Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[NH:27]([CH2:32][CH2:33][C:34]#[N:35])[CH2:28][CH2:29][C:30]#[N:31]>C(Cl)(Cl)Cl>[C:30]([CH2:29][CH2:28][N:27]([CH2:32][CH2:33][C:34]#[N:35])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:31]
Reactant: ClSCl
Reactant: N#CCCNCCC#N
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(SN(CCC#N)CCC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 50 ml of chloroform, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to -5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for one hour. After cooling to -10° to -5° C., 6.2 g (0.05 mole) of iminodipropionitrile was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of chloroform, the reaction mixture was washed with 100 ml of water three times. The chloroform layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of impurities. Yield: 12.2 g (65.2%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([CH2:24][CH2:23][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH:26]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: Nc1cccc(CCN2CCCC2)c1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 74.6 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (197 mg, 0.635 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (120 mg, 0.635 mmol) to afford the desired product (220 mg, 74%) as a yellow solid: ESI MS m/z 464 [C25H26BrN3O+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:19]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Reactant: O=Cc1ccccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(C)(C)Nc1c(-c2ccccn2)nc2sccn12

Procedure:
Compound 5 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:21])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1.C=O.[C:24]([BH3-])#N.[Na+]>>[ClH:1].[ClH:1].[CH3:3][O:4][C:5](=[O:21])[CH2:6][N:7]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[CH3:24]
Reactant: COC(=O)CNC1CCN(Cc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)CN(C)C1CCN(Cc2ccccc2)CC1

Procedure:
Prepared from N-[1-benzyl-4-piperidinyl]glycine methyl ester dihydrochloride, paraformaldehyde and sodium cyanoborohydride.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]2)=[CH:10][CH:9]=1)#[N:7]>CN(C)C=O.O>[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]2[CH2:4][CH3:5])=[CH:10][CH:9]=1)#[N:7]
Reactant: CCI
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(C#N)cc2n1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1 l flask, 23.5 g of ethyl 6-cyanoindole-2-carboxylate was dissolved in 300 ml of dimethylformamide, and 6.6 g of 60% NaH was slowly added thereto at 0° C. 17.6 ml of iodoethane was then added thereto at −10˜0° C. and the mixture was stirred for 2 hours at room temperature. The reaction solution was cooled and, after adding ice, diluted with water and then extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(1:3)]. The fractions containing the desired product were combined and then evaporated to obtain 26.2 g of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:23][Si:24]([C:27]#[C:28][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[NH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: CCOC(=O)Nc1c(F)cc(F)cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1c(F)cc(F)cc1C#C[Si](C)(C)C
Yield: 67.3 %

Procedure:
In a 2L flask, 2-bromo-4,6-difluoro-N-carbethoxy aniline (42 g, 150 mmol) in CH3CN (500 mL) is degassed with vacuum and purged with N2. Dichlorobis(triphenylphosphine)palladium(II) (10.5 g, 15 mmol, 10 mol %), followed by CuI (710 mg, 4 mmol, 2.5 mol %) and triethyl amine (41 mL) are added and rinsed in with 100 mL of CH3CN. Trimethylsilyl acetylene (31.8 ml, 225 mmol) is added and reaction is refluxed under N2. Approximately 2 hours later, the starting material is consumed, indicated by TLC (20% ethyl acetate/hexane, UV). The reaction is cooled, filtered, concentrated, and the residue is dissolved in ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, concentrated, and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 30 g of 2-(trimethylsilylethynyl)-4,6-difluoro-N-carbethoxyaniline (71%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH3:12].[Cl-].[Al+3].[Cl-].[Cl-].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([C:7]1[CH:6]=[C:5]([CH3:8])[C:4]([O:9][CH3:10])=[C:3]([O:11][CH3:12])[C:2]=1[CH3:1])=[O:24]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1c(C)ccc(C)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Temperature: 0 °C
Reaction time: 19 h
Yield: 45.6 %

Procedure:
A solution of 0.227 g (1.5 mmol) of 3,6-dimethylveratrole in 1 mL of methylene chloride was added to an ice cooled mixture of 0.245 g (1.8 mmol) of aluminum chloride and 0.416 g (1.9 mmol) of 6-bromohexanoyl chloride in 3 mL of methylene chloride. The reaction mixture was kept at 0° for 19 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated to an oil which was chromatographed on 60 g of silica gel using 10% ethyl acetate-hexane to give 0.235 g of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 342 (C16H23BrO3).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1>CO>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: Brc1cccc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Br)n1

Procedure:
In a nitrogen atmosphere, sodium methoxide (36.6 g) was added to 2,6-dibromopyridine (93.0 g) in methanol (200 mL) in an ice bath. The mixture was refluxed for 5 hours and was allowed to cool. The resulting crystals were collected by filtration and the filtrate was concentrated. Water was then added to the residue and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent gave the title compound as a yellow oil (69.5 g, substantially pure product).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[CH:10][CH:9]=[CH:8][C:7]=1[O:19][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCO
Reactant: CC(=O)OCCCCCBr
Product: COC(=O)/C=C/c1c(C#CCCCCO)cccc1OCCCCCOC(C)=O
Yield: 77 %

Procedure:
Using the procedure of example 63, (E)-3-[2-hydroxy-6-(6-hydroxy-1-hexynyl)phenyl]-2-propenoic acid methyl ester from the preceding example was converted into the title compound by alkylation with 5-bromopentylacetate. The product was obtained as a colorless oil in 77% yield.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.Br[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>C(OCC)C>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Brc1cccs1
Reactant: Brc1cccc2ccccc12
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: c1csc(-c2cccc3ccccc23)c1
Reaction time: 0.5 h

Procedure:
2-Bromothiophene (1.45 ml, 0.015 m) in diethyl ether (20 ml) was added slowly to magnesium turnings (0.48 g, 0.02 m) and iodine (trace) in diethyl ether (10 ml). It was stirred for 30 min before being added to 1-bromonaphthalene (2.07 g, 0.01 m) and catalyst in diethyl ether (25 ml). The reaction was worked up the usual way yielding a brown oil (2.49 g). The brown oil was purified by column chromatography. Flash silica (104 g) eluted with petroleum ether (600 ml) and increased to 5% diethyl diethyl ether/petroleum ether separated a clear pale green oil (1.50 g, 71% yield); m/z 210 (M+); (Found: C, 80.26; H, 4.91; S, 15.10. C14H10S requires: C, 80.00; H, 4.76; S, 15.24); H NMR (CDCl3), δ7.17 (dd, J=3.2, 5.6 Hz 1H), δ7.23 (dd, J=<1, 3.2 Hz, 1H), δ7.41 (dd, J=<1, 5.6 Hz, 1H), δ7.45 (d, J=4.8 Hz, 1H), δ7.47 (d, J=4.8 Hz, 1H) δ7.48 (d, J=8 Hz, 1H), δ7.55 (dd, J=<1, 8 Hz, 1H), δ7.83 (d, J=8 Hz, 1H), δ 7.88 (dd, J=3.2, 4.8 Hz, 1H), δ8.20 (dd, J=5.6, 4.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:2].CI.[C:19](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[N:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:8]=[CH:9][CH:10]=1)[CH3:19])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1ccnn1-c1nccs1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(C)c1ccnn1-c1nccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2-thiazol-2-yl-2H-pyrazol-3-yl)-acetic acid ethyl ester (100 mg, 0.42 mmol), methyl iodide (66 mg, 0.46 mmol) and cesium carbonate (151 mg, 0.46 mmol) in DMF (6 mL) is stirred at room temperature overnight. The reaction is quenched with NH4Cl (aq.) (6 mL) and ethyl acetate (30 mL). The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×30 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (hexane/ethyl acetate 3:1) to give 2-(2-thiazol-2-yl-2H-pyrazol-3-yl)-propionic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:17][C:16](=[O:18])[C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[H-].[Na+].CI.Cl.[CH2:31](OCC)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]([CH3:31])[C:16](=[O:18])[C:9]3([CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:8]=[C:7]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[CH:25]=1
Reactant: CN1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1NC2=O
Reactant: CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)N=C(c1ccccc1)c1cc(Cl)ccc1N(C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.6 g (0.0016 mole) of 7-chloro-5-phenyl-1'-methyl-spiro[1H-1,4-benzodiazepine-3,4'-piperidin]-2(3H)-one are dissolved in 15 ml of absolute dimethylformamide and reacted with 0.1 g of sodium hydride (55-60% strength dispersion) at 70° C. After 30 minutes, the mixture is cooled to 25° C., 0.22 g (0.0016 mole) of methyl iodide in 10 ml of absolute dimethylformamide is added and the mixture is stirred for 2 hours. After the solvent has been distilled off, the residue is taken up in water and the mixture is extracted with methylene chloride. For purification, the product is chromatographed on aluminum oxide 90 (Merck), activity level II-III, with a cyclohexane/methylene chloride/methanol mixture (6:3:1), and the base thus obtained is converted into the hydrochloride by treatment with diethyl ether/HCl.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[CH:10][N:9]=1.[CH3:15][C:16]1[C:21]2[N:22]=[CH:23][NH:24][C:20]=2[CH:19]=[C:18]([OH:25])[CH:17]=1>CN(C=O)C>[Cl:14][C:12]1[N:11]=[CH:10][N:9]=[C:8]([O:25][C:18]2[CH:17]=[C:16]([CH3:15])[C:21]3[N:22]=[CH:23][NH:24][C:20]=3[CH:19]=2)[CH:13]=1
Reactant: Cc1cc(O)cc2[nH]cnc12
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2[nH]cnc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
0.830 g (6.00 mmol) potassium carbonate were added to 307 mg (2.00 mmol) 4,6-dichloropyrimidine and 295 mg (2.00 mmol) 7-methyl-3H-benzimidazol-5-ol in 1.50 mL DMF and the mixture was stirred for 8 h at 50° C. Then the mixture was added to ice water added and extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 1N aqueous sodium hydroxide solution and extracted with EtOAc. The organic phase was dried on sodium sulphate, filtered, evaporated down and dried under HV.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][CH2:19][CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])[C:7]#[N:8])=[CH:4][CH:3]=1.[OH:26]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([N:16]3[C:21](=[O:22])[NH:20][C:19](=[O:26])[CH:18]=[N:17]3)=[CH:11][C:10]=2[Cl:23])[C:7]#[N:8])=[CH:24][CH:25]=1
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N2N=CCNC2=O)cc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In 20 ml of acetic acid was dissolved 2.0 g of 2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4,5-dihydro-1,2,4-triazin-3(2H)-one. To the solution was added three times as much mol. of 30% hydrogen peroxide. The reaction was allowed to proceed for 3 hours at 100° C. After completion of the reaction, the reaction mixture was poured into ice-water. Resulting crystalline precipitate was collected by filtration to afford 1.8 g of the titled compound as colorless crystals, m.p. 290-292° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:23]([F:26])([F:25])[F:24])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[C:15]([CH3:22])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:29](OC)[N:30](C)C.[O:35]1[CH2:39]CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:23]([F:26])([F:24])[F:25])=[CH:10][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:19][CH:29]=[N:30][O:35][CH3:39])=[O:18])=[C:15]([CH3:22])[CH:14]=2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(N)=O
Reactant: COC(OC)N(C)C
Reactant: C1CCOC1
Product: CON=CNC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.18 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-methylbenzoic acid amide representing mixed geometrical isomers (isomeric ratio of 10:1) that was synthesized according to Synthetic Example 9 in 3 mL of tetrahydrofuran, 0.11 g of N,N-dimethylformamide dimethyl acetal was added and the mixture was stirred for 2 hours at room temperature. After that, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in 3 mL of tetrahydrofuran, and a solution of 45 mg of methoxyamine hydrochloride in 1 mL of water was dripped in at room temperature. After the mixture was stirred for 1.5 hours, whereinto ethyl acetate was added, an organic layer was washed twice with water and then dehydrated and dried with saturated saline followed by anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By washing the resulting solid with a mixed solvent of diisopropylether and acetonitrile, 60 mg of aimed product was obtained as pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH:21][OH:22].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[CH3:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:21]([OH:22])[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1cccc(Nc2ccccc2CNO)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N(O)Cc1ccccc1Nc1cccc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
Acetyl chloride (0.53 g, 6.8 mmol) is added dropwise at 0° C. to a solution of 2-[(2,3-dimethylphenyl)amino]-N-hydroxybenzenemethanamine (1.64 g, 6.8 mmol) and sodium acetate (840 mg, 10 mmol) in 2:1 dioxane/water (100 ml). The reaction mixture is stirred at room temperature for 30 minutes. The product is extracted into ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated to a residue which is recrystallized from cyclohexane to give pure N-[[2-[(2,3-dimethylphenyl)amino]phenyl]methyl]-N-hydroxyacetamide (1.02 g, 53%); mp 93°-98° C.
Reaction SMILES: CO[C:3](OC)([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1)[CH:4](O)C.[CH2:19](N(CC)CC)C.S(Cl)(Cl)(=O)=O.[C:31](=[O:34])([O-])[OH:32].[Na+]>C(Cl)Cl>[CH2:13]([C:10]1[CH:9]=[CH:8][C:7]([CH:3]([CH3:4])[C:31]([O:32][CH3:19])=[O:34])=[CH:12][CH:11]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: O=C([O-])O
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)O
Reactant: CCN(CC)CC
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 3 h
Yield: 84 %

Procedure:
In this example, 2.52 g of α-hydroxy-p-isobutylpropiophenone dimethylacetal and 2.02 g of triethyl amine were dissolved in 50 ml of methylene chloride. To the solution was added 1.75 ml of sulfuryl chloride at -50° C. The mixture was stirred at the same temperature for 3 hours. Then, 20 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the mixture followed by fractionation. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily residue was purified in a manner similar to Example 1 to obtain 1.85 g of methyl 2-(4-isobutylphenyl)propionate (yield 84%).
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.[F:7][C:8]1[CH:29]=[CH:28][C:11]([CH2:12][N:13]2[CH2:27][CH2:26][N:16]3[C:17]4[N:25]=[CH:24][CH:23]=[CH:22][C:18]=4[NH:19][CH2:20][CH2:21][CH:15]3[CH2:14]2)=[CH:10][CH:9]=1.CN(CC)C.[OH-].[Na+]>C(Cl)Cl.O.CO>[CH:1]1([CH2:4][N:19]2[CH2:20][CH2:21][CH:15]3[CH2:14][N:13]([CH2:12][C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=4)[CH2:27][CH2:26][N:16]3[C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]2=3)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(CN2CCN3c4ncccc4N(CC4CC4)CCC3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclopropanecarbonyl chloride (0.043 ml, 0.478 mmol) was added to a solution of the product of Example 64C (97 mg, 0.31 mmol) in CH2Cl2 (2.0 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was taken up in 1 M NaOH (5 mL) and extracted with ethyl acetate (2×10 mL). The combined extract was washed with saturated brine (5 mL), dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in tetrahydrofuran (5 mL) and stirred with alane-N,N-dimethylethylamine complex (Aldrich, 0.5 M in toluene, 2.9 mL, 1.45 mmol) at room temperature for 90 minutes. Methanol (1 mL) was added followed by water (5 mL) and 25% NaOH (1 mL). The mixture was stirred at room temperature for 10 minutes, and the aqueous phase was separated and extracted with ethyl acetate (2×7 mL). The combined organic was washed with saturated brine (5 mL), dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (SiO2 eluted with CH2Cl2—CH3OH 95:5) and then by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with aqueous 0.1 M (NH4)2CO3—CH3OH, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 0.15-0.23 (m, 2H), 0.51-0.61 (m, 2H), 0.94-1.06 (m, 1H), 1.66-1.80 (m, 1H), 1.80-1.95 (m, 1H), 2.19 (t, J=9.7 Hz, 1H), 2.42 (td, J=10.5, 3.1 Hz, 1H), 2.59 (d, J=10.9 Hz, 1H), 2.74-2.84 (m, 1H), 2.95 (d, J=6.4 Hz, 2H), 3.22 (ddd, J=11.5, 6.1, 4.1 Hz, 1H), 3.30-3.39 (m, 1H), 3.38-3.48 (m, 2H), 3.52 (d, J=6.4 Hz, 2H), 3.61 (dt, J=12.5, 3.4 Hz, 1H), 6.75 (dd, J=7.8, 4.7 Hz, 1H), 6.95 (dd, J=7.8, 1.7 Hz, 1H), 6.97-7.05 (m, 2H), 7.32 (dd, J=8.5, 5.8 Hz, 2H), 7.80 (dd, J=4.7, 1.7 Hz, 1H); MS (DCI) m/z 367 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:29])[CH2:14][C:15]([CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=O)[CH3:11].[CH2:30]([O:32][C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36])[CH3:31]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:34]([C:33]([O:32][CH2:30][CH3:31])=[O:38])=[C:35]([CH3:36])[NH:37][C:15]=1[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:29])[CH3:11]
Reactant: CCOC(=O)CC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 90 %

Procedure:
13 g of 2-chlorobenzaldehyde, 28 g of phthalimidoacetoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 250 ccs of ethanol are heated to the boil under reflux for about 70 hours, the mixture is allowed to cool, whilst stirring, and after filtering, light yellow crystals of melting point 174°-176° C. are obtained; yield: 90%.