Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]>>[C:18]1([CH3:23])[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1I
Reactant: C#Cc1ccc(C2CC2C(=O)OC)cc1
Product: COC(=O)C1CC1c1ccc(C#Cc2ccccc2C)cc1

Procedure:
The title compound was prepared from methyl 2-(4-ethynylphenyl)cyclopropanecarboxylate (80 mg, 0.40 mmol) and 1-iodo-2-methylbenzene (113 mg, 0.56 mmol) according to the general procedure IF to give 45 mg (39%) of a pale yellow solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:10): Rf=0.41 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.52-7.41 (m, 3H), 7.25-7.20 (m, 2H), 7.20-7.12 (m, 1H), 7.07 (d, J=8.2 Hz, 2H), 3.72 (s, 3H), 2.57-2.51 (m, 1H), 2.50 (s, 3H), 1.92 (ddd, J=8.5, 5.3, 4.2 Hz, 1H), 1.63 (dt, J=9.2, 5.0 Hz, 1H), 1.33 (ddd, J=8.4, 6.5, 4.7 Hz, 1H); 13C NMR (CDCl3) δ 173.6, 140.3, 140.2, 131.8, 131.6, 129.5, 128.3, 126.2, 125.6, 123.0, 121.7, 93.1, 88.5, 52.0, 26.2, 24.2, 20.8, 17.2; ESI-MS m/z 313.1 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.I[C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1>>[OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:29])([F:28])[F:30])[NH:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[C:5](=[O:8])[CH2:4]1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Reactant: O=C1CC(CO)CN1
Product: O=C1CC(CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1

Procedure:
4-Hydroxymethylpyrrolidin-2-one, which is a known compound described in a publication (Journal of Chemical Research, Synopses, vol. 9, pp. 430-431, (1996)) and the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step D of Example 1-1 were used as raw materials. Using such raw materials, the captioned compound was synthesized by a reaction similar to step E of Example 1-1.
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.NO.N1C=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask was charged with a suspension of 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), and pyridine (0.25 mL, 3.0 mmol) in ethanol (10 mL) and stirred at RT overnight. Crude product concentrated and absorbed onto silica gel, then chromatographed using 97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), Rt 2.06 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[CH3:38][N:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH2:48][NH2:49])=[N:40]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:49][CH2:48][C:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:39]([CH3:38])[N:40]=1)=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: Cn1nc(CN)c2ccccc21
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nn(C)c3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-indazol-3-yl)-methylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][OH:14])[CH2:8]2.[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:23])[O:14][CH2:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: COc1cccc2c1CCC(CO)C2
Solvent: c1ccncc1
Product: COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methanol (192 mg) and N,N-diphenylcarbamoyl chloride (348 mg) in pyridine (180 mg) was stirred at 100° C. for 2 hours, cooled to room temperature, and partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed successively with brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diethyl ether to afford (1,2,3,4-tetrahydro-5-methoxy-2-naphthyl)methyl N,N-diphenylcarbamate (218 mg) as a pale purple powder.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[O:20]=[C:21]1[NH:25][CH2:24][CH2:23][N:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[C:12]1([C:4]2[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[N:30][C:29]([NH:28][CH2:27][CH2:26][N:22]3[CH2:23][CH2:24][NH:25][C:21]3=[O:20])=[N:31][CH:3]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N=C(N)NCCN1CCNC1=O
Reactant: CN(C)C=C(C(=O)c1cccs1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1NCCN1CCNc1ncc(-c2ccccc2)c(-c2cccs2)n1
Temperature: 100 °C

Procedure:
3-(Dimethylamino)-2-phenyl-1-(thiophen-2-yl)prop-2-en-1-one (1 g, 3.88 mmol) in N-methylpyrrolidone (10 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methylpyrrolidone 5.82 mL, 5.82 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured into cold water. The aqueous layer was extracted three times with dichloromethane. All the organic layers were combined and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=1.2 g. MS (M+H)+ 366.
Reaction SMILES: [CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([CH:23]=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[O-:27]Cl=O.[Na+]>CC(O)(C)C>[CH:1]([NH:14][C:15]([C:17]1[C:18]([OH:25])=[N:19][C:20]([C:23]([OH:27])=[O:24])=[N:21][CH:22]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ncc(C(=O)NC(c2ccccc2)c2ccccc2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of step G product (2-h, 0.7 g) in t-BuOH (35 mL) was added NaH2PO4.12H2O (0.6 g, 1.7 mmol) followed by H2O (6 mL) and NaClO2 (0.95 g, 10.5 mmol). After being allowed to stir at the ambient temperature overnight, the reaction mixture was evaporated under vacuum to remove t-BuOH, diluted with H2O, treated with aq. HCl to pH 2 and the solid was filtered and the cake was washed with water and dried under vacuum to afford compound 2-i as a crude (0.35 g), which was directly used for next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.[C:16](Cl)(=[O:18])[CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
Triethylamine (0.65 ml, 4.65 mmol) was added to a solution of 200 mg (1.16 mmol) of 4-bromoaniline in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 5 min. Acetyl chloride (0.165 ml, 2.33 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hr. The reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, and the reaction solution Was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in that order, was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 249 mg (yield 99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)=[C:3]([Cl:5])[Cl:4].[NH4+]=S>C(O)C.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([C:2]([Cl:1])=[C:3]([Cl:4])[Cl:5])[CH:7]=1)[NH2:12]
Reactant: Cc1cc(C(Cl)=C(Cl)Cl)cc([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc(C(Cl)=C(Cl)Cl)c1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
To a warm solution of 3-(trichlorovinyl)-5-nitrotoluene (10.95 g) in 150 ml of ethanol, an aqueous solution of ammonium sulfide (30 ml of a commercial 46-52% aqueous solution diluted to 90 ml with water) was added in one portion. The resulting heterogeneous solution was heated in a 100° C. oil bath for 30 minutes. The hot reaction mixture was filtered and the precipitate thoroughly washed with ethanol. The filtrate was diluted with 1.2 L of brine and then extracted with methylene chloride (2×400 ml). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Concentration afforded 9.36 g of an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9].[I-:12].[Na+]>CC(=O)CC>[I:12][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][Si:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C[Si](C)(C)C#CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: C[Si](C)(C)C#CCCCCI
Reaction time: 10 h
Yield: 96.2 %

Procedure:
A mixture of 6-chloro-1-trimethylsilylhex-1-yne (14.0 g.) and sodium iodide (30 g) in butanone (100 ml) was heated at reflux, with stirring, for 10 hours. After this time the solvent was removed in vacuo and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water and brine before drying over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to leave 6-iodo-1-trimethylsilylhex-1-yne as a yellow oil (20.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>O.O1CCOCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)CC(c1cccc(Cl)c1)c1ccc2cc[nH]c2c1
Temperature: 95 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
A mixture of 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (0.4 g, 2.0 mmol), 3-chlorophenyl boronic acid (0.62 g, 4.0 mmol), [RhCl(cod)]2 (49 mg, 0.10 mmol) and TEA (0.42 ml, 3.0 mmol) in water (6 ml) and 1,4-dioxane (1 ml) was stirred at 95° C. for 18 hours. The reaction mixture was cooled to room temperature, and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(3-chloro-phenyl)-propionic acid methyl ester XL (90 mg, 62% yield) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[CH:25]=[C:24]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[NH:23][C:22]=1[CH:34]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:34][C:22]4[NH:23][C:24]([C:26]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[O:27])=[CH:25][C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (93 mg, 0.33 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (73 mg, 0.33 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at room temperature for 3 days. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 110.3 mg (69%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.43 (br s, 1H, NH), 11.74 (br s, 1H, NH), 9.23 (br s, 1H), 8.33 (s, 1H), 7.73 (dd, J=2.5 & 6.7 Hz, 1H), 7.44 (m, 1H), 7.32-7.37 (m, 2H), 6.61 (d, J=2.28 Hz, 1H), 3.69 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2), 2.22 (s, 3H, CH3). MS 483 [M+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][NH:35][N:36]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[N:36]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2nn[nH]n2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCn1nnc(-c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)n1
Temperature: 80 °C

Procedure:
To the mixture of 1-(2-(2-amino-5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (106 mg, 0.2 mmol, 1 eq) in anhydrous dimethylformamide (2 mL) under nitrogen atmosphere was added potassium carbonate (41.4 mg, 1.5 eq) and (2-bromoethoxy)-tert-butyldimethylsilane (0.06 mL, 1.3 eq). The resulting mixture was stirred and heated at 80° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. Gradient column chromatography (EtOAc-Hex from 1:100 to 3:1) gave 1-(2-(2-amino-5-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea as a fluffy white solid in the amount of 77 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([SH:12])[NH:9]2)=[CH:4][C:3]=1[F:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH2:27]Br>CN(C)C=O>[CH2:16]([O:15][C:13]([C:7]1[C:6](=[O:18])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:19])[CH:4]=2)[N:9]2[CH2:26][CH2:27][S:12][C:8]=12)=[O:14])[CH3:17]
Reactant: BrCCBr
Reactant: CCOC(=O)c1c(S)[nH]c2cc(Cl)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(Cl)c(F)cc3c1=O)CCS2
Temperature: 25 °C

Procedure:
Three grams (0.01 mol) of ethyl 7-chloro-6-fluoro-2-mercapto-4-oxo-1,4-dihydroquinoline-3-carboxylate was dissolved in 10 ml of dimethyl formamide, then 4.1 grams (0.03 mol) of anhydrous potassium carbonate was added thereto and, with stirring at a room temperature, 1.9 grams (0.01 mol) of ethylene dibromide was dropped thereinto. The mixture was stirred at a room temperature overnight. The content was concentrated under reduced pressure and water was added to the residue. Crystals separated out therefrom were collected by filtration immediately, washed with water, dried and the crystals were recrystallized from ethanol to give the title compound. Colorless crystals. Yield 3.5 grams (94 percent). All of melting point, elementary analysis data, infrared absorption spectra, and nuclear magnetic resonance spectra coincided with those in example 15.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:19])([F:18])[F:1])=[CH:5][CH:6]=2)=[N:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2ccc(OC(F)(F)F)cc2)nc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc(CCl)cn2)cc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
[6-(4-Trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol (0.40 g, 1.49 mmol) was dissolved in CH2Cl2 (7.2 ml) and treated dropwise at 0° C. with SOCl2 (0.22 ml, 2 eq.). The reaction mixture was kept at 0° C. for 5 min and at RT for 30 min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents produced 0.419 g (1.46 mmol, 98%) of the title compound as off-white solid of mp. 34–36° C.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][O:10][C:11]([C:13]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:17][C:18]=2[CH3:19])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][O:10][C:11](=[O:12])/[CH:13]=[C:18](\[NH2:17])/[CH3:19])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C(C)(C)C)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C(C)(C)C)cc1
Yield: 78 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-tert.-butylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-tert.-butylbenzyl ester of melting point 161° C (from ethanol).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][CH:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])[CH:17](O)[C:18]([CH3:21])([CH3:20])[CH3:19].O>CS(C)=O>[Cl:12][C:13]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:14]=1[O:15][C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[CH:17][C:18]([CH3:20])([CH3:21])[CH3:19]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An equimolar amount of potassium tert.-butylate is added to 54.6 g (0.1 mole) of the tosylate of 1,1-bis-(2,4-dichlorophenoxy)-3,3-dimethylbutan-2-ol in 200 ml of dry dimethylsulfoxide. The mixture is stirred for 30 minutes at room temperature, after which it is hydrolyzed with water and then extracted twice with the same volume of ethyl acetate, the organic phase is dried and the solvent is distilled off under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A round bottom flask equipped with magnetic stirrer and nitrogen inlet was charged with 2,4-dichlorobenzaldehyde (1.75 g, 10.0 mmol), acetone (44.1 ml, 0.60 mol) and water (20 ml). The mixture was cooled to 0° C. and a solution of sodium hydroxide (0.44 g, 11.0 mmol) in water (20 ml) was added drop wise during 1 hour to the vigorous stirred suspension. The reaction mixture was stirred for an additional 1.0 hour. The reaction mixture was concentrated in vacuo, poured onto 10% HCl (100 ml) and extracted with ethyl acetate (3×50 ml). Combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (350 g) (eluent: n-hexane/ethyl acetate 1:1) to afford 1.9 g (88% of theory) of (E)-4-(2,4-dichloro-phenyl)-but-3-en-2-one in form of a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]3[S:17]C(=S)N[C:14]3=[O:19])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+]>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][C:13](=[S:17])[C:14]([OH:19])=[O:20])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1cc(-c2ccccc2)cs1
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=S)Cc1cc(-c2ccccc2)cs1
Temperature: 95 °C
Yield: 74 %

Procedure:
A suspension of product 5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, 4.6 mmol) in 12 mL of 10% aqueous NaOH was heated to 95° C. for 1 h. The solution was cooled to room temperature and diluted with water. The aqueous phase was washed with EtOAc, and acidified with 10% HCl. The precipitate that was formed was filtered, washed with water and dried under reduced pressure to get the product 3-(4-phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, yield 74%). MS (ESI) m/z: Calculated for C13H10O2S2: 262.01. found: 261.0 (M−H)−. The crude product was carried through without further purification
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[O:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:12][CH2:11]2)[O:16][CH2:7][CH2:8]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
A solution of 10.4 g. of cyclopropanecarbonyl chloride in 150 ml. of dichloromethane is rapidly added to a solution of 12.5 g. of 4-piperidone ethylene acetal (1,4-dioxa-8-azaspiro[4.5]decane) and 20 g. of triethylamine in 200 ml. of dichloromethane, causing the solution to reflux. Heating to reflux with stirring is continued overnight; the mixture is cooled and the precipitated triethylammonium chloride filtered off. The mother liquor is concentrated to about half volume, washed with water, dried over anhydrous potassium carbonate, and stripped to dryness. The residual oil quickly solidifies, and on crystallization from 300 ml. hexane yields cyclopropyl 1,4-dioxa-8-azaspiro[4.5]dec-8-yl ketone, m.p. 72°-74°, as white needles. Reduction of 14.0 g. of this compound in 60 ml. freshly chromatographed, peroxide-free ether by dropwise addition to a suspension of 2.5 g. of lithium aluminum hydride in similarly treated ether, followed by three hours of refluxing, yields 8-(cyclopropylmethyl)-1,4-dioxa-8azaspiro[4.5]decane as a colorless oil. Hydrolysis of this ethylene acetal by refluxing in 2N hydrochloric acid, followed by basification with 50% sodium hydroxide, extraction into ether, drying of the extrct, and stripping off the solvent, yields a crude product which distills at 111°-122°/16 mm. to give 1-(cyclopropylmethyl)-4-piperidone, shown by gas-liquid chromatography to be 95-99% pure.