Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1ccc(O)c(O)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccc(O)c(O)c1

Procedure:
The title compound was prepared from 3,4-dihydroxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 11.79 (s, 1H), 9.55 (s, 1H), 9.28 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH3:10])=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[N:7]=[N:6][N:5]([CH2:1][CH2:2][C:3]#[C:4][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:9]=2[CH3:10])=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nnc(-c2ccc(F)cc2)c1C
Product: Cc1c(-c2ccc(F)cc2)nnn1CCC#Cc1ccccn1
Yield: 57.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazole (87 mg, 0.38 mmol, Example 257(B)) and 2-bromopyridine (66 mg, 0.42 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 68 g (0.22 mmol, 58%) of 2-(4-(4-(4-fluorophenyl)-5-methyl-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a white powder (M.P.=130-131° C.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([NH:32][CH2:33][CH2:34][OH:35])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([NH:32][CH2:33][CH2:34][O:35][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CCc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccccc1OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (4.2 ml, 26.4 mmol) was added to a mixture of 2-(tritylamino)ethanol (6.08 g, 20.0 mmol), methyl 3-(2-hydroxyphenyl)propionate (5.00 g, 26.4 mmol), triphenylphosphine (6.91 g, 30.5 mmol) and THF (90 ml) at room temperature under nitrogen, and the mixture was standing for 20 hours at room temperature. The solvent was removed in vacuum. The residue was purified on SiO2, eluting with ethyl acetate-hexane (1:15), to afford the titled product as a colorless oil. (5.88 g, 49%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:6]=2[O:7][CH:8]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O>C(O)(=O)C>[CH:2]([C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:6]=2[O:7][CH:8]=1)=[O:1]
Reactant: O=c1c(CO)coc2c3c(ccc12)CCCC3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1coc2c3c(ccc2c1=O)CCCC3
Temperature: 60 °C

Procedure:
This compound is prepared by adding a mixture of 23.0 g (0.1 mole) of 3-(hydroxymethyl)-7,8,9,10-tetrahydro-4H-naphtho-[1,2-b]pyran-4-one and 150 ml of glacial acetic acid to a solution of 29.8 g (0.1 mole) of sodium dichromate dihydrate in 150 ml of glacial acetic acid, keeping the temperature at about 50°C with cooling. After the initial exotherm, the reaction is heated at 60°C for one-half hour, water (1-liter) is added, and the mixture is heated at 75°C for about one-half hour to generate a precipitate. The cooled mixture is filtered and the crude product is purified by dissolving in methylene chloride and filtering through a layer of silica gel. The aldehyde is obtained by removal of solvent from the filtrate. ##SPC32##
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N:11]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:10][C:3]=1[C:2]([F:18])([F:19])[F:1])#[N:6]
Reactant: N#Cc1ccc(NCCC(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN(CCC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in example 1B using 2-(trifluoromethyl)-4-[(3,3,3-trifluoropropyl)amino]benzonitrile and tert-butyl bromoacetate: 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.8 Hz, 1H), 6.84 (d, J=2.6 Hz, 1H), 6.73 (dd, J=8.8, 2.6 Hz, 1H), 4.03 (s, 2H), 3.74 (t, J=7.5 Hz, 2H), 2.57-2.45 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.CC([O-])=O.[Na+].Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1.CC(O)=O>O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCC(NC(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide, 0.05 mol of anhydrous NaOAc, 0.05 mol of 4-methoxyphenylhydrazine hydrochloride, and 155 ml of glacial HOAc was stirred for 1 hr at room temperature and then refluxed for 1 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 191°-193°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(F)cc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
A solution of 80 mg (0.33 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 66 mg (0.40 mmol) of 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline, 63 mg (0.33 mmol) of EDC and 50 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([F:10])([F:9])[F:8])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:11][C:12]([F:13])([F:14])[F:15])[CH2:6][C:7]([F:8])([F:10])[F:9])[CH3:2]
Reactant: CCOC(=O)C(=CC(F)(F)F)CC(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(F)(F)F)CC(F)(F)F
Yield: 99.1 %

Procedure:
4,4,4-Trifluoro-2-(2,2,2-trifluoroethyl)-but-2-enoic acid ethyl ester (5.0 g, 20.0 mmol) in THF (20 mL) was treated with Pd/C (2.5 g, 5%), and H2 (1 atm.) at 25° C. for 17 h. The reaction mixture was filtered through a pad of the Celite® reagent, rinsed with Et2O (50 mL) and the filtrate was distilled to remove Et2O and THF to afford the product as colorless liquid (5.0 g, 99%).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:20])=[CH:8][C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
4-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (335 mg) described in Preparation Example 22, 1-(2,4-dimethylphenyl)piperazine (199 mg), 1-hydroxybenzotriazole 1 hydrate (142 mg) were dissolved in N,N-dimethylformamide (5 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (202 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (436 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].[C:18]1([N+:24]#[N:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:1]([NH:8][C:9](=[O:14])[C:10](=[N:25][NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11](=[O:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(=O)NCc1ccccc1
Reactant: N#[N+]c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C(=NNc1ccccc1)C(=O)NCc1ccccc1
Temperature: 0 °C

Procedure:
7.27 g (0.038) of N-benzyl-3-oxobutyramide were dissolved in a solution of 5.32 g (0.133 mol) of NaOH in 58 ml of water. To the ice-cooled stirred solution, 0.040 mol of phenyldiazonium chloride were added dropwise at such a rate as to keep the temperature at 0° C. The precipitated solid was filtered and recrystallised from MeOH yielding 9 g of the title compound. M.p.=101°-103° C.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].[C:30]([C:34]1[C:39](Cl)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1>[C:30]([C:34]1[C:39]([O:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:11]2)=[N:38][N:37]2[N:41]=[CH:42][N:43]=[C:36]2[CH:35]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)c1cc2ncnn2nc1Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ncnn2nc1OCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Yield: 32.9 %

Procedure:
4-(Diphenylmethoxy)-1-piperidineethanol (740 mg) was dissolved in dried tetrahydrofurane (18 ml), followed by addition of sodium t-butoxide (251 mg). The mixture was refluxed under heating for 25 minutes. After the mixture was cooled, 7-tert-butyl-6-chloro[1,2,4]triazolo[1,5-b]pyridazine (501 mg) was added thereto. The mixture was refluxed under heating for 2 hours. After the mixture was cooled, ice-water was added thereto, followed by extraction with ethyl acetate. The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica-gel column chromatography and eluted with ethyl acetate. Fractions containing the objective compound were collected and recrystalized from ethyl acetate to yield the title compound (380 mg).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32][CH:33](P(=O)(OCC)OCC)[C:34]2=[O:36])[CH2:29][CH2:28]1.C(O)C>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@H:27]1[N:35]2[C@@H:30]([CH2:31][CH2:32]/[C:33](=[CH:8]\[C:7]3[CH:10]=[CH:11][C:12]([N:13]4[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]4)=[C:5]([O:4][CH3:3])[CH:6]=3)/[C:34]2=[O:36])[CH2:29][CH2:28]1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3ccc(F)cc3F)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4ccc(F)cc4F)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
Lithium hydroxide (406 mg) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (550 mg) and diethyl [(3S,8aR)-3-(2,4-difluorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (1.8 g) in tetrahydrofuran (5 mL)-ethanol (20 mL), and the reaction solution was stirred under shading at room temperature for 12 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.76 g of the title compound as a colorless solid. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:4][O:3]1.[C:12]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]2C(N[C:23](=[O:24])[C:18]=12)=O)(OCC)=[O:13].C(N(CC)CC)C>C(#N)C>[CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:12](=[O:13])[C:17]3[C:18](=[CH:19][CH:25]=[CH:26][CH:27]=3)[C:23]2=[O:24])[CH2:4][O:3]1
Reactant: CC1(C)OCC(CCCN)O1
Reactant: CCOC(=O)c1cccc2c1C(=O)NC2=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCCN2C(=O)c3ccccc3C2=O)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)propylamine (1.05 g, 6.60 mmol) and carboethoxyphthalimide (1.45 g, 6.60 mmol) in acetonitrile (10 mL) at room temperature was added triethylamine (0.92 mL, 6.60 mmol) in one portion and the resuting mixture was stirred at room temperature for 18 hours, evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with brine, 10% citric acid solution and brine, then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6]P(=O)(OCC)OCC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[H-].[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:6][C:5]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CCOP(=O)(Cc1cc(OC)c(OC)c(OC)c1)OCC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C=Cc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
Reaction of diethyl 3,4,5-trimethoxybenzylphosphonate (5.4 g, 17 mmol) with 3,4-dimethoxybenzaldehyde (2 g, 12 mmol) in presence of NaH (0.97 g, 20 mmol), under the conditions noted in example 1, gave 1-(3,4-dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethylene, m.p. 150–152° C.; IR (KBr) νmax 2934, 2835, 1583, 1510, 1331, 1249, 1125, 1024, 1004, 976, 850 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.06 (1H, s), 7.05 (1H, dd, J=8.0, 1.9 Hz), 6.97 (1H, d, J=16.0 Hz), 6.89 (1H, d, J=16.0 Hz), 6.87 (1H, d, J=8.0 Hz), 6.73 (2H, s), 3.95 (3H, s), 3.92 (6H, s), 3.91 (3H, s), 3.87 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:14]#[N:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:14]#[N:15])([C:10]([O:12][CH3:13])=[O:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)C(C#N)Cc1cccc(Cl)c1
Product: COC(=O)CC(C#N)(Cc1cccc(Cl)c1)C(=O)OC

Procedure:
In the same manner as Example 1-(b), 26.5 g of methyl 3-(3-chlorophenyl)-2-cyanopropionate was reacted with methyl bromoacetate to obtain methyl 4-(3-chlorophenyl)-3-cyano-3-methoxycarbonylbutyrate.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][CH:9]([OH:17])[CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH:9]([OH:17])[CH:10]([CH2:15][CH3:16])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:3]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: [H][H]
Reactant: CCCCC(CC)C(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCCCC(CC)C(O)CCC1CCC(O)C1CCCCCCC(=O)O
Yield: 77.9 %

Procedure:
A stirred solution of 7-[2-hydroxy-5-(4-ethyl-3-hydroxyoct-1-enyl)-cyclopentyl]heptanoic acid [0.6 g; prepared as described in Example 4(iii)] in ethanol (25 ml.) was reduced with hydrogen at a hydrogen pressure of 6.3 kg./cm2 and in the presence of a 5% palladium on charcoal catalyst (0.68 g.). The catalyst was then filtered off and the filtrate evaporated to give 7-[2-hydroxy-5-(4-ethyl-3-hydroxyoctyl)cyclopentyl]heptanoic acid (0.47 g.), νmax 1700 cm-1 (Found: C, 71.2; H,11.7%; C22H42O4 requires C, 71.4; H, 11.4%). N.M.R. (approximately 10% solution in deuterochloroform) 0.65-1.05δ (2 overlapping triplets, terminal CH3 groups), 1.05-2.2δ (overlapping multiplets, cyclic and chain CH2 groups), 2.30δ (triplet CH2C=O),3.60-3.88δ, 4.2δ (multiplets, methylidene groups attached to hydroxy groups), 5.6-6.6δ broad singlet, OH and COOH groups).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][NH:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(N)cc1C
Solvent: CCOCC
Product: COC(=O)CNc1ccc(C)c(C)c1
Yield: 81.7 %

Procedure:
3,4-Dimethylaniline (70.0 g) and methyl bromoacetate (44.2 g) were stirred at 100° under nitrogen for 2 h. The cooled reaction mixture was poured into ether (700 ml) and filtered. The collected solid was washed with ether (2×100 ml) and the combined filtrates were concentrated to give a solid (45.6 g) which was purified by FCC on triethylamine deactivated silica eluting with dichloromethane: petroleum ether (1:3) to give a solid (21.8 g), a portion of which (2.5 g) was purified further by FCC as above to give the title compound (2.06 g), m.p. 53°-55°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1.C(N(CC)CC)C>CC#N>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: COc1ccccc1CN(CCCCCCBr)Cc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccccc1CN(CCCCCCN1CCc2ccccc2C1)Cc1ccccn1
Reaction time: 48 h
Yield: 73 %

Procedure:
The compound 2 (0.44 g, 1.13 mmol), 1,2,3,4-tetrahydroisoquinoline (0.22 g, 1.69 mmol) and triethylamine (0.218 g, 1.69 mmol) were added to 300 mL CH3CN, and the solution was stirred for two days. Purification was carried out on a silica gel TLC plate that was developed in 4% methanolic NH3 (7 M NH3 in methanol)/96% CH2Cl2. The product was obtained as pale yellow oil (73%). 1H NMR (CDCl3) δ 8.488 (dd, 1H, Ar), 7.616 (ddd, 1H, Ar), 7.573 (dd, 1H, Ar), 7.497 (dd, 1H, Ar), 7.219 (ddd, 1H, Ar), 7.090 (m, 4H, Ar), 7.004 (d, 1H, Ar), 6.933 (ddd, 1H, Ar), 6.833 (d, 1H, Ar), 3.789 (s, 3H, —OCH3), 3.766 (s, 2H, —CH2—), 3.671 (s, 2H, —CH2—), 3.608 (s, 2H, —CH2—), 2.895 (t, 2H, —CH2—), 2.712 (t, 2H, —CH2—), 2.491 (t, 2H, —CH2—), 2.455 (t, 2H, —CH2—), 1.554 (m, 4H, —CH2—CH2—), 1.298 (m, 4H, —CH2—CH2—). Mass Spec.=443.62 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])=[O:29])=[CH:23][CH:22]=1)#[N:20]>CN(C)C(=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH2:30][C:28](=[O:29])[NH:27][C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:33]=3)[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(NC(=O)COc2cccc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4ccc(C#N)cc4)c3)sc2C1
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Add ((S)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.10 g, 0.37 mmol) followed by O-(7-aza-benzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) and N,N-diisopropylethyl (0.13 mL, 0.70 mmol) amine to a solution of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid (0.10 g, 0.34 mmol) in N,N-dimethylacetamide (3 mL). Heat the mixture to 50° C. for 2 h then cool to room temperature and dilute with water causing a solid to precipitate from solution. Collect the light yellow solid by filtration, wash with water, and dry on the filter pad to provide 0.14 g of ((S)-2-{3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(O)(O)(=O)=O.[NH2:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][C:3]=1[C:4]([NH:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1)=[O:6]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a thermally controlled reaction vessel, add 2-chloro-5-[(2,2-dimethylpropanoylamino)methyl]benzoic acid (420 g, 1.56 mol, 1.0 equiv), 2-aminoimidazole monosulfate (349 g, 1.87 mol, 1.2 equiv), N,N-dimethylformamide (2.94 L), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (722 g, 2.18 mol, 1.4 equiv), and N,N-diisopropylethylamine (869 mL, 4.98 mol, 3.2 equiv). Heat the resulting suspension to an internal temperature of 80° C. for 18 hours. Cool the reaction mixture to 10° C., pour the mixture into ice water (14 L), and stir for 90 min. Collect the solids by filtration, dry the material in air for 24 h, and in a vacuum oven at 50° C. for 24 h. Slurry the solid material in isopropanol (7 L), heat to an internal temperature of 73° C. for 3 h, and cool to 10° C. Filter the suspension to isolate the solid material. Dry the material in air for 24 h and in a vacuum oven at 55° C. for 48 h to give the title compound as an off-white solid (435 g, 83.4%). 1H NMR (DMSO-d6, 400 MHz): δ 11.84 (s, 2H), 8.13 (t, 1H, J=6.0 Hz), 7.47 (d, 1H, J=8.3 Hz), 7.40 (d, 1H, J=1.7 Hz), 7.31 (dd, 1H, J=8.3, 2.0 Hz), 6.73 (s, 2H), 4.27 (d, 2H, J=5.9 Hz), 1.12 (s, 9H). MS (m/z) (35Cl/37Cl) 335/337 (M+1).