Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:41]1[CH:40]=[CH:39][C:6]([CH2:7][CH2:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[N:10]=2)=[CH:5][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: Cc1ccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(CCc2nc(Nc3ccc(N4CCNCC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.5 %

Procedure:
To tert-butyl 4-(4-((4-(3-carbamoyl-4-methylphenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I73) (0.029 g, 0.054 mmol) in DCM (2 mL) was added TFA (0.100 mL, 1.36 mmol) and the mixture stirred overnight (16 hours) at room temperature. The resulting mixture was then concentrated under reduced pressure and the residue taken up in EtOAc (10 mL). The resulting organic suspension was washed with 10% aqueous NaOH (10 mL) and the aqueous layer extracted with EtOAc (2×10 mL). The combined organics were washed with water (15 mL) then concentrated under reduced pressure. The residue was taken up in DCM (4 mL) and TFA (0.200 mL) and stirred overnight (16 hours). The resulting mixture was concentrated under reduced pressure then diluted with EtOAc (15 mL). The resulting solution was washed with 10% aqueous NaOH (15 mL) then the aqueous layer was extracted with EtOAc (15 mL). The combined organic extracts were washed with water (20 mL) then dried using a phase separation cartridge before concentrating under reduced pressure to give the title compound (19) (5.1 mg, 21%); 1H NMR (400 MHz, d6-DMSO) δ 9.96 (s, 1H), 8.60 (s, 1H), 7.67 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.16 (m, 2H), 6.90 (d, J=9.1 Hz, 2H), 3.01 (m, 8H), 2.83 (m, 4H), 2.32 (s, 3H). LCMS Method C: rt 4.76 min; m/z 485.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:14]([SnH:18]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])/[C:10](=[CH:9]/[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)/[C:11]([NH2:13])=[O:12])[CH2:24][CH2:25][CH3:26]
Reactant: NC(=O)CCc1ccc(Cl)c(Cl)c1
Reactant: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(Cl)c(Cl)c1)C(N)=O
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
3-(3,4-dichlorophenyl)propionic acid amide (21 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=3:1) to give (E)-2-(tributylstannyl)-3-(3,4-dichlorophenyl)acrylamide (12.3 mg, 24%) as a pale yellow oily substance.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C=CC=CC=1.O.C1(CC2C=CC=CC=2)C=CC=CC=1.SCCCS(O)(=O)=O>>[C:1]1(=[O:21])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)CCCS
Solvent: O
Solvent: c1ccc(Cc2ccccc2)cc1
Product: O=C1C=CC=C2C1=Cc1ccccc12
Temperature: 53 °C

Procedure:
9-Fluorenone (3.65 g, 0.0200 mol, 1.00 equiv.), molten phenol (39.6 g, 0.420 mol, 20.8 equiv.), deionized water (0.055 g, 3.06 mmol, 0.151 equiv.) and diphenylmethane (32.83 g) is added to the reactor (reactor design 2). The reaction mixture is heated to 53° C. with stirring under a pad of nitrogen. 3-Mercaptopropanesulfonic acid (0.170 g, 1.10 mmol, 0.0537 equiv.) is added slowly over approximately 1 minute to the reaction mixture at 53° C. The reaction is monitored throughout the reaction period by collecting samples and analyzing by HPLC. The 9-fluorenone is found to be 49% consumed within 2 hours and 77% consumed within 4.5 hours. HPLC analysis (analytical method 3) gives the following relative area % analysis for the reaction products (fluorenone area not included) at 77% conversion:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1>>[CH3:17][N:18]([CH3:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:34])[CH3:35])=[CH:29][CH:28]=2)[C:14]([CH:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[CH:23][CH:24]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)CCC2
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(C(C)C)cc32)cc1
Yield: 28.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.07 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-isopropyl-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained. melting point: 123-125° C.
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH2:13]([S:15]SCC)[CH3:14].[OH-].[Na+]>O.C(OCC)C>[Br:1][C:2]1[C:6]([S:15][CH2:13][CH3:14])=[CH:5][S:4][CH:3]=1
Reactant: CCSSCC
Reactant: Brc1cscc1Br
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCSc1cscc1Br
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
A mixture of 9.68 g of 3,4-dibromothiophene and 80 mL of diethylether was cooled to −70° C., 27 mL of n-butyl lithium (1.63 M hexane solvent) was added over 30 minutes, and the mixture was stirred at −70° C. for 30 minutes. To the mixture was added 5.86 g of diethyl disulfide at such a rate that the internal temperature is maintained at −60° C. or less, and the mixture was stirred at −70° C. for 2 hours. The reaction mixture was heated to −35° C. and then 100 mL of water was added. After heating to room temperature, a 2 N aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 3.27 g of 3-bromo-4-ethylthiothiophene.
Reaction SMILES: [CH2:1]([CH:8]([CH:14]([OH:16])[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH2:1]([CH:8]([CH:14]([O:16][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccccc1)C(C)OC(=O)c1ccccc1
Yield: 85 %

Procedure:
A mixture of 0.04 mol of ethyl 2-benzyl-3-hydroxybutyrate, 0.045 mol of pyridine, 0.05 mol of benzoyl chloride and 40 ml of dried tetrahydrofuran (THF) was refluxed by heating for 8 hrs, and then was allowed to react at room temperature for further 12 hrs. Upon the completion of the reaction, the reaction mixture was filtered, and the solid component was wished with diethyl ether for three times. The organic phases were combined, wished well with saturated saline, and then dried over anhydrous sodium sulfate. After removing the solvent, residue was subjected to column chromatography to give a colorless liquid. Yield 85%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH2:18][CH2:17]3)=[O:13])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:32](=[O:34])[CH3:33])[CH2:18][CH2:17]3)=[O:13])[CH:2]=1
Reactant: CC(=O)Cl
Reactant: O=C(Nc1cnc2ccccc2c1)c1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)N1CCc2cc(C(=O)Nc3cnc4ccccc4c3)ccc21
Yield: 84 %

Procedure:
A solution of 2,3-dihydro-1H-indole-5-carboxylic acid quinolin-3-ylamide (77 mg, 0.266 mmol) and N,N-diisopropylethylamine (0.060 mL, 0.345 mmol) in 1,2-dichloroethane (2 mL) was treated with acetyl chloride (0.020 mL, 0.292 mmol). The resultant solution was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated in water (1 mL) and saturated aqueous sodium bicarbonate (1 mL). The product was collected by filtration, to give the product 74 mg (84%). MS: m/z 332 (MH+). 1H NMR (DMSO-d6): δ 2.21 (s, 3H), 3.24 (t, 2 H), 4.18 (t, 2 H), 7.59 (t, 1 H), 7.67 (t, 1 H), 7.89-7.98 (m, 4 H), 8.15 (d, 1 H), 8.84 (s, 1 H), 9.14 (s, 1 H) and 10.566 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH3:10])[O:8][C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])=[N:6]1)=[O:4].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)[C@H](C)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (0° C.) solution of (4S,5S)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (0.529 g, 1.20 mmol) and DBU (360 μL, 2.40 mmol) in CH2Cl2 (10.0 mL) was added BrCCl3 (125 μL, 1.26 mmol). The mixture was then warmed to room temperature. After 18 hours, the mixture was diluted with CH2Cl2 (50 mL) and extracted with saturated aqueous ammonium chloride (2×50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to afford the title compound as white solid. MS m/z 438.74 (MH+).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:41])[CH2:18][C@@H:19]1[C@@H:22]([C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[CH3:24])[C:21](=[O:40])[NH:20]1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[O:41]=[C:17]1[CH2:18][C@H:19]2[N:20]([C:21](=[O:40])[C@@H:22]2[C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[CH3:24])[C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of 4-nitrobenzyl 2-diazo-4-[(2R,3S)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate (58.0 mg) and rhodium (II) acetate (0.1 mg) in benzene (3.4 ml) was refluxed for 30 minutes. After cooling to ambient temperature, the mixture was filtered with a diatomaceous earth and evaporated to give 4-nitrobenzyl (2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]-heptane-2-carboxylate (47.8 mg) as an amorphous solid.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].P(=O)(O)(O)O.[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:1][CH:2]=[C:3]([CH3:4])[CH3:5])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: C=CC(=C)C
Agent: O=P(O)(O)O
Product: CC(=O)OCC=C(C)C

Procedure:
Although the addition of acetic acid to isoprene in the presence of a catalytic amount of phosphoric acid will occur slowly at room temperature to yield prenyl acetate (systematically named as 3-methyl-2-buten-1-yl acetate), gentle heating of the reaction mixture in a pressure vessel at temperatures of approximately 40° C. to 100° C. is preferred if one wishes to conduct the process in several hours.
Reaction SMILES: Cl[CH2:2]Cl.[CH2:4]([N:6]([CH2:9][CH3:10])[CH2:7][CH3:8])C>>[N:6]1[CH:7]=[CH:8][CH:2]=[CH:10][CH:9]=1.[CH3:4][NH:6][CH3:7]
Reactant: CCN(CC)CC
Reactant: ClCCl
Product: CNC
Product: c1ccncc1

Procedure:
in a solvent, such as dichloromethane, and in the presence of triethylamine and dimethylamine pyridine provides a compound of the formula ##STR54##
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2N[C:16]3[CH:22]=[C:21]([C:23]([NH2:25])=[O:24])[CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH:29]([CH3:31])[CH3:30].[CH3:32]C(C)=O>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:18]([CH:29]([CH3:31])[CH3:30])[C:17]3[C:16]([CH:32]=2)=[CH:22][C:21]([C:23]([NH2:25])=[O:24])=[CH:20][CH:19]=3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: NC(=O)c1ccc2nc(N3CCC(Cc4ccccc4)CC3)[nH]c2c1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)n1c(N2CCC(Cc3ccccc3)CC2)cc2cc(C(N)=O)ccc21
Yield: 50 %

Procedure:
A mixture of 4-benzylpiperidinyl-benzimidazole-5-carboxamide (318 mg, 1 mMol), solid KOH (280 mg, 5 mMol) and 2-iodopropane (1 g, 6 mMol) was refluxed in 20 mL acetone for 20 h. After the removal of acetone in vacuo, the residue was extracted from water with methylene chloride (3×50 mL). The combined extract was dried, evaporated and chromatographed to yield 180 mg (50%) of the desired product. 1HNMR (CDCl3): δ=7.7 (s, 1H); 7.4-7.1 (m, 7H); 4.8-4.6 (m, 1H); 3.0-2.7 (br, m, 4H); 2.6 (d, 2H); 1.8-1.45 (m, 3H); 1.5 (d, 6H); 1.3-1.1 (m, 2H). MS (ESI) m/e 360 (M).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[N:9]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[C:10]=[S:11]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:10]([NH:9][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1)=[S:11]
Reactant: Cc1ccc(Cn2c(CC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: Nc1ccncc1N
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(CC3CCN(CCNC(=S)Nc4cnccc4N)CC3)nc3ccccc32)cc1
Yield: 100 %

Procedure:
A mixture of 5.2 parts of 3,4-pyridinediamine, 19 parts of 2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1-[(4-methylphenyl)methyl]-1H-benzimidazole and 225 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated, yielding 24 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[1-[(4-methylphenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-ethyl]thiourea (405).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH2:11]([Si:13]([CH2:22][CH3:23])([CH2:20][CH3:21])[C:14]#[C:15][CH2:16][CH2:17][CH2:18]I)[CH3:12].[CH3:24][N:25]([CH3:37])[C:26]1([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Cl-].[NH4+].C([O:42]CC)C>>[CH3:24][N:25]([CH3:37])[C:26]1([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:28][C:29]([CH2:18][CH2:17][CH2:16][C:15]#[C:14][Si:13]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:11][CH3:12])([OH:42])[CH2:30][CH2:31]1
Reactant: CCOCC
Reactant: CC[Si](C#CCCCI)(CC)CC
Reactant: CN(C)C1(c2cccs2)CCCCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Product: CC[Si](C#CCCCC1(O)CCC(c2cccs2)(N(C)C)CC1)(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a heated apparatus a 1.7 M solution of tert-butyl lithium in pentane (22.3 mL, 37.9 mmol) was slowly added in drops to a solution of triethyl-(5-iodopent-1-inyl)silane (5.64 g, 18.9 mmol) in absolute diethyl ether (50 mL) at an inside temperature of −70° C. to −75° C. with argon. After 120 min at this temperature a solution of 4-dimethylamino-4-(thiophen-2-yl)cyclohexane (4.22 g, 18.9 mmol) in absolute diethyl ether (100 mL) was slowly added in drops and subsequently stirred for 30 min. The reaction solution was then heated to room temperature and mixed with saturated ammonium chloride solution (100 mL). The phases were separated and the aqueous phase extracted with diethyl ether (3×50 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (7.02 g) was purified by means of flash chromatography (100 g, 20×4.0 cm) with cyclohexane /ethyl acetate (2:1).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1>>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[NH:17][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Product: c1ccc(-c2csc3ncnc(NC4Cc5ccccc5C4)c23)cc1
Yield: 100 %

Procedure:
Using 4-chloro-5-phenylthieno[2,3-d]pyrimidine (50 mg, 0.20 mmol) and 2-aminoindan (110 mg, 0.80 mmol), a similar procedure to Production Example 190 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (67 mg, 0.20 mmol) having the following physical properties:
Reaction SMILES: [CH3:1][C:2]([CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:3][CH2:4][CH3:5].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>>[CH2:13]([O:15][CH:16]([O:12][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:2]([CH3:1])=[CH:3][CH2:4][CH3:5])[CH3:17])[CH3:14]
Reactant: CCC=C(C)C(O)CCCCC
Reactant: C=COCC
Product: CCC=C(C)C(CCCCC)OC(C)OCC
Yield: 68.1 %

Procedure:
10.0 g of 4-methyl-3-decen-5-ol and 12.7 g of ethyl vinyl ether are reacted analogously to Example 9 to give 9.7 g of 5-[1'-ethoxyethoxy]-4-methyl-3-decene, boiling point 115° C./12 Torr, nD20 =1.4349, odour: green, bitterish, citrus-like, reminiscent of chocolate.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)[CH:3]=1.C(S[C:15]1[C:16]([C:25]([N:27]([CH3:38])[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[O:26])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)C.C(=O)(O)[O-].[Na+].[S:44]([O-:48])([O-])(=[O:46])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:44]([C:15]1[C:16]([C:25]([N:27]([CH3:38])[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=2)=[O:26])=[N:17][CH:18]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:20]=1)(=[O:48])=[O:46])[CH3:3]
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(C(F)(F)F)cnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(C(F)(F)F)cnc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.23 g of m-chloroperbenzoic acid (purity of 68%) was added to a mixture of 0.10 g of 3-ethylsulfanyl-N-methyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (Compound of Present Invention 24) and 5 mL of chloroform under ice cooling, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.10 g of 3-ethylsulfonyl-N-methyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide (hereinafter, referred to as Compound of Present Invention 25).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([O:18]C)=[O:17])[CH:7]=[CH:6][N:5]=[CH:4]1>O.CO>[N:3]1([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[C:15]([CH:20]=2)[C:16]([OH:18])=[O:17])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: COC(=O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1

Procedure:
Sodium hydroxide (0.8 g, 20 mmol) in distilled water (3 ml) was added to a solution of methyl 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate (E and Z isomers) (2.4 g;.6.6 mmol) in methanol (30 ml). The mixture was refluxed for 6 hours. After evaporation and acidification with 12N HCl to pH 6, the residue was extracted with dichloromethane and evaporated to dryness to give 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid (mixture of E and Z isomers).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:18]=2[CH2:36][OH:37])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:11]1([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)(=[O:27])=[O:28])[C:18]=2[CH:36]=[O:37])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(CO)c(-c3ccccc3)c3ccccc32)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C=O)c(-c3ccccc3)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of oxalyl chloride (1.37 g, 10.8 mmol) in DCM (30 mL) at −78° C. and under a nitrogen atmosphere was added DMSO (1.50 mL, 21.6 mmol). After stirring for 10 min at −78° C., a solution of [3-phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]methanol (2.27 g, 6.01 mmol) in DCM (20 mL) was added and stirring was continued for 1.5 h. Triethylamine was added and, after stirring for 10 min at −78° C., the mixture was slowly warmed to RT. The reaction mixture was poured into a 1.0M aq HCl solution and extracted with DCM (×3). The combined organic layers were washed with water, then brine, dried (Na2SO4) and concentrated in vacuo affording the title compound as a gum which then solidified on standing to give an off-white solid (2.26 g, 100%). 1H NMR (CDCl3, 400 MHz): δ 10.22 (1H, s), 8.31 (1H, d, J=8.56 Hz), 7.86-7.81 (2H, m), 7.60-7.41 (7H, m), 7.33-7.21 (3H, m), 2.37 (3H, s)