Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][N:19]=2)=[N:16][N:15]=[C:14]1/[CH:28]=[CH:29]/[C:30]([NH:32][NH:33][C:34]([C:36]1[CH:41]=[CH:40][N:39]=[C:38]([O:42][CH3:43])[CH:37]=1)=O)=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N:13]1[C:14](/[CH:28]=[CH:29]/[C:30]2[O:31][C:34]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([O:42][CH3:43])[CH:37]=3)=[N:33][N:32]=2)=[N:15][N:16]=[C:17]1[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][N:19]=1
Reactant: COc1cc(C(=O)NNC(=O)/C=C/c2nnc(-c3ccc(S(C)(=O)=O)cn3)n2-c2ccc(OC(F)(F)F)cc2Cl)ccn1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cn4)n3-c3ccc(OC(F)(F)F)cc3Cl)o2)ccn1
Reaction time: 2 h

Procedure:
N′-[(E)-3-[4-(2-chloro-4-trifluoromethoxyphenyl)-5-(5-methylsulfonyl-2-pyridyl)-1,2,4-triazol-3-yl]prop-2-enoyl]-2-methoxy-pyridine-4-carbohydrazide was dissolved into dichloromethane (10 mL), and triphenylphosphine (0.19 g, 0.736 mmol), carbon tetrabromide (0.24 g, 0.736 mmol) and triethylamine (0.18 mL, 1.30 mmol) was added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 2-(4-(2-chloro-4-trifluoromethoxyphenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-(methylsulfonyl)pyridine as a yellow solid. Yield: 0.07 g, 30%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O.[OH-].[Na+]>[CH2:16]([S:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cl
Reaction time: 18 h

Procedure:
4Chloro-3-mercapto-5-sulfamylbenzoic acid (0.27 g) is dissolved in water (25 ml) by addition of 1 N sodium hydroxide until pH 8. Benzyl bromide (0.15 ml) is added and the reaction mixture stirred for 18 hours. Addition of 4 N hydrochloric acid until pH 1.5 precipitates a crude material which is collected by filtration, washed with water, and recrystallized from aqueous ethanol to yield 3-benzylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of 241° - 242.5° C.
Reaction SMILES: [C:1]([N:5]([CH2:10][C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)[CH2:6][CH2:7][C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].CCOP(Cl)(OCC)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[C:1]([N:5]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:7]([C:8]#[N:9])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N(CCC#N)C[C@@H](O)c1ccc(Cl)cc1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)N1C[C@H](C#N)[C@H](c2ccc(Cl)cc2)C1
Reaction time: 0.5 h
Yield: 10.7 %

Procedure:
3-{t-Butyl[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-amino}propanenitrile (5 g, 17.80 mmol) prepared according to the process described in WO 2004/09126 was dissolved in THF (27 mL). The reaction mixture was cooled to −20° C. or less, to which was added chlorodiethylphosphate (2.69 ml, 18.70 mmol). The reaction temperature was maintained at 12˜18° C., during which 1M LHMDS (37.4 ml, 37.38 mmol) was added dropwise over 2 hours. After the reaction was completed, water (45 mL) was added while the temperature was maintained at 15° C. or less. The resulting mixture was stirred for 30 minutes and extracted with EtOAc. Thus extracted organic solution was concentrated in vacuo and purified by column chromatography (eluent: EtOAc/Hex=1/3) to give the title compound (0.5 g, 10.69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1C=O.[C:29]([O:35][CH2:36][CH3:37])(=[O:34])[CH2:30][C:31]([CH3:33])=O.[OH-].[Na+].[C:40](O)(=O)C>O>[CH2:36]([O:35][C:29]([C:30]1[C:31]([CH3:33])=[N:1][C:2]2[C:7]([CH:40]=1)=[CH:6][CH:5]=[C:4]([NH:10][C:11]([C:13]1[C:14]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=3)=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:12])[CH:3]=2)=[O:34])[CH3:37]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2nc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4′-Trifluoromethyl-biphenyl-2-carboxylic acid (3-amino-4-formyl-phenyl)-amide (769 mg, 2.0 mmol) and ethyl acetoacetate (260 mg, 2.0 mmol) were dissolved in 10 ml of acetic acid and heated at 80 C. After 2.5 h, the mixture was cooled to room temperature, diluted with water and brought to pH 10 with 2N NaOH. The mixture was extracted with ethyl acetate (2×50 ml), the combined organic layers washed with brine, dried over magnesium sulfate, and concentrated to give 815 mg of a yellow solid. This material was purified by chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane to provide 349 mg (36%) of the title compound as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([Cl:22])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:6]1=[O:16].N1C=CC=CC=1.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>O>[F:34][C:33]([F:36])([F:35])[S:30]([O:21][C:19]1[CH:18]=[C:17]([Cl:22])[C:3]([CH2:4][CH:5]2[CH2:9][CH2:8][N:7]([CH:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)[C:6]2=[O:16])=[C:2]([Cl:1])[CH:20]=1)(=[O:31])=[O:29]
Reactant: O=C1C(Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
Charge a flask with 3-(2,6-dichloro-4-hydroxybenzyl)-1-cyclohexylpyrrolidin-2-one (Example 175) (7.5 g, 22 mmol) dissolve with pyridine (200 mL) and cool to 0° C. under nitrogen. Add Tf2O (10 mL, 26 mmol) slowly and warm to room temperature. Stir at room temperature for 30 minutes. Pour into water (1 L) and extract with ether. Wash ether layer twice with water. Dry over sodium sulfate, filter and concentrate. Purify over silica gel (10% ethyl acetate in hexanes) to yield 8.5 g (82%) of the title compound as a white solid. Mass spectrum (apci) rn/z=474.1 (M+H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](B(O)O)[CH:6]=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([CH3:34])[C:25]=1OS(C(F)(F)F)(=O)=O)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:25]2[C:24]([CH3:34])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[CH3:15])[CH:6]=1
Reactant: COC(=O)c1cc(C)c(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: COCOc1ccc(C)c(B(O)O)c1
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: CO
Product: COC(=O)c1cc(C)c(-c2cc(O)ccc2C)c(C)c1

Procedure:
In a manner similar to that of Example 11(d), by reaction of 3.7 g (18.8 mmol) of 4-methoxymethoxy-1-methylbenzene-2-boronic acid (described in Example 16(c)) with 5.3 g (17 mmol) of methyl 3,5-dimethyl-4-trifluoromethanesulphonyloxybenzoate, 17 mL of 2.0M potassium carbonate solution and 1 g (0.82 mmol) of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a yellow oil (m=3.0 g; Y=65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[NH2:42][C:43]1[S:44][CH:45]=[CH:46][N:47]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:42][C:43]2[S:44][CH:45]=[CH:46][N:47]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nccs4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-aminothiazole (15 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (19.0 mg, yield 33.4%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6](OC)[CH:5]=1)=[O:3].S(OC)([O:16][CH3:17])(=O)=O.[C:20](=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:9]([O:10][CH3:20])=[CH:11][C:12]=1[O:16][CH3:17])=[O:3]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(C(C)=O)c(OC)c1
Reaction time: 2 h

Procedure:
10 g of acetovanillone (0.06 mol) was methylated with 10.25 g of dimethyl sulfate (0.083 mol) and 8.0 g of sodium carbonate. The reaction mixture was stirred at 80°-90° C for 2 hr. while 6 ml of water were added dropwise over the last 1.2 hr. Addition of water, acidification, and extraction with benzene produced a nearly quantitative yield of 2,4-dimethoxyacetophenone containing less than 0.3% acetovanillone.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])(=[O:8])[C:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(Nc1ccccc1F)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccccc1F)C1=CNCCC1
Yield: 70 %

Procedure:
Fifty grams of N-nicotinoyl-2-fluoroaniline was dissolved in 700 ml of 10% hydrous ethanol. To the solution, 5 g of 10% palladium-on-carbon was added and the mixture was reduced with hydrogen at room temperature and at atmospheric pressure. When a stoichiometric amount of hydrogen was absorbed, the reaction was stopped and the catalyst was removed. the liquid reaction mixture was concentrated and the resulting crystal was recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-fluoroaniline having a melting point of 137° to 140° C. Yield=70%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][CH:35]=[CH:34]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc4[nH]ccc4c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 100.5 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 5-aminoindole (0.072 g, 0.54 mmol), the title compound (0.184 g, 99%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:30][CH3:31])[C:3]=1[C:32](=[O:34])[NH2:33].Br[CH2:36][C:37](=O)[C:38]([O:40][CH2:41][CH3:42])=[O:39].O>C(O)(=O)C.CN(C)C=O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:4]3[N:5]=[C:6]([S:8][CH3:9])[N:7]4[CH:36]=[C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:1]=[C:2]4[C:3]=3[C:32](=[O:34])[NH2:33])=[C:12]([O:30][CH3:31])[CH:13]=2)[CH2:18][CH2:19]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(=O)CBr
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1nc(SC)nc(N)c1C(N)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c(SC)nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3OC)c(C(N)=O)c2n1
Temperature: 60 °C

Procedure:
A mixture of the product of Example 13D (1 g, 2.0 mmol), ethyl 3-bromo-2-oxopropanoate (796 mg, 4.1 mmol) and acetic acid (2 drops) in dimethylformamide (20 mL) was heated at 60° C. for 16 hours. After cooling to ambient temperature, the mixture was poured into water and extracted with dichloromethane (2×100 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 98/2 dichloromethane/methanol to give the title compound. MS: 586 (M+H+).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:3])[CH3:2].[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][N:27]3[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:31][CH2:32]3)=[CH:21][CH:20]=2)[CH3:18])[N:11]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C=O)cc2)n1
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCC(NC(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
Title compound was prepared as a white solid (32 mg, 59% yield), with procedures similar to those used to prepare Intermediate 128, but utilizing 4-((S)-1-(4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-ylamino)ethyl)benzaldehyde and tert-butyl piperidin-4-ylcarbamate. MS m/z 539.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12](=[O:15])[NH:13]Cl)=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C@@H:43](N)[CH3:44])=[CH:39][CH:38]=1>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:12]([NH:13][C@H:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[CH:38][CH:39]=2)[CH3:44])=[O:15])=[CH:6][CH:5]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CN(C(=O)NCl)c2ccc(C3CCCCC3)cc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN(C(=O)N[C@@H](C)c2ccc(Cl)cc2)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 2 h

Procedure:
A 2 L reaction flask equipped with mechanical stirring was charged with N-chlorocarbamoyl-4-[(4-cyclohexylphenylamino)methyl]benzoic acid methyl ester (94 g, 0.244 mmol), N-methyl-2-pyrrolidinone (1.0 L) and triethylamine (68 mL, 0.487 mol). To the clear solution was added drop wise (S)-1-(4-chlorophenyl)ethylamine (38.0 g, 0.244 mol), keeping the internal reaction temperature below 30° C. Stirring was continued for 2 hours, then the reaction mixture was partitioned between water (1.0 L) and ethyl acetate (1.0 L). After extensive mixing, the organic layer was separated, and washed with a 5% aqueous solution of citric acid (500 mL), and saturated ammonium chloride (500 mL), before drying with anhydrous sodium sulphate. Solvent was removed, and the residual oil was evaporated once from acetonitrile. This product was sufficiently pure for further synthesis. Yield: 103 g (84%).
Reaction SMILES: [OH-].[K+].Cl.[C:4]([NH2:12])(=[NH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:12]=[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:11]=1
Reactant: O=C(C=Cc1ccccc1Br)c1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1ccccc1-c1cc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
23 g (409 mmol) of potassium hydroxide are dissolved in 500 ml of ethanol, 40 g (255 mmol) of benzamidine hydrochloride 2 and 129 g (452 mmol) of (3-(bromophenyl)-1-phenyl-2-propen-1-one 1, dissolved in 500 ml of ethanol, are added at room temperature, and the mixture is stirred under reflux for 3 h. After cooling to room temperature, the precipitated solid is filtered off with suction, washed with a little ethanol and dried, leaving 55 g (129 mmol), 50%, of the product in the form of colourless crystals.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.[NH2:12][CH2:13][C@@H:14]([OH:16])[CH3:15].Cl.NCC(N)=O>>[OH:16][C@@H:14]([CH3:15])[CH2:13][NH:12][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: C[C@H](O)CN
Reactant: O=C(O)C1CC12CCCCC2
Agent: Cl
Agent: NCC(N)=O
Product: C[C@H](O)CNC(=O)[C@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 6 for the product from Example 1B and substituting (S)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); MS (CI) m/z 212 (M+H)+.
Reaction SMILES: [C:1]([N:3]=[C:4]([S-:6])[S-:5])#[N:2].[K+].[K+].[OH2:9].[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[OH:9][C:1]1[N:3]=[C:4]([S:6][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:5][N:2]=1
Reactant: O
Reactant: N#CN=C([S-])[S-]
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: CO
Product: Oc1nsc(SCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 194.4 of dipotassium N-cyano-dithioimidocarbonate, 150 ml of water, 1 liter of methanol and 126.7 g of benzyl chloride was stirred at room temperature for 1 hour and after filtering, methanol was evaporated from the filtrate 2.5 liters of water were added again to the residue and then 110 ml of 30% hydrogen peroxide were slowly added. The mixture was stirred for one half hour at 40° C and then 15 hours at 20° C. The mixture was acidified with hydrochloric acid and was vacuum filtered. The precipitate was crystallized from toluene to obtain 80 g of 3-hydroxy-5-benzylthio-1,2,4-thiadiazole melting at 125° C.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[CH3:31][S:32][CH2:33]CO>CCOCC>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:31][S:32][CH3:33])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: CSCCO
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCSC)C3=O)N1CC1NC12
Product: NC(=O)O
Yield: 72 %

Procedure:
A solution of mitomycin A (100 mg) in 2 ml of 2-(methylthio)ethanol was stirred at room temperature under nitrogen for 45 minutes with 500 mg of a 1.6% solution of KOH in 2-(methylthio)ethanol. The reaction mixture was diluted with ether and decomposed with dry ice. Components in the etherial solution were separated on a silica gel column using ether as a solvent, which elutes the 2-(methylthio)ethanol, followed by a mixture of chloroform and methanol 9:1 or 8:2, which elutes the product. The product was further purified by preparative thin layer chromatography on silica gel with a mixture of chloroform and methanol 9:1. This procedure gave 85 mg (72%) of the title compound, having a melting point of 72°-86° C. (decomposition) and providing the following analysis:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18]C)=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1.O>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([OH:18])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(CSc2ccc(O)cc2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O
Product: COc1cc(CSc2ccc(O)cc2)cc(OC)c1O
Temperature: -78 °C
Yield: 62.8 %

Procedure:
3,4,5-Trimethoxybenzyl 4-hydroxyphenyl thioether (3 g, 9.8 mmol), prepared as described in Example 1, was dissolved in 60 ml of dry methylene chloride, and cooled to -78° C. A solution of borontribromide (2.8 ml, 29.5 mmol) in 10 ml of methylene chloride was added dropwise to the above solution. The mixture was stirred to room temperature, and immediately cooled to 0° C. Water (50 ml) was then added dropwise, and the methylene chloride layer was separated. The crude product, obtained after being dried over magnesium sulfate and concentrated, was purified on silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give 1.8 g (63% yield) of 4-hydroxy-3,5-dimethoxybenzyl 4-hydroxyphenyl thioether as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:23]>N1C=CC=CC=1>[C:1]1([CH:7]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:8]([NH2:9])=[S:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(c1ccccc1)c1cccnn1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)C(c1ccccc1)c1cccnn1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A 1.0 g quantity (0.005 mols) of 2-phenyl-2-(3-pyridazinyl)acetonitrile was dissolved in 50 ml of dry pyridine in a sealed tube, and 4 ml of triethylamine was added. After allowing the resulting solution to stand for 1.5 hours, dry hydrogen sulfide was passed through the solution in a steady stream at room temperature for 15 minutes. The sealed mixture was then left to stand at room temperature for 24 hours. The reaction mixture was concentrated in a vacuum to give a yellow solid cake. Recrystallization of the concentrate from ethanol afforded 1.1 g (94% yield) of 2-phenyl-2-(3-pyridazinyl)thioacetamide in the form of pale yellow plates, m.p. 161° to 163° C.