Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using a similar procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (0.1 g) was reacted with oxalyl chloride (0.093 ml) and DMF (3 drops) in methylene chloride (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 2-(4-benzyloxy-2-methoxyphenyl)acetyl chloride. A mixture of the material so obtained, 3-amino-4,5-dimethylisoxazole (0.062 g), diisopropylethylamine (0.065 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml) was stirred at ambient temperature for 14 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained N-(4,5-dimethylisoxazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.77 (s, 3H), 2.28 (s, 3H), 3.55 (s, 2H), 3.74 (s, 3H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.09 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 367.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCN(S(F)(F)F)CC>C1COCC1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(CC)S(F)(F)F
Agent: [F-]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](C2CC=C(C(F)(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 10 mmol of 4-(trans-4-propylcyclohexyl)cyclohexanone, 11 mmol of trimethyl(trifluoromethyl)silane, 10 mmol of tetrabutylammonium fluoride and 50 ml of THF is stirred for 2 hours at 0° C. After customary work-up, the crude product is dissolved in 20 mml of THF, 10 mmol of DAST are added, and the mixture is heated to boiling. After customary work-up, the crude product is purified by chromatography and crystallization.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].[C:21]([O:25][C:26](=[O:39])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:38])[CH:36]=[CH2:37])([CH3:24])([CH3:23])[CH3:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH4+].[Cl-]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH:4]([C:13]1[CH:18]=[CH:17][C:16](/[CH:37]=[CH:36]/[C:35](=[O:38])[NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:39])=[CH:15][CH:14]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)C(CCC1CCCN1C)c1ccc(Br)cc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CCC1CCCN1C)c1ccc(/C=C/C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-bromo-phenyl)-4-(1-methyl-pyrrolidin-2-yl)-butyric acid methyl ester (2.27 g, 6.67 mmol), (2-acryloylamino-phenyl)-carbamic acid tert-butyl ester (2 g, 7.2 mmol), Pd2(dba)3 (160 mg, 0.175 mmol), tri-o-tolylphosphine (160 mg, 0.526 mmol) and triethylamine (1.6 g, 15.8 mmol) in DMF (12 mL) was stirred at 100 degrees Celsius under N2 for 4 hours. After cooling to room temperature, the mixture was poured into a saturated aqueous solution of NH4Cl, and extracted with ethyl acetate (80 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography to obtain pale yellow solid. (1.74 g, 50%). MS: calc'd 522 (MH+), exp 522 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=[CH2:12])[C:5](=[O:9])[CH:6](Cl)[Cl:7])[CH:2]=[CH2:3].COCCOCCOC.C(Cl)[Cl:23]>>[CH2:1]([N:4]1[CH2:10][CH:11]([CH2:12][Cl:23])[CH:6]([Cl:7])[C:5]1=[O:9])[CH:2]=[CH2:3]
Reactant: ClCCl
Reactant: C=CCN(CC=C)C(=O)C(Cl)Cl
Solvent: COCCOCCOC
Product: C=CCN1CC(CCl)C(Cl)C1=O
Reaction time: 0.5 h

Procedure:
Twenty and eight-tenths grams of N,N-diallyl dichloroacetamide was mixed with 25 g. of diethylene glycol dimethyl ether (diglyme), 1 g. of ferrous chloride (FeC12 ·4H2 0) added and the mixture was heated at reflux for 30 minutes. The conversion was monitored by the appearance of a new carbonyl peak at ~ 5.8 microns in the infrared. An additional gram of ferrous chloride (FeC12 ·4H2 0) was added and heating was continued for an additional 30 minutes. The reaction mixture was diluted with methylene chloride, washed with water and dried and stripped. The dark liquid product was distilled under vacuum to give 8.4 g. of light yellow oil, b.p. 124°-127° C. at 0.25 mm. nD30 1.4850.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:13].[CH3:14][C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>C(O)C>[CH2:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:13][C:20]([C:18]3[S:19][C:15]([CH3:14])=[CH:16][CH:17]=3)=[N:1][C:2]=2[CH:7]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: Cc1ccc(C=O)s1
Reactant: CCS(=O)(=O)c1ccc(O)c(N)c1
Agent: CC(=O)[O-]
Agent: [Pb+4]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc2oc(-c3ccc(C)s3)nc2c1
Temperature: 70 °C
Yield: 0.3 %

Procedure:
To a stirred solution of 2-amino-4-(ethylsulfonyl)phenol (452.7 mg, 2.25 mmol) in ethanol (17 mL) was added 5-methyl-2-thiophenecarboxaldehyde (242 μL, 2.25 mmol). The mixture was heated at 70° C. for 70 min. After cooling, a small amount of precipitate was formed. After filtration and evaporation of the filtrate, the resulting product was dissolved in acetonitrile (9.8 mL) and lead tetraacetate (887 mg, 2 mmol) was added. The resulting mixture was heated at 100° C. for 5 min. After cooling, the reaction mixture was filtered off, and the filtrate evaporated in vacuo. The resulting mixture was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v, and then purified by reverse phase HPLC to afford 2.2 mg (0.3%) of the title product (LCMS RT=6.41 min, MH+ 308.1)
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[ClH:10].C([OH:13])C>>[ClH:10].[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[OH:13])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Product: N=C(O)c1ccc(F)cc1

Procedure:
In anhydrous ethanol, compound [I'], commercially available 4-fluorobenzonitrile is reacted with gaseous hydrogen chloride to yield compound [J'], 4-fluorobenzimidate hydrogen chloride. Compound [J'] is reacted with gaseous ammonia to yield compound [K'], 4-fluorobenzamidine hydrogen chloride.
Reaction SMILES: C(N1CCNC1=NC#N)C1C=CC=CC=1.[CH2:16]([N:23]1[CH2:27][CH2:26][NH:25][S:24]1(=[O:29])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:30]([NH:37][C:38]([C:40]1[S:44][C:43](Br)=[N:42][C:41]=1[CH3:46])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][C:38]([C:40]1[S:44][C:43]([N:25]2[CH2:26][CH2:27][N:23]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:24]2(=[O:29])=[O:28])=[N:42][C:41]=1[CH3:46])=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: O=S1(=O)NCCN1Cc1ccccc1
Agent: N#CN=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)S2(=O)=O)sc1C(=O)NCc1ccccc1
Yield: 78 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 2-benzyl-1,2,5-thiadiazolidine 1,1-dioxide to react with N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 78% yield: mp 135-137° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 10H), 5.99 (t, J=5.6 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 4.25 (s, 2H), 4.00 (t, J=6.6 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.5, 156.6, 153.4, 137.7, 133.7, 128.9, 128.8, 128.6, 127.8, 127.7, 119.4, 51.4, 45.0, 44.1, 43.9, 17.3; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][N:19]([C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(=O)C(F)(F)F)([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][NH:19][C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(CN[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 55.6 %

Procedure:
To a solution of methyl 1-benzyl-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido) methyl)piperidine-4-carboxylate (68 mg, 0.143 mmol) in methanol (2 mL) was added sodium hydroxide (1M, 1 mL, 6.00 mmol), and the mixture was stirred at room temperature for 30 h. The mixture was purified using reverse-phase HPLC under the acidic conditions. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 29 mg of product (HCl salt) as white solid. MS: (M+H)+=365.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.39 (m, 1H), 1.67 (br. s., 1H), 1.96-2.10 (m, 2H), 2.18-2.39 (m, 2H), 2.61-2.74 (m, 1H), 2.86-3.03 (m, 2H), 3.08-3.24 (m, 2H), 3.59 (br. s., 1H), 4.22-4.50 (m, 2H), 7.11-7.39 (m, 5H), 7.46 (br. s., 3H), 7.62 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][N:17]([CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: ClCCN1CCCC1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(CCN3CCCC3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 1-(2-chloroethyl)pyrrolidine and cesium carbonate in N,N-dimethylacetamide for 3 days at r.t. to give N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-N-(2-pyrrolidin-1-yl-ethyl)-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 572.6 ([M+H]+)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15].[I-].[Na+]>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:15][CH2:14][O:16][CH2:17][CH3:18])[C:5]=1[CH3:13]
Reactant: Cc1[nH]c2ccccc2c1Br
Reactant: CCOCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCn1c(C)c(Br)c2ccccc21
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Under ice-cooling, sodium hydride (60% in oil, 1.44 g, 36.0 mmol) was added to a solution of 3-bromo-2-methyl-1H-indole (6.30 g, 30.0 mmol) in N,N-dimethylformamide (30 mL) by small portions, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 1 hr. 2-Bromoethyl ethyl ether (5.07 mL, 45.0 mmol) and sodium iodide (0.747 g, 4.50 mmol) were added to the reaction mixture, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-25% ethyl acetate/hexane) to give the title compound (6.30 g, yield 74%) as a dark-purple oil. MS m/z 282 (MH+).
Reaction SMILES: [CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[NH2:14][C:12]1[S:13][C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:10][N:11]=1
Reactant: NC(=S)NN=CC=Cc1ccccc1
Solvent: O
Product: Nc1nnc(C=Cc2ccccc2)s1
Reaction time: 4 h
Yield: 78.6 %

Procedure:
A mixture of 70.0 g (0.35 m) of cinnamaldehyde thiosemicarbazone and 56.0 g (1.16 m) of ferric ammonium sulfate dodecahydrate was pulverized with a mortar and pestle and added portionwise to 1400 ml of hot water. The mixture was stirred at 60°-100° C. for 11/4 hr., during which time the color of the mixture changed from yellow-orange to dark red and much of the solid material went into solution. The mixture was filtered hot to yield 54.5 g of a brown granular product. The mother liquors were cooled under refrigeration and refiltered to give another 12.3 g of product. The crude product was pulverized and triturated twice with chloroform to remove the residual starting material and the dark brown impurities from the product, leaving 27.4 g of a beige microcrystalline powder. An additional 4.60 g of product was recovered by concentrating the chloroform filtrate. Total yield was 32.0 g (0.16 m), mp. 212°-214° C. (dec.). This procedure is novel and is of general utility for preparing these types of compounds. The novel procedure for this particular product is defined as:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:23]([CH3:26])([CH3:24])[CH3:22])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cccc(Cl)n1
Reaction time: 3 h
Yield: 45.9 %

Procedure:
6-Chloropyridine-2-carboxylic acid (5.00 g, 31.7 mmol) was dissolved in DCM (150 mL) and oxalyl chloride (5.45 mL, 63.5 mmol) and DMF (1 mL) were added. The reaction mixture was stirred for 3 h, concentrated in vacuo and azeotroped with DCM. The residue was dissolved in THF (150 mL) and potassium tert-butoxide (3.39 mg, 47.6 mmol) was added. The reaction mixture was stirred for 18 h, quenched with water (250 mL) and extracted with DCM (3×150 mL). The combined organic fractions were washed with sat aq NaHCO3 (150 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.11 g, 46%) as a white solid. LCMS (ES+): 236.1 [MNa]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12.C([O-])([O-])=O.[K+].[K+].[CH3:27][CH:28]([SH:30])[CH3:29]>O1CCOCC1>[CH:28]([S:30][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][C:3]=12)([CH3:29])[CH3:27]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)Sc1c(C=O)cnc2c1ccn2COCC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (500 mg, 1.61 mmol) in dioxane (5 mL) were added K2CO3 (668 mg, 4.83 mmol) and 2-propanethiol (0.3 mL, 3.22 mmol). The reaction mixture was stirred for overnight for 70° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (5% to 20% Ethyl acetate/Hexane) as a solvent to afford title compound (320 mg, 56% yield). MS m/z: [M+1].
Reaction SMILES: [N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH2:24][OH:25])=[CH:18][CH:17]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl>C1COCC1.[Pd]>[N:1]1([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:21]=3)[N:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])[N:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C#CCO)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(CCCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a magnetically stirred suspension of 14 mg of palladium (10 wt % on carbon) taken in 8 ml of THF was added compound 2-1 (80 mg, 0.165 mmol) dissolved in 3 ml of THF. The resulting mixture was stirred at room temperature for 2 h under an atmosphere of hydrogen. Then to the mixture was added 10 ml of DCM and the catalyst was filtered and the residue was concentrated and purified by flash column chromatography (petroleum ether-ethyl acetate, 6:4) to afford 61 mg (76%) of 4-1 as a white solid.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1.C(O)(=O)C.[CH2:19]([NH2:22])[CH2:20][CH3:21]>O>[CH2:19]([NH:22][C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][N:4]=1)[CH2:20][CH3:21]
Reactant: CCOC(=O)c1cnc(SC)nc1O
Reactant: CCCN
Solvent: CC(=O)O
Solvent: O
Product: CCCNc1ncc(C(=O)OCC)c(O)n1

Procedure:
2-Methylthio-5-ethoxycarbonyl-4-hydroxypyrimidine (2 mmol, 428 mg) was heated on an oil bath at 160° C. with n-propylamine acetate (1 ml) for 1 hour. The semi solid was cooled and then treated with 50 ml boiling water, and the solid product was filtered off (yield 400 mg, 88%)
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]>>[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42](/[CH:45]=[C:12](/[C:10]2[CH:9]=[CH:8][C:6]3[S:7][C:3]([CH3:2])([CH3:33])[S:4][C:5]=3[CH:11]=2)\[CH3:13])=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]
Reactant: CCOC(=O)Oc1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCOC(=O)Oc1ccc(/C=C(\C)c2ccc3c(c2)SC(C)(C)S3)cc1

Procedure:
In analogy to Example 45, by reacting [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide with ethyl 4-formylphenyl carbonate, there was obtained ethyl p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenyl carbonate, melting point 93°-94° C. Hydrolysis of this compound with aqueous potassium hydroxide in ethanol gave p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenol, melting point 123°-124° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 8 Step A in DCM (20 mL) was added boron tribromide (11.7 mL, 1.0 M in DCM, 11.7 mmol). After 15 min, the reaction mixture was allowed to warm to ambient temperature. After an additional 2 h, the reaction mixture was cooled to 0° C., then was quenched by dropwise addition of sat. aq. NaHCO3 (gas evolution) and was extracted with DCM. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 392.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.78 (s, 1H), 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.48 (dd, J=7.0, 1.5 Hz, 1H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.36 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=2)[CH:9]=1)=[O:4].[O:18]1[C:22](B(O)O)=[CH:21][C:20]2[CH:26]=[CH:27][CH:28]=[CH:29][C:19]1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC(O)=O.CC(O)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:17])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:22]2[O:18][C:19]3[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=3[CH:21]=2)[CH:9]=1)=[O:4]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1cc(-c2cccc(Br)c2)nn1C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2-c2cc3ccccc3o2)nn1C
Temperature: 100 °C
Yield: 58.3 %

Procedure:
1.40 g (4.74 mmol) of 5-(3-bromo-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (6′) (and ethyl ester) was dissolved in 15 ml of toluene and 1.6 ml of H2O. Then 1.54 g (9.49 mmol) of benzo[b]furan-2-boronic acid, 5.42 g (25.52 mmol) of K3PO4, 0.29 g (1.04 mmol) of tricyclohexylphosphine and 0.117 g (0.52 mmol) of palladium-II-acetate were added. The reaction mixture was degassed (argon) several times at each addition. The reaction was heated (100° C.) for 24 h. At RT, the mixture was partitioned between chilled water/EtOAc (3×). The organic phases were washed with water, with aqueous sat. NaHCO3, dried (Na2SO4), filtered (black palladium complex stayed with Na2SO4) and evaporated. Then the residual product was dissolved in hot CH2Cl2 and crystallized at RT. It was filtered to give 0.918 g (58%) of 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester as white powder. MS: 332.2 (M+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[N:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])=[CH:21][CH:22]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccncc1
Yield: 79.8 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (401 mg), N,N-dimethylformamide (6 ml), potassium carbonate (0.68 g) and 4-(chloromethyl)pyridine (406 mg) according to the similar method described in Production Example 4 was obtained 500 mg of 2-(4-pyridylmethyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (7)).