Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([O:31]CC)=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O.[OH-].[Li+].C(O)(=O)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[S:17][C:18]4[CH2:24][CH2:23][CH2:22][CH:21]([N:25]5[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]5)[C:19]=4[CH:20]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1CN(C2CCCc3sc(-c4noc(-c5ccc(CC(C)C)cc5)n4)cc32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Cc1ccc(-c2nc(-c3cc4c(s3)CCCC4N3CC(C(=O)O)C3)no2)cc1
Yield: 63.2 %

Procedure:
The title compound (26 mg) was synthesized in a yield of 64% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using ethyl 1-{2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzothien-4-yl}-azetidine-3-carboxylate (44 mg, 0.094 mmol) that was obtained in Example 8 (8g), lithium hydroxide monohydrate (8.7 mg, 0.20 mmol), and acetic acid (11 μl, 0.20 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:5]=1[C:6](=[O:19])[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]2=[O:18])([O-])=O.[H][H].O=O>[Pd].C(O)C>[NH2:1][C:4]1[C:5]2[C:6](=[O:19])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:18])[C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=O
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 97.5 %

Procedure:
0.13 Gram of a 5% palladium on carbon catalyst was added to a mixture of 13 grams of 5-nitrotetrahydroanthraquinone and 1200 grams of ethanol, and hydrogen was fed into the resultant mixture for absorption in an amount of 3 mols per mol of the 5-nitro compound at room temperature and under atmospheric pressure. The solution was first pale yellow in color, and then gradually turned yellowish brown and finally pale yellow again. Then, after the hydrogen in the reactor was replaced by nitrogen, 20 grams of a 20% sodium hydroxide solution was added to the reaction solution, the color of which immediately turned dark reddish brown through dark reddish purple and a small amount of glossy crystals were precipitated. The reaction was completed rapidly and air was fed into the reaction solution for oxidation. Upon determination, it was found that 1 mole of oxygen was absorbed per mol of the 5-nitro compound. As a result of the oxidation, the reaction solution turned reddish orange with reddish orange-colored crystals being precipitated. The resultant solution was subjected to filtration, followed by extraction of the resultant cake with acetone for separation of the catalyst. The resultant filtrate was dried to obtain 11 grams of 1-aminoanthraquinone having a purity of 95%.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[C:6](=O)([O:15]N1C(=O)CCC1=O)[O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14].C(N(CC)CC)C>C(#N)C>[C:6](=[O:15])([O:7][N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]1=[O:14])[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: OCC1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(OCC1CC1)ON1C(=O)CCC1=O
Reaction time: 8 h

Procedure:
To a stirred solution of cyclopropylmethanol (1.0 g, 13.8 mmol) in acetonitrile (15 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (7.1 g, 27.7 mmol) and triethylamine (5.8 mL, 41.6 mmol). The reaction was stirred overnight then quenched with saturated NaHCO3 (aq.) and extracted with ethyl acetate (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as an amber oil: 1H NMR (300 MHz, CDCl3) δ 4.16 (d, J=7.5 Hz, 2H), 2.84 (s, 4H), 1.26 (m, 1H), 0.70-0.64 (m, 2H), 0.40-0.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([CH3:17])[CH:11]=1.N(OCCC(C)C)=O.[I:26]I>C(Cl)(Cl)Cl>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([I:26])=[C:12]([CH3:17])[CH:11]=2)=[C:2]([F:1])[CH:7]=1
Reactant: II
Reactant: COc1ccc(-c2ccc(N)c(C)c2)c(F)c1
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc(I)c(C)c2)c(F)c1

Procedure:
2′-fluoro-4′-methoxy-3-methylbiphenyl-4-amine (190 mg, 0.822 mmol), 3-methylbutyl nitrite (144.4 mg, 1.233 mmol), iodine (251 mg, 0.986 mmol) and chloroform (7 ml) were refluxed in an oil bath for 3.5 hours then allowed to cooled to ambient overnight. Reaction crude was purified by flash chromatography (SiO2, Biotage 40+M cartridge) eluted with a EtOAc/hexanes gradient mixture. Related fractions were pooled and concentrated in vacuo to afford the title compound. LCMS was showing the solid to be about 70A % pure. LCMS (ESI) calc.=LCMS (ESI) calc.=341.99; found=341.94 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]=[O:9].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1
Reactant: OCCO
Reactant: O=Cc1sc(Br)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1cc(Br)c(C2OCCO2)s1
Yield: 80.8 %

Procedure:
A mixture consisting of the product from Step A (11.0 g, 40.7 mmol), TsOH (0.25 g) and ethylene glycol (5.06 g, 81.5 mmol) in toluene (150 mL) was heated at reflux temperature for 1.5 h, water was removed by a Dean-Stark trap. The reaction mixture was cooled and poured into a saturared aqueous solution of sodium bicarbonate (100 mL). The organic layer was separated, dried (MgSO4), and evaporated to dryness. Purification of this crude material by column chromatography (silica, 6% ethyl acetate/hexane) gave 10.33 g of an oil (81%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)(=[O:37])=[O:36])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3cccnc3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyridin-3-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11m, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.69 (d, 1H), 8.59 (d, 1H), 7.98 (m, 1H), 7.88 (m, 2H), 7.49-7.38 (m, 4H), 7.24 (m, 2H), 7.11 (m, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.90 (s, 1H), 4.54 (s, 2H), 4.49 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.49 (t, 2H); MS 502 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][C@H:6]2[C:9]3[C:14]([CH2:15][CH2:16][C@H:5]2[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.CC(C)([O-])C.[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][C@@H:5]2[CH2:16][CH2:15][C:14]3[C:9]([C@@H:6]2[CH2:7]1)=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC[C@@H]2CCc3ccccc3[C@@H]2CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a suspension of cis-1,3,4,5,5a,6,7,11b-octahydro-3-oxo-2H-naphth[1,2-c]azepine (1.0 g, 4.65 mmol), from Step 3 of Example 75, in 20 mL of dry THF, was added potassium t-butoxide (0.78 g, 6.9 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h and then cooled to 0° C. and benzyl bromide (0.8 mL, 6.7 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 3 h and then poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystalized from ether/hexane to afford 1.1 g (79% yield) of the title compound, m.p. 114°-115° C.; MS DCl--NH3M/Z: 306 (M+H)+ ; 1H NMR (CDCl3) δ1.5-2.2 (5H, m), 2.42-2.54 (1H, m), 2.58-3.03 (5H, m), 3.79 (1H, dd, J=9.5, 13.6 Hz), 4.44 (1H, d, J=13.6 Hz), 4.95 (1H, d, J=13.6 Hz), 6.47-6.5 (1H, m), 6.97-7.45 (8H, m).
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2.C1(C)C=CC(S(O[CH2:27][CH2:28][Cl:29])(=O)=O)=CC=1>C(O)C>[Cl:29][CH2:28][CH2:27][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2
Reactant: O=C1CCc2cc(O)ccc21
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C1CCc2cc(OCCCl)ccc21
Reaction time: 25 h

Procedure:
To a solution of sodium ethoxide in ethanol prepared from 5.68 g of sodium and 500 ml of absolute ethanol, 36.75 g of 5-hydroxy-1-indanone in 500 ml of slightly-heated ethanol are added in the course of 30 minutes. Then, 74.5 g of β-chloroethyl p-toluenesulphonate in 100 ml of ethanol are dropwise added, and the mixture is refluxed under stirring for 25 hours. Then the mixture is cooled, the insolubilized sodium p-toluenesulphonate 40 g, dry) is filtered off, and the ethanol is evaporated till dryness under vacuum. The residue (71.6 g) is treated with water (250 ml) and methylene chloride (250 ml); the aqueous phase is extracted two further times with methylene chloride, and the organic extracts are washed twice with 100 ml of 10% sodium hydroxide and with water till neutralization. The solvent is evaporated and the residue (54 g) is purified over silica-gel column; by eluting with methylene chloride:hexane (9:1) the excess β-chloro-ethyl p-toluenesulphonate is separated, and the desired product is isolated with methylene chloride; 26.6 g (51%) of a yellow solid are obtained. M.P. 79°-82° C. and analysis correct.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)Nc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-phenylacetamide (0.040 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylaminobenzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was heated at 70° C. for 3 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane and then 1% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.006 g, 12%); 1H-NMR (500 MHz, DMSO-d6) 2.76 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.23 (s, 2H, NCH2CO), 3.75 (br s, 4H, piperazine N(CH2)2), 6.81 (d, J=7.90 Hz, 2H) and 8.01 (d, J=8.49 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.07 (t, J=7.27 Hz, 1H, p-ArH), 7.32 (t, J=8.48 Hz, 2H, m-ArH), 7.67 (d, J=8.48 Hz, 2H, o-ArH), 8.06 (s, 1H, imidazo[4,5-b]pyridine 5-H), 9.77 (s, 1H, CONH), 13.11 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][NH2:30]>C(OCC)(=O)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:29][NH2:30])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CC(C)(C)c1ccc(C(=O)NN)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-tert-butyl benzoic acid (0.2 g, 1.2 mmol in 10 mL of dry THF) cooled to 0° C. and treated with N-methyl-morpholine (1.6 mL, 14.6 mmol) as well as isobutyl chloroformate (1.7 mL, 1.3 mmol). Then the mixture was stirred for 10 minutes at 0° C. After hydrazine (0.6 g, 3.6 mmol) was added to the reaction mixture, it was stirred 3 hours at 25° C. The reaction was then diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution as well as brine, and concentrated in vacuum. The crude material was chromatographed on silica gel eluting with hexanes/ethyl acetate=2:1 to give 4-tert-butyl-benzoic acid hydrazide.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ncnc(Cl)c12
Reactant: Nc1cccc(Cl)c1
Solvent: CCO
Product: Cc1c(C)n(Cc2ccccc2)c2ncnc(Nc3cccc(Cl)c3)c12

Procedure:
0.6 g of 4-chloro-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine and 0.28 ml of m-chloroaniline are heated at reflux in 10 ml of ethanol for 17 hours. The brown solution is concentrated to dryness by evaporation, the residue is taken up in ethyl acetate, and the ethyl acetate solution is washed until neutral with sodium hydrogen carbonate solution and water, dried and concentrated by evaporation. The residue is crystallised from ethyl acetate/hexane. 4-(m-Chloroanilino)-5,6-dimethyl-7-benzyl-pyrrolo[2,3-d]pyrimidine is obtained in the form of white crystals having a melting point of 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH:16]=O.[CH2:18]([O:20][C:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22])[CH3:19]>>[Cl:1][C:2]1[CH2:7][C@H:6]2[C@H:4]([C@H:5]2[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1/[CH:16]=[CH:23]/[C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=C(Cl)C[C@@H]2[C@H](CCc3ccccc3)[C@H]12
Product: CCOC(=O)/C=C/C1=C(Cl)C[C@@H]2[C@H](CCc3ccccc3)[C@H]12

Procedure:
±(1S,5R,6S)-3-chloro-6-phenethylbicyclo[3.1.0]hex-2-ene-2-carbaldehyde (11 mmol crude weight) was olefinated with ethoxycarbonylmethylene triphenylphosphorane (4.6 g, 13.2 mmol) according to General Procedure 1.1.B to afford the title compound. The material was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 10% EtOAc. 2.2 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08-1.19 (m, 1H), 1.23-1.31 (m, 1H), 1.30-1.37 (m, 3H), 1.39-1.51 (m, 1H), 1.59-1.68 (m, 1H), 2.14 (td, J=7.25, 3.03 Hz, 1H), 2.38 (dd, J=19.57, 2.68 Hz, 1H), 2.53-2.66 (m, 2H), 2.92 (dd, J=19.55, 7.88 Hz, 1H), 4.20-4.31 (m, 2H), 6.04 (d, J=15.72 Hz, 1H), 7.10-7.22 (m, 3H), 7.23-7.31 (m, 2H), 7.61 (d, J=15.72 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](Cl)=[N:21][OH:22])=[CH:18][C:17]=1[CH3:26].C(=O)([O-])O.[K+]>O1CCCC1>[Br:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:11]([F:14])([F:12])[F:13])[O:22][N:21]=2)=[CH:18][C:17]=1[CH3:26]
Reactant: Cc1cc(C(Cl)=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 90.5 %

Procedure:
In a solution of 22.7 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene produced in Step 1 and 26.0 g of 4-bromo-α-chloro-3-methylbenzaldoxime produced in Step 2 in 120 mL of tetrahydrofuran, 15.7 g of potassium hydrogen carbonate was added, and stirred under reflux with heat for 5 hours. After the completion of the reaction, the reaction mixture was left and cooled to room temperature, insoluble material was filtered off, and then the solvent was distilled off under reduced pressure. 150 mL of water was added in the residue, stirred at room temperature for 18 hours, and then precipitated crystal was filtered off, and dried to obtain 38.6 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:8]1.[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[CH3:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[CH2:10][CH2:11][CH:7]([N:3]3[CH2:4][CH2:5][CH2:6][CH:2]3[CH3:1])[CH2:8]2)=[CH:13][C:14]=1[C:19]([F:22])([F:20])[F:21])=[O:27]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: CC1CCCN1C1CCN(c2ccc(N)c(C(F)(F)F)c2)C1
Product: Cc1ccc(C(=O)Nc2ccc(N3CCC(N4CCCC4C)C3)cc2C(F)(F)F)c(C)c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-2-trifluoromethyl-phenylamine with 2,4-dimethyl benzoyl chloride. MS: 446.2 (M+H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)=[CH:6][CH2:5]1)[CH2:2][CH3:3].C([CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2C=[CH:31][C:30](C#C)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)CC>>[CH2:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2([C:11]#[C:12][C:21]3[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[CH2:29][CH2:30][CH3:31])=[CH:25][CH:26]=3)[CH:17]=[CH:16][CH:13]=[CH:14][CH2:15]2)=[CH:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C#Cc1ccc(C2=CCC(CCC)CC2)cc1
Reactant: C#Cc1ccc(C2CCC(CCC)CC2)cc1
Product: CCC/C=C/c1ccc(C#CC2(C3=CCC(CCC)CC3)C=CC=CC2)cc1
Yield: 72 %

Procedure:
In the same manner as in Example 17 except that 4-(4-propylcyclohexenyl)phenylacetylene, (3.4 g, 0.015 moll was used in place of 4-(4-propylcyclohexyl)phenylacetylene, the reaction was carried out to obtain 1-(4-propylcyclohexenyl)phenyl-2-[4-(1-trans-pentenyl)phenyl]acetylene (2.7 g). Yield: 72%.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:20]([NH:1][CH:2]1[C:8]2=[N:9][C:10]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][N:15]=3)=[CH:11][C:12](=[O:13])[N:7]2[CH2:6][CH2:5][O:4][CH2:3]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1COCCn2c1nc(-c1ccncn1)cc2=O
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=c1cc(-c2ccncn2)nc2n1CCOCC2NCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of 0.090 g (0.35 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in 3.5 ml of dichloromethane was added 0.040 mL (0.36 mmol) of benzaldehyde, 0.184 g (0.87 mmol) of sodium triacetoxyborohydride and few drops of glacial acetic acid. The reaction mixture was stirred at room temperature for 15 hours. The residue was dissolved in dichloromethane and a saturated aqueous solution of sodium carbonate, extracted with dichloromethane and washed with saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 95/5/0.5 to give 0.022 g (13%) of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=1)=[O:4].[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][C:39]3[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=3)[CH:12]=2)[N:7]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(O)ccc3n2-c2ccc(OC(C)C)cc2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)c1ccc(-c2c(C(=O)OC)c3cc(Oc4ccc(Cl)cc4)ccc3n2-c2ccc(OC(C)C)cc2)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)-2-(4-methoxycarbonylphenyl)indole-3-carboxylic acid methyl ester (150 mg, 0.32 mmol, see step (b) Example 43) and 4-chlorophenylboronic acid (100 mg, 0.64 mmol). Yield 97 mg (54%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(C=CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C)cc1
Yield: 100.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.3 g, 99%) as an oily product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=CC=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[NH:11][C:12](=[S:15])[NH:13][N:14]=1.Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([C:10]2[NH:14][N:13]=[C:12]([S:15][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:11]=2)[O:1][C:5]=1[CH3:6]
Reactant: S=c1[nH]nc(-c2cc3ccccc3o2)[nH]1
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)oc1C
Yield: 59 %

Procedure:
Prepared in a similar manner to example 1 using 5-(benzofuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 6a) and 2-(bromomethyl)pyridine hydrobromide. Yield 59%. 1H NMR (500 MHz, CDCl3): δ 4.37 (s, 2H), 7.26-7.34 (m, 5H), 7.4-7.42 (d,1H), 7.55-7.57 (d, 1H), 7.65-7.67 (d, 1H), 7.75 (t, 1H), 8.62 (s, 1H). MS(M+H, 309).