of acetic acid was added 2 ml of the oxidant. After stirring at ambient temperature for 1 hr, the acetic acid was removed under vacuum and the residue was dissolved in 50 ml of ethyl acetate and washed with 30 ml of water. The aqueous layer was extracted with ethyl acetate (2×40 ml) and the combined ethyl acetate solution was dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (10% EtOAc/CH2Cl2) to give 120 mg of the desired compound (80%). Mass spectrum: (M+H)+ =743. 1H NMR (CDCl3): d 0.85-0.98 (m, 18H), 3.90-4.02 (m, 2H), 460 (m, 1H), 5.35 (br d, 1H), 6.10 (br d, 1H), 6.20 (br d, 1H), 7.35 (m, 10H).
Reaction SMILES: [CH3:1][S:2][CH2:3]Cl.[CH3:5][C:6]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[C:34]([OH:38])[CH:35]=[N:36][CH:37]=2)=[CH:28][CH:27]=1)([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:12][N:11]=1)[CH:7]([CH3:9])[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].OS([O-])(=O)=O.[Na+]>CN(C=O)C>[CH3:5][C:6]([C:10]1[N:11]=[CH:12][C:13]([C:16]2[N:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:14][CH:15]=1)([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:37]=[N:36][CH:35]=[C:34]([O:38][CH2:3][S:2][CH3:1])[CH:33]=2)=[CH:30][CH:31]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CSCCl
Reactant: CC(C)C(C)(c1ccc(-c2cncc(O)c2)cc1)c1ccc(-c2ccc(C(F)(F)F)nn2)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSCOc1cncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(F)(F)F)nn4)cn3)C(C)C)cc2)c1
Temperature: 40 °C

Procedure:
Chloromethyl methyl sulfide (12.0 μL, 0.140 mmol) was added to a stirred suspension of 6a (42.0 mg, 0.0910 mmol) and cesium carbonate (46.0 mg, 0.140 mmol) in DMF (2.00 mL) at rt, and the resulting mixture was heated at 40° C. for approximately 2 h. The reaction mixture was cooled to rt, and second portions of cesium carbonate (46.0 mg, 0.140 mmol) and chloromethyl methyl sulfide (12.0 μL, 0.140 mmol) were added. The resulting mixture was heated at 40° C. for about another 3 h. After cooling to rt, the reaction mixture was poured into 10% aqueous sodium hydrosulfate and extracted three times with diethyl ether. The combined organic extracts were washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 20%-50% EtOAc/hexanes as eluent) afforded the title compound 6b. m/z (ES) 525 (MH)+ 1HNMR (500 MHz, CDCl3): δ 9.28 (d, 1H, J=2.1 Hz), 8.51 (br, 1H), 8.45 (dd, 1H, J=2.4, 8.3 Hz), 8.32 (br, 1H), 8.07 (d, 1H, J=8.9 Hz), 7.92 (d, 1H, J=9.0 Hz), 7.55 (m, 6H), 5.25 (s, 2H), 3.21 (m, 1H), 2.28 (s, 3H), 1.81 (s, 3H), 0.93 (d, 3H, J=6.4 Hz), 0.89 (d, 3H, J=6.6 Hz).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:9]#[N:10])([O-:5])=[O:4].[CH3:29]N(C=O)C>O>[CH3:29][N:14]([C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1)[C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CN(C)C=O
Reactant: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C#N)cc3[N+](=O)[O-])ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (60%, 6.44 mmol) is added portionwise to a solution of 3-nitro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylamino)benzonitrile (30, R4=CH3, 4.29 mmol) in DMF (15 mL) at 0° C. The reaction mixture is slowly warmed up to room temperature and stirred for 1 h. To the mixture is added dropwise Mel (6.44 mmol) and the reaction mixture is stirred at room temperature for 5 h. The mixture is diluted with H2O and extracted with Et2O. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane to give (31) (R4=CH3).
Reaction SMILES: [CH3:1][CH:2]([CH2:24][CH3:25])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]([CH3:23])[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:6][CH2:5]1.NN.O.[CH3:29][CH2:30][CH2:31]CCC.CCOC(C)=O>CCO>[CH3:1][C:2]1[C:24]([CH3:25])=[CH:31][CH:30]=[CH:29][C:3]=1[N:4]1[CH2:5][CH2:6][N:7]([CH:10]([CH3:23])[CH2:11][NH2:12])[CH2:8][CH2:9]1
Reactant: CCC(C)CN1CCN(C(C)CN2C(=O)c3ccccc3C2=O)CC1
Reactant: CCCCCC
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(C(C)CN)CC2)c1C
Temperature: 70 °C
Yield: 44.7 %

Procedure:
2-{2-[4-(2,3-dimethylpropyl)piperazin-1-yl]propyl}isoindole-1,3-dione (3.0 g, 7.95 mmol) prepared in Reference 2 was dissolved in 50 ml EtOH, then H2NNH2.H2O (1.54 ml, 31.80 mmol) was added and stirred at about 70° C. The reaction progress and completion were confirmed using TLC (hexane: EtOAc=1:1). Upon completion of the reaction, while the temperature was kept at room temperature, the resulting solution was filtered to remove insolubles. The solvent was removed by distilling it under reduced pressure, followed by adding water and extracting the aqueous layer with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the title compound.