Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:44])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][S:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[O:44])=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:35]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSc4ccccc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CS(=O)c4ccccc4)cc2)CCO3)cc1
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-(phenylthiomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.1 g) in dichloromethane (30 ml) was added 70% m-chloroperbenzoic acid (0.046 g) at the temperature ranging from −20 to −10° C., and the mixture was stirred for 30 minutes. To the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-(phenylsulfinylmethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 108) (0.11 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)=[O:4].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)#[N:14].[O-2].[Al+3].[O-2].[O-2].[Al+3]>C1C=CC=CC=1>[C:3](=[O:4])([O:2][CH3:1])[O:5][C:6]1[CH:12]=[CH:11][C:9]([N:10]=[CH:19][C:18]2[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)Oc1ccc(N)cc1
Agent: [Al+3]
Agent: [O-2]
Solvent: c1ccccc1
Product: COC(=O)Oc1ccc(N=Cc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 0.835 g. of p-methoxycarbonyloxyaniline and 0.655 g. of p-cyanobenzaldehyde is gassed with argon in 50 ml. of benzene and heated under reflux for 1 hour (bath temperature 130°). The resulting water is separated with a water separator. During an additional hour, benzene condensed in the reflux condenser is now passed back into the reaction vessel through a layer of 20 g. of aluminium oxide (act. I). After cooling, the reaction mixture is freed from solvent in vacuum at 50°C. bath temperature, whereby there remain 1.395 g. of yellowish crystals which are recrystallized several times from isopropanol up to constant melting point and clearing point and up to the disappearance of side-products in the gas chromatogram. The pure, slightly yellowish p-[(p-cyanobenzyliden)amino]phenyl methyl carbonate obtained has a melting point of 145.1°-146.2° and a clearing point of 163.4°. UV (EtOH): ε270 = 20,250, ε324 = 10,800 (shoulders at 243 and 221 nm; minima at 312 and 233 nm).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7](C(OC(C)(C)C)=O)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(=[S:3])[NH2:2].Cl[CH2:24][C:25](=O)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[NH:7][N:6]=[CH:5][C:4]=2[C:1]2[S:3][CH:24]=[C:25]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC(C)(C)OC(=O)n1ncc(C(N)=S)c1-c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1csc(-c2cn[nH]c2-c2ccc(F)cc2)n1
Yield: 68.8 %

Procedure:
A solution of the mixture (415 mg, 1.29 mmol) obtained in step 6 and ethyl 4-chloroacetoacetate (0.192 mL, 1.42 mmol) in EtOH (3.6 mL) was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent gradient; 50→66% ethyl acetate/hexane) to give ethyl {2-[5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetate (294 mg, 69%) was obtained as a colorless oil
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[OH:8][S:9]([OH:12])(=[O:11])=[O:10].[OH:13][OH:14]>>[OH:11][S:9]([OH:12])(=[O:10])=[O:8].[CH3:1][C:2]1([O:13][O:14][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OO
Reactant: CC1(O)CCCC1
Agent: O=S(=O)(O)O
Product: CC1(OOC2(C)CCCC2)CCCC1
Reaction time: 2.5 h

Procedure:
A 250 ml tri-neck round bottom flask was equipped and a 50 ml addition funnel and the flask was cooled <0 C. 30 g of 1-methylcyclopentanol (0.3 M, 1 EQ) was added to the flask. 70% H2SO4 solution was prepared and cooled in an ice bath. The H2SO4 (12.71 ml, 0.91 M, 3 EQ) was added drop wise over 15 minutes and the reaction mixture was stirred for ˜2.5 hours in order to allow all the 1-methylcyclopentanol to dissolve. With the reaction stirring, 8.11 ml of H2O2 35% (wt) (0.24 M, 0.8 EQ) was added drop wise over 15 minutes. The reaction was left stirring overnight. The reaction mixture was transferred to a separation funnel and extracted three times with 50 ml of pentane each time. Organic layers were collected and the aqueous was set aside. The organic layers were extracted 3 times with 50 ml of 1N NaOH each time to remove excess acid. The organic layer was collected, dried and concentrated. The residue was purified by chromatography on a silica column using pentane as the mobile phase. The product fractions were concentrated to yield 973 mg of di(1-methyl-cyclopentyl)peroxide as a colorless oil. 13C-NMR (CDCl3) δ 24.43, 24.75, 37.13, 89.23
Reaction SMILES: [C:1]([CH:3]1[C:7](=O)[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].Cl.[NH2:17][NH2:18].C(=O)([O-])O.[Na+]>C(O)C>[NH2:2][C:1]1[NH:18][N:17]=[C:7]2[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:3]=12
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1 g (4.76 mmol) of tert-butyl 3-cyano-4-oxopyrrolidine-1 carboxylate in ethanol (28 mL) was added 0.326 g (4.76 mmol) of hydrazine hydrochloride and the reaction mixture heated at ° C. for 3 h. The mixture was cooled to 0° C. and saturated aqueous sodium hydrogen carbonate (60 mL) added. The solvent was evaporated in vacuo and the aqueous phase extracted with ethyl acetate (10×10 mL). The combined organic fractions were dried (anhydrous sodium sulfate), filtered and the solvent evaporated in vacuo. The resulting residue was chromatographed on a Biotage Horizon® system (silica gel, 0 to 10% methanol/ethyl acetate gradient) to yield the title compound as a orange solid. LC/MS 225.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH2:21]([O:20][C:14](/[CH:15]=[CH:1]/[C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:13])[CH:4]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]c(C=O)cc1C
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C=C/c1cc(C)c(C(=O)OCC)[nH]1
Temperature: 100 °C
Reaction time: 38 h
Yield: 47.7 %

Procedure:
Ethyl 5-formyl-3-methyl-1H-pyrrole-2-carboxylate 470 mg, monoethyl malonate 378 mg, piperidine 0.05 mL and pyridine 6 mL were mixed and stirred at 100° C. for 38 hours. Ice water was added to the reaction liquid and the precipitate was recovered by filtration. The precipitate was washed with water and dried in flowing air under heating to provide 311 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:33]N>CO>[Cl:1][C:2]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=2)[CH:23]=[CH:22][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:33]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: NN
Reactant: CN(C)C=C1CC(N2CCC(Cc3ccc(-c4cnn(C)c4)cc3Cl)C2=O)CCC1=O
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccc(CC3CCN(C4CCc5n[nH]cc5C4)C3=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Dissolve 3-[2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one (Preparation 30) (0.327 g, 0.745 mmol) in methanol (3.0 mL), and hydrazine hydrate (0.038 mL) stir the resulting orange solution for 17 hours at room temperature. Filter the mixture, rinse with cold methanol and vacuum dry to 0.138 g of a solid. MS (m/z): 410 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[N:31][C:32]([CH3:38])=[N:33]2)(=O)=O>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][O:27][C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[N:31][C:32]([CH3:38])=[N:33]5)[CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19]
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Product: Cc1ncc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similar manner to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (23 mg, 0.059 mmol), 2-aminothiazole (18 mg, 0.18 mmol), and diisopropylethylamine (0.03 mL, 0.18 mmol) in anhydrous DMF (0.3 mL) was added HATU (68 mg, 0.18 mmol) under argon. The reaction mixture was stirred at rt for 5 min and at 80° C. for 5 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 110, 6 mg, 0.013 mmol, 22% yield) as a pink solid. MS found: (M+H)+=470. 1H-NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s) 7.32-7.43 (5H, m) 7.33 (1H, d, J=8.65 Hz) 7.22-7.28 (3H, m) 7.14-7.20 (4H, m) 6.94 (1H, d, J=3.56 Hz) 6.60 (1H, d, J=3.05 Hz) 4.59 (1H, s) 1.46 (6H, d, J=2.54 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[C:7]2[C:8](=[O:10])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccn1
Reactant: O=C(O)c1c(F)cccc1S
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cccc(F)c12
Temperature: 135 °C
Yield: 1.5 %

Procedure:
A mixture of 6-fluoro-2-mercaptobenzoic acid (5.00 g, 29.0 mmol), 2-cyanopyridine (3.05 g, 29.3 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 48 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.11 g, 1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:17])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc(Br)c1
Temperature: 80 °C

Procedure:
Step H1. A mixture of 3,5-dibromo-toluene (4.25 g, 17 mmol), NBS (3 g, 17 mmol), and AIBN (150 mg) in carbon tetrachloride (50 mL) was heated at 80° C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1,3-dibromo-5-(bromomethyl)benzene was obtained as a white residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.S(=O)(O)[O-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: Nc1ccc(O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Nc2ccc3cc(Br)ccc3c2)cc1
Yield: 70 %

Procedure:
A mixture of 334 mg (1.50 mmol, Aldrich) of 6-bromo-2-naphthol, 218 mg (2.00 mmol, Aldrich) of 4-aminophenol, and 1.0 g of sodium bisulfite in 5 ml of H2O was heated to 150° in a closed Pyrex tube for 76 hours. The reaction was cooled, added to 25 ml of H2O and extracted with 25 ml of ethyl acetate. The organic extract was dried (MgSO4) and concentrated in vacuo to give a solid. The crude solid was purified by flash chromatography (10×5.0 cm, 1: EtOAc/petroleum ether) followed by recrystallization (EtOAc/petroleum ether) to afford 330 mg (70%) of title compound as small grey-white crystals, m.p. 179°-180°.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH3:52])[CH2:46][C@H:47]1[CH2:51][CH2:50][CH2:49][O:48]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH3:52])[CH2:46][C@H:47]2[CH2:51][CH2:50][CH2:49][O:48]2)=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@H]2CCCO2)c(F)c1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 40.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-[(R)-tetrahydrofuran-2-ylmethyl]acetamide (10 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.5 mg) was obtained.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[S-:35][C:36]#[N:37].[K+]>CS(C)=O>[CH3:32][Si:31]([CH3:33])([CH3:34])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:9][CH2:8][C@H:7]([CH2:6][S:35][C:36]#[N:37])[CH2:12][CH2:11]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: N#C[S-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Agent: [K+]
Solvent: CS(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSC#N)CC4)c3)ncnc21
Temperature: 68 °C

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (0.10 g, 0.00020 mol) was dissolved in DMSO (1.00 mL) with potassium thiocyanate (0.082 g, 0.00084 mol). The reaction was heated at 68° C. for 4 days at which time LCMS analysis showed ˜4:1 product/starting material ratio. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using 1:1 EtOAc/hexanes to give the product. LC/MS (M+H)+: 469, 1H NMR (CDCl3): δ 8.89 (s, 1H), 8.36 (s, 1H), 8.31 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (m, 1H), 3.60 (m, 2H), 3.05 (m, 2H), 2.37 (m, 2H), 2.10 (m, 4H), 1.70-1.93 (m, 3H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C-:35]#[N:36].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:35]#[N:36])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [C-]#N
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1ccc(CN(CCCCCCC#N)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 86.8 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1[6-[(methylsulfonyl)oxy]hexyl]urea, 0.5 g of sodium cyanide, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-70° C. for 16 hours. The mixture was poured into water and extracted with dichloromethane. The procedure of Example 518 was continued and gave 1.5 g (88% yield) of the desired product as a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])=[CH:4][CH:3]=1.[H][H]>CO.[C].[Pd]>[C:5]1([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH3:14])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CC1CNCCN1c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CO
Product: CC1CNCCN1c1ccccc1
Yield: 100 %

Procedure:
1-(4-chlorophenyl)-2-methylpiperazine (300 mg, 1.4 mmol) was dissolved in methanol (3 ml), and the resulting solution was mixed with palladium carbon (150 mg) and stirred at a room temperature for 21 hours in an atmosphere of hydrogen. The reaction solution was filtered, and the thus obtained residue was thoroughly washed with ethanol. The washed solution and filtrate were combined, and the solvent was evaporated therefrom under a reduced pressure to obtain 260 mg of the title compound (1.4 mmol, 100% in yield).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][S:9][S:10][CH2:11][CH2:12][NH:13]C(=O)OC(C)(C)C)=[O:5]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:13][CH2:12][CH2:11][S:10][S:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=1[OH:1]
Reactant: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1ccccc1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCSSCCNC(=O)c1ccccc1O
Reaction time: 3 h

Procedure:
tert-Butyl 2-(2-(2-(2-hydroxybenzamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 1.08 mmol) was taken up in 25% TFA in CH2Cl2 (10 mL) and allowed to stand at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford a quantitative yield of N-(2-(2-(2-aminoethyl)-disulfanyl)-ethyl)-2-hydroxybenzamide as the TFA salt.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:25])[C:4]2[C:9]([C:10](=[O:24])[C:11]=1[CH2:12][CH2:13][CH:14]([CH3:23])[CH2:15][CH:16](C(O)=O)[C:17]([OH:19])=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2>C(Cl)(Cl)Cl.C(O)C>[CH3:1][C:2]1[C:3](=[O:25])[C:4]2[C:9]([C:10](=[O:24])[C:11]=1[CH2:12][CH2:13][CH:14]([CH3:23])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC1=C(CCC(C)CC(C(=O)O)C(=O)O)C(=O)c2ccccc2C1=O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC1=C(CCC(C)CCC(=O)O)C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
4.3 Parts of 2,3,5-trimethyl-6-(5',5'-dicarboxy-3'-methylpentyl)-1,4-benzoquinone (Formula (IV) wherein R=H3C; Z=H) obtained in Reference Example 1 is heated at 140°C for 1 hour. It is then subjected to thin-layer chromatography with chloroform-ethanol (19:1) as the developer and recrystallized from ligroine. Th described procedure gives 2.97 parts of 2,3,5-trimethyl-6-(5'-carboxy-3'-methylpentyl)-1,4-benzoquinone (Formula (I) wherein R=H3C; Z=H) as yellowish needles. melting point 58°C-61°C.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]2[CH2:16][CH2:15][CH:14]([O:17][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOC1CCC(C2CCC(O)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC1CCC(C2CCC(OS(C)(=O)=O)CC2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4′-propoxybicyclohexyl-4-ol (1 g) and triethylamine (0.81 ml) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (0.39 ml) at 0-5° C., and stirred for 3 hours. The reaction mixture was washed with water and brine, and dried, and evaporated under reduced pressure to give 4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.44 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16](OCC)=[O:17])[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:16](=[O:17])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21]
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CN
Product: CNC(=O)C(C)c1ccc(O)c(O)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 2 g of ethyl 3,4-diacetoxyphenylpropionate and 2.1 g of a 40% aqueous methylamine solution was heated to 150° C. with stirring for 2 hours in an autoclave. After cooling, the reaction mixture was acidified, extracted three times with 25 ml of ethyl acetate and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography using silica gel. A solvent mixture of chloroform:methanol=20:1 was used as eluent. Pure N-methyl-3,4-dihydroxyphenylpropionamide thus obtained was 0.35 g.