Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=1.[K+].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH-:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>CS(C)=O.O>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=2)(=[O:31])=[O:32])=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Reactant: CC(C)(C)c1ccc(S([NH-])(=O)=O)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 1.0 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 20 ml of DMSO was added 1.76 g of 4-tert.-butyl-benzene sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 250 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and cooled to 0° C. The precipitated product was filtered off and dried in vacuo to give 1.05 g of 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide as a pale beige powder. LC-MS: tR=5.64 min, [M+1]+=462.51, [M−1]−=460.63.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:22])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[N:26]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:12][C:11](=[O:22])[C:2]([CH3:1])=[C:3]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1F
Reactant: Cc1cccc(C(=O)CC(=O)C(C)C(=O)c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cccc(-c2cc(=O)c(C)c(-c3ccccc3)n2-c2ccccc2F)c1
Yield: 51.7 %

Procedure:
To 30 ml of xylene were added 2.0 g (0.0068 mole) of 2-methyl-5-(3-methylphenyl)-1-phenyl-1,3,5-pentanetrione, 7.6 g (0.068 mole) of 2-fluoroaniline, 2.0 g (0.012 mole) of para-toluenesulfonic acid and 14.0 g of Molecular Sieves 5A, followed by refluxing the resulting mixture for 1 hour. After cooling the reaction mixture, solid matter was filtered off and the filtrate was mixed with 100 ml of chloroform and then washed successively with 50 ml of 10% hydrochloric acid, 50 ml of a 10% aqueous solution of sodium hyroxide and water. The filtrate was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was crystallized from a 1:3 mixed solvent of chloroform and hexane to give 1.3 g of 1-(2-fluorophenyl)-3-methyl-6-(3-methylphenyl)-2-phenyl-4-(1H)-pyridinone having a melting point of 211°-214° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH2:4][CH2:3]1.Cl/[C:7](=[N:13]\[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:11]([O:10][C:8]([C:7]1[CH2:1][C:2]2([CH2:5][CH2:4][CH2:3]2)[O:14][N:13]=1)=[O:9])[CH3:12]
Reactant: C=C1CCC1
Reactant: CCOC(=O)/C(Cl)=N/O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC2(CCC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methylenecyclobutane (2 mL, 21.6 mmol) in ethyl acetate (125 mL) was added (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (6.55 g, 43.2 mmol) and solid sodium bicarbonate (16.3 g, 194 mmol). The reaction mixture was sealed and stirred at room temperature for 6 hours. More (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (4 g, 26.4 mmol) and sodium bicarbonate (8 g, 95.2 mmol) were added and the reaction was stirred at room temperature for an additional 12 hours. The reaction was diluted with ethyl acetate and washed successively with water and brine, dried (MgSO4) and concentrated to yield crude 5-oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester, contaminated with (Z)-Ethyl 2-chloro-2-(hydroxyimino)acetate and related compounds.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
Combine 4-hydroxy-benzaldehyde (1 equiv), 6-chloro-nicotinonitrile (1 equiv), and potassium carbonate (1.5 equiv) in dimethylformamide (0.1 M) and warm to 130° C. with stirring. After 3 h, cool to ambient temperature, dilute reaction mixture with water and extract with ethyl acetate (3×). Wash combined organic extracts with water and brine successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes:ethyl acetate 6:4) to provide the title compound as a white solid.
Reaction SMILES: [N+](=[CH:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5])=[N-].[ClH:11].CCOCC>C(O)C>[Cl:11][CH2:3][C:4]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)=[O:5]
Reactant: [N-]=[N+]=CC(=O)c1cscn1
Reactant: Cl
Solvent: CCOCC
Solvent: CCO
Product: O=C(CCl)c1cscn1

Procedure:
4-Thiazolyl diazomethyl ketone, 0.1 g, is treated in 1 ml ethanol at 0° with HCl gas for a few seconds. Dilution with ether and scratching produces a copious white ppt which is filtered and washed 3× with ether, taken up in water, the pH made to 7 with K2HPO4, and extracted 3× with ether. The ether solution is dried with MgSO4, filtered and evaporated, affording 77 mg 4-thiazolyl chloromethyl ketone. IR (CHCl3) 5.85μ. NMR (δ, CDCl3): 4.95d, J=1, CH2Cl; 8.4m, 8.95m, J=1, H-2 and H-5.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].Cl.[CH3:16][NH:17][O:18][CH3:19].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:4]=1
Reactant: Cc1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.63 g of 4-methyl-3-sulfamoyl-benzoic acid, 1.92 g of N,O-dimethylhydroxylaminehydrochloride, and 5.02 mL of triethylamine in methylene chloride (120 mL) is treated with 8.32 g of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate. The reaction mixture is stirred overnight at room temperature, washed sequentially with saturated aqueous sodium bicarbonate, water and a saturated sodium chloride solution, dried (magnesium sulfate) and concentrated in vacuo. The crude material is purified by silica gel chromatography (1:2 hexanes/ethyl acetate) to give N-methoxy-4,N-dimethyl-3-sulfamoyl-benzamide as a white powder. MS (m/z): 257 (M−1); Rf 0.25 (1:2 hexanes/ethyl acetate).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:1][CH:2]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:3](=[O:4])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:36]
Reactant: COC(=O)CCCCCCC(=O)Cl
Reactant: COc1ccc(C(O)C(=O)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)OC(C(=O)c1ccccc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 2-hydroxy-2-(4-methoxyphenyl)-1-phenyl-ethanone (8.2 g, 0.034 mol) prepared in Step 3 and triethylamine (5.21 g, 0.051 mol) in methylene chloride (100 mL) was slowly added a solution of 7-chlorocarbonylheptanoic acid methyl ester (5.64 g, 0.034 mol) in methylene chloride (20 mL). A final reaction solution was stirred at room temperature for 12 hours and then diluted with 200 mL of methylene chloride. The obtained organic layer was washed twice with 100 mL of a saturated sodium bicarbonate solution and then successively washed twice with 100 mL of a brine solution. The obtained organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, to give 12.90 g (yield: 92%) of octanedioic acid 1-(4-methoxyphenyl)-2-oxo-2-phenylethyl ester methyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[NH:9][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[C:11]([CH3:13])[N:12]=2)[CH:7]=1.[H][H]>[Pd].C(N(CC)CC)C.CO>[CH3:13][C:11]1[N:12]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([NH:22][CH3:23])=[CH:4][C:5]=2[O:20][CH3:21])[NH:9][C:10]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: [H][H]
Reactant: CNc1cc(OC)c(-c2nc(C)c(-c3cccnc3)[nH]2)cc1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1ccc(-c2nc(C)c(-c3cccnc3)[nH]2)c(OC)c1
Yield: 22.3 %

Procedure:
A mixture of 2-(5-Chloro-4-methylamino-2-methoxyphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.50 g) and 10% palladium on carbon (7.5 g) in a mixture of triethylamine (0.64 ml) and methanol (20 ml) was hydrogenated at ambient temperature under atmospheric pressure of hydrogen gas. After removal of the insoluble substance by filtration, the filtrate was evaporated under reduced pressure. The residue was triturated in diisopropyl ether to give 4-methyl-2-(4-methylamino-2-methoxyphenyl)-5-(3-pyridyl)imidazole (0.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[O:15][C@H:10]2[C:11]([NH:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C1(C)C(C)=CC=CC=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[SH:31]>CO>[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31][C@@H:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C@@H:10]([OH:15])[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: Nc1ccccc1S
Solvent: Cc1ccccc1C
Solvent: CO
Product: CNC(=O)[C@H](O)[C@@H](Sc1ccccc1N)c1ccc(OC)cc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
A mixture of (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxy-N-methylpropionamide (829 mg) and xylene (10 ml) is refluxed with heating under nitrogen atmosphere. When the reflux is started, a solution of 2-aminothiophenol (551 mg) and anhydrous ferric chloride (0.065 mg) in methanol (0.08 ml) is added immediately into the reaction mixture, and the mixture is reacted at the same temperature for 5 minutes, and cooled to room temperature. The precipitated crystals are collected by filtration, washed with xylene, and dried at 60° C. to give (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)-N-methylpropionamide (1.06 g).
Reaction SMILES: [Na].[C:2]([O:6][C:7]([C:9]1[C:23]2[CH:22]3[CH2:24][CH:18]([CH2:19][NH:20][CH2:21]3)[C:17]=2[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](Cl)=[N:14]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[CH3:26][OH:27]>>[C:2]([O:6][C:7]([C:9]1[C:23]2[CH:22]3[CH2:24][CH:18]([CH2:19][NH:20][CH2:21]3)[C:17]=2[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([O:27][CH3:26])=[N:14]2)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CO
Reactant: CC(C)(C)OC(=O)c1c2c(cc3nc(Cl)ccc13)C1CNCC2C1
Agent: [Na]
Product: COc1ccc2c(C(=O)OC(C)(C)C)c3c(cc2n1)C1CNCC3C1

Procedure:
Sodium metal (˜12 mg) was dissolved in methanol (1 mL) under nitrogen with stirring and treated with a solution of 6-chloro-5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaen-10-carboxylic acid tert-butyl ester (118 mg, 0.33 mmol) in methanol (3 mL) and brought to reflux for 18 hours. The mixture was cooled, concentrated, treated with H2O and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution and filtered through a cotton plug then concentrated to an oil (165 mg). (TLC: 5% methanol/CH2Cl2 Rf 0.55).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:22][OH:23]>ClCCl>[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]=[O:23]
Reactant: O=[N+]([O-])c1cccc(CO)c1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.43 g (39.09 mmol) of pyridinium chlorochromate (PCC) were added to a solution of 6.11 g (32.57 mmol) of (2-chloro-3-nitrophenyl)methanol in 120 ml of dichloromethane, and the mixture was stirred at room temperature for 12 hours. After complete conversion, the solvent was evaporated to dryness under reduced pressure. The residue obtained was purified chromatographically on silica gel (mobile phase dichloromethane/methanol 20:1). This gave 4.82 g (25.97 mmol, 79.7% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][NH:32][CH3:33])[CH2:26][CH2:25]1.N1C=CC=CC=1>ClCCl>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[N:24]1[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][N:32]([CH3:33])[S:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:12])=[O:11])[CH2:28][CH2:29]1
Reactant: CNCCN1CCN(c2nc3ccccc3[nH]2)CC1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)N(C)CCN2CCN(c3nc4ccccc4[nH]3)CC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.7 %

Procedure:
A mixture of 2,4-dichloro-5-methylbenzenesulphonyl chloride (81 mg, 0.31 mmol), {2-[4-(1H-Benzimidazol-2-yl)-piperazin-1-yl]-ethyl}-methyl-amine hydrochloride salt (D23) (80 mg, 0.31 mmol) and pyridine (0.5 ml) in dry dichloromethane (5 ml) was stirred at room temperature for 17 h. The mixture was then diluted with dichloromethane (30 ml), washed with aqueous sodium bicarbonate (1×10 ml) and dried.(MgSO4). The solvent was evaporated and the residue was co-evaporated with toluene (5 ml). Column chromatography of the residue (eluting with methanol-dichloromethane gradient) gave the product as a yellowish solid (25 mg, 17%); MS: m/z (MH+)=482.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:9]1[NH:13][CH:12]=[C:11]([C:14]([O:16]CC)=O)[C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=2[F:39])=[O:27])=[CH:21][CH:20]=1)(=[O:8])[NH2:7]>>[F:39][C:30]1[CH:31]=[CH:32][C:33]([C:35]([F:36])([F:37])[F:38])=[CH:34][C:29]=1[NH:28][C:26](=[O:27])[NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:10]2[C:11]([C:14]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:16])=[CH:12][NH:13][C:9]=2[C:6]([NH2:7])=[O:8])=[CH:24][CH:23]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Product: NC(=O)c1[nH]cc(C(=O)N2CCCC2)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1

Procedure:
The process is performed in a manner similar to that described in Example 39 but starting with pyrrolidine and ethyl 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-3-carboxylate. After a similar work-up, 3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-4-(pyrrolidine-1-carbonyl)-1H-pyrrole-2-carboxamide is obtained; ES+: m/z=504 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]2[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=2[CH3:18])=[CH:9][CH:10]=1)=[O:4].[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:3]([C:5]2[N:6]=[N:7][C:8]([O:11][CH2:12][C:13]3[C:14]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:15][O:16][C:17]=3[CH3:18])=[CH:9][CH:10]=2)=[O:4])[CH2:25][CH2:26]1
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 74 %

Procedure:
As described for example 1e, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (100 mg, 74%) which was obtained as a colourless oil after purification by chromatography (silica, 0 to 5% methanol in dichloromethane). MS: m/e=375.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9]([O:18][C:19](=[O:29])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:10]3[C:15](=[C:16]([OH:17])[C:6]=2[CH:5]=1)[CH:14]=[CH:13][CH:12]=[CH:11]3)(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:4]1[O:8][C:7]2[C:9]([O:18][C:19](=[O:29])[CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:10]3[C:15](=[C:16]([O:17][C:30](=[O:32])[CH3:31])[C:6]=2[CH:5]=1)[CH:14]=[CH:13][CH:12]=[CH:11]3)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(O)c3ccccc3c(OC(=O)CNC(=O)OC(C)(C)C)c2o1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c2ccccc2c(OC(=O)CNC(=O)OC(C)(C)C)c2oc(C(C)=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
In an 100 ml round-bottom flask, 0.8 gram (2.0 mmoles) of 2-acetyl-4-hydroxy-9-[(tert-butoxycarbonyl)amino]acetoxy-naphtho[2,3-b]furan (prepared in example 12) was dissolved in 30 ml of DMF with mild heating. To the solution, added 0.9 ml of TEA and 0.5 ml of acetic anhydride. The mixture was sealed or isolated from air, and then had been stirred vigorously at room temperature overnight. After addition of 100 ml of ethyl acetate, the reaction mixture was extracted with 80 ml of ice-cooled aqueous 3% citric acid solution twice, and dried with anhydrous sodium sulfate. The organic phase was evaporated to dryness. Product was purified by silica gel chromatograph using dichloromethane as elution solvent. 0.6 gram (1.36 mmole) of product was obtained with yield of 68.0% and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.44 (s, 9H), 2.62 (s, 3H), 2.63 (s, 3H), 4.34 (d, J=6, 2H), 7.67-7.71 (m, 3H), 8.15-8.17 (m, 2H), 8.25 (s, 1H). Mass (M+H) is 442, Mass [M-(tert-butyl)+2H] is 386.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[OH:35][C:36]1([C@@H:42]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:55])[F:54])[CH:47]=2)[C:43]([OH:45])=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.[CH3:57][C@H:58]1[CH2:63][NH:62][CH2:61][C@@H:60]([CH3:64])[NH:59]1>C(Cl)Cl>[CH3:57][CH:58]1[NH:59][CH:60]([CH3:64])[CH2:61][N:62]([C:43](=[O:45])[C@@H:42]([C:36]2([OH:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][C:53]([F:56])([F:54])[F:55])[CH:47]=2)[CH2:63]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(O)[C@H](c1cccc(OC(F)(F)F)c1)C1(O)CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)[C@H](c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC(C)N1
Reaction time: 18 h
Yield: 93.2 %

Procedure:
In one experiment, (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (41.73 g, 94.35 mmol) and triethylamine (88 mL, 630 mmol) were added to a mixture of (R)-2-(1-hydroxycyclohexyl)-2-(3-(trifluoromethoxy)phenyl)acetic acid (20.0 g, 62.9 mmol) and cis-2,6-dimethylpiperazine (7.17 g, 62.9 mmol) in methylene chloride (150 mL) at RT. After stirring for 18 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (50 to 100% ethyl acetate in heptane) to afford 1-(3,5-Dimethyl-piperazin-1-yl)-2-(R)-(1-hydroxy-cyclohexyl)-2-(3-trifluoromethoxy-phenyl)-ethanone (24.3 g, 93%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:13])[CH:4]=1)[CH3:2].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:12]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([OH:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(C(=O)OC)c(O)c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(O)c(C(=O)OC)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.5 %

Procedure:
To a solution of methyl 4-ethyl-2-hydroxybenzoate (1.43 g) in acetic acid (15.0 mL) was added bromine (1.40 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr under argon atmosphere. To the reaction mixture was added water, the resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (2.21 g) as a mixture with methyl 3,5-dibromo-4-ethyl-2-hydroxybenzoate (2:1). This compound was used in the next step without an additional purification.
Reaction SMILES: [C:1]([CH:3]([C:5]1[C:14]([CH3:15])=[CH:13][C:12]2[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[C:14]([CH3:15])=[CH:13][C:12]3[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:19])([CH3:18])[C:7]=3[CH:6]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#CC(O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Product: CC(=O)Oc1ccc(C#CC(O)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Yield: 24.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.28 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenemethanol with 1.44 g (5,5 mmol) of 4-iodophenyl acetate, 480 mg (25%) of the expected compound, with a melting point of 129°-130° C., were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[S:8][C:7]=1[NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:22]=1)=O)C.O.[NH2:35][NH2:36]>C(O)C>[CH2:31]([N:28]([CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:7]1[S:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:10]([CH3:11])[C:6]=1[C:4]([NH:35][NH2:36])=[O:3])=[O:33])[CH2:29][CH3:30])[CH3:32]
Reactant: NN
Reactant: CCOC(=O)c1c(NC(=O)c2cccc(CN(CC)CC)c2)sc(CN2CCCCC2)c1C
Solvent: O
Solvent: CCO
Product: CCN(CC)Cc1cccc(C(=O)Nc2sc(CN3CCCCC3)c(C)c2C(=O)NN)c1
Reaction time: 12 h

Procedure:
Subsequently, 2-(3-diethylaminomethyl-benzoylamino)-4-methyl-5-piperidin-1-ylmethylthiophene-3-carboxylic acid ethyl ester (79 mg) was dissolved in ethanol (10 ml), hydrazine monohydrate (2 ml) was added dropwise to the solution at room temperature, and a reaction was then allowed to proceed at that temperature for 12 hr. After the completion of the reaction, the reaction system was concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 3-diethylaminomethyl-N-(3-hydrazinocarbonyl-4-methyl-5-piperidin-1-ylmethylthiophen-2-yl)-benzamide as a useful intermediate (30 mg, yield 38%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CS(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][CH:27]=2)=[CH:17][CH:16]=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:26][CH:27]=3)=[CH:19][CH:20]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 47 %

Procedure:
In substantially the same manner as in Working Example 8, 2-methylimidazole was allowed to react with 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[4-[3-(2-methyl-1-imidazolyl)propyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 47%. Recrystallization form ethyl acetate-hexane gave colorless prisms, mp 93-94° C.