Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]C)=O)[NH:6]2.CC(C)([O-])C.[K+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].Cl>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:12](=[O:14])[CH:23]([C:22]([O:26][CH3:27])=[O:25])[CH2:24][N:6]3[C:7]=2[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1Cn2c(cc3c(Br)cc(F)cc32)C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 81.8 %

Procedure:
To a suspension of the indole of Step 4 (4 g, 15 mmol) in a mixture of 10:1 toluene/THF (100 mL) at r.t. was added potassium t-butoxide (15 mL of a 1M solution in THF). The reaction mixture was stirred for 2 minutes and methyl acrylate (2.5 g, 30 mmol) was added. The mixture was stirred at reflux for 5 hours and cooled to r.t. Then 1N HCl was added to acidify to pH 3 and the reaction mixture was extracted with EtOAc and the combined organic layers were concentrated. The residue was swished in EtOAc/Hexanes to give 4 g of the desired compound as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:19](=[O:21])[NH2:20])[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]=2[C:9]([CH3:29])=[CH:8][CH:7]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:22]([N:11]1[C:10]2[C:9]([CH3:29])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][C:16]=2[C:19](=[O:21])[NH2:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)COc1ccc(C)c2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(OCC(=O)O)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A slurry of 32 mg (0.0795 mmol) of [9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid methyl ester in 1 ml of tetrahydrofuran and 3.5 ml of methanol was treated with 0.3 ml of an aqueous 2 N sodium hydroxide solution and stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1:1 ethyl acetate/tetrahydrofuran and 0.2 N HCl solution. After another extraction with 1:1 ethyl acetate/tetrahydrofuran, the extracts were washed with brine, dried over magnesium sulfate and concentrated to afford (27 mg) of the title compound. mp. 253-254° C. ESIMS m/e 389 (M++1), 387 (M+−1) NMR (300 MHz, d6-DMSO): δ12.83 (br, 1H); 7.75 (br, 1H); 7.53 (d, J=8.2, 1H); 7.41-7.34 (m, 2H); 7.28-7.17 (m, 3H); 7.07 (m, 2H); 6.90 (d, J=7.2, 2H); 6.49 (d, J=8.1, 1H); 5.89 (s, 2H); 4.79 (s, 2H); 2.52 (s, 3H).
Reaction SMILES: C(C1C=CC=CC=1)(=O)C.C(NCCCCCCNCC1C=CC=CC=1)C1C=CC=CC=1.C([N:39]([CH2:75][C:76]([C:78]1[CH:83]=[CH:82][C:81]([O:84]CC2C=CC=CC=2)=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=1)=[O:77])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46](CC1C=CC=CC=1)[CH2:47][C:48](=[O:67])[C:49]1[CH:54]=[CH:53][C:52]([O:55]CC2C=CC=CC=2)=[C:51]([NH:63][C:64]([NH2:66])=[O:65])[CH:50]=1)C1C=CC=CC=1>CC(C)=O>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([CH:48]([OH:67])[CH2:47][NH:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][NH:39][CH2:75][CH:76]([OH:77])[C:78]2[CH:83]=[CH:82][C:81]([OH:84])=[C:80]([NH:92][C:93]([NH2:95])=[O:94])[CH:79]=2)=[CH:50][C:51]=1[NH:63][C:64]([NH2:66])=[O:65]
Reactant: NC(=O)Nc1cc(C(=O)CN(CCCCCCN(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: c1ccc(CNCCCCCCNCc2ccccc2)cc1
Solvent: CC(=O)c1ccccc1
Solvent: CC(C)=O
Product: NC(=O)Nc1cc(C(O)CNCCCCCCNCC(O)c2ccc(O)c(NC(N)=O)c2)ccc1O

Procedure:
Following the procedures of Example 14, the above prepared acetophenone and N,N'-dibenzyl-hexamethylenediamine are refluxed in acetone for 12 hours and the resulting N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-ureidophenyl)-2-oxoethyl]-hexamethylenediamine is hydrogenated to yield N,N'-bis[2-(4-hydroxy-3-ureidophenyl)-2-hydroxyethyl]-hexamethylenediamine.
Reaction SMILES: [CH3:1][CH:2]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:3].C([Li])CCC.CO[C:20](Cl)=[O:21]>C1COCC1>[CH3:1][C:2]1([CH3:3])[S:4](=[O:5])(=[O:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:20]1=[O:21]
Reactant: CC(C)S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (propane-2-sulfonyl)-benzene (CAS#4238-09-9), which can be prepared as described in Cram, D. J. et al. Journal of the American Chemical Society, 1967, 89, 2072-2077, (1.18 g, 6.4 mmol) in THF (60 mL) at 0° C. is added a 2.5 M solution of n-butyl lithium in hexanes (5.8 mL, 14.7 mmol). The reaction is slowly warmed to room temperature over an hour, at which time it is re-cooled to −78° C. and methylchloroformate (0.74 mL, 9.6 mmol) is added. The reaction is brought to room temperature and permitted to stir for 16 hours. The reaction is then quenched with saturated aqueous NH4Cl and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:4) to provide 2,2-dimethyl-1,1-dioxo-1,2-dihydro-1lambda*6*-benzo[b]thiophen-3-one. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 6 H), 7.79-7.86 (m, 1 H), 7.92-7.99 (m, 1 H), 8.03 (d, J=8.1 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH3:18])=[O:16].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:15]([N:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1)([O:17][CH3:18])=[O:16]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)N1CCN(Cc2ccccc2)CC1
Yield: 81.8 %

Procedure:
To a solution of 35.2 g (0.20 mole) of 1-benzylpiperazine in 100 ml of CHCl3 was added dropwise over a period of 30 minutes a solution of 17.0 g (0.18 mole) of methyl chloroformate in 110 ml of CHCl3. The mixture was allowed to reflux during 2.5 hours and was made basic with 16 g of sodium hydroxide in 100 ml of water. The nonaqueous layer was separated, dried over magnesium sulphate and concentrated. The residue was distilled b.p. 108°-10° C. at 0.1-0.2 mmHg to give 34.5 g of 1-carbomethoxy-4-benzylpiperazine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8](N)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].C(ON=O)CC(C)C.C[Si](C)(C)[Br:33].C(=O)(O)[O-].[Na+]>BrCBr>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][C:8]([Br:33])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(N)nc1C(F)(F)F
Reactant: C[Si](C)(C)Br
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: BrCBr
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a suspension of 2.11 g 5-amino-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid methyl ester in 20 ml dibromomethane was added 1.59 g isoamylnitrite and the mixture was cooled to 0° C. To the resulting suspension was added 2.922 g trimethylbromosilane and the mixture was stirred at 0° C. for 10 min (no conversion by HPLC) and at room temperature for 3 h. To the dark reaction mixture was added another 1.59 g isoamylnitrite and the mixture was stirred at room temperature for 6 h. The dark reaction mixture was pored onto ice and ca 20 ml 10% sodium bicarbonate and the product was extracted with dichloromethane (2.64 g raw material which crystallized) and purified by chromatography on silica gel (20 g hep:EE=9:1 to 1:1) to yield 2.290 g of the title compound as white crystals. MS (M+H at 396.8 and 394.9).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[O:30]1[C:34]([C:35]2[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=2)[NH2:38])=[CH:33][N:32]=[CH:31]1.Cl>O1CCOCC1.CC(O)C>[F:26][C:25]([F:28])([F:27])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]4[CH:39]=[CH:40][CH:41]=[C:35]([C:34]5[O:30][CH:31]=[N:32][CH:33]=5)[CH:36]=4)[N:7]=3)=[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][N:11]3[N:10]=2)[CH:18]=1)=[O:29]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)C(F)(F)F
Reactant: Nc1cccc(-c2cnco2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1)C(F)(F)F
Temperature: 90 °C
Yield: 82.2 %

Procedure:
To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 0.002 mol) (see Example 1, Step C) in 1,4-dioxane (25 mL) and i-PrOH (5 mL) was added 3-(1,3-oxazol-5-yl)aniline (1.15 g, 0.007 mols) followed by catalytic 12M HCl. After heating overnight at 90° C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent was removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), the organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes then 100% EtOAc) to provide the product (0.89 g, 69%) as an off-white solid. ES-LC/MS m/z=542 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:9]=1[NH:10][C:11]1[C:12]([CH3:20])=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:7]#[N:8].C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1)CCC.C(N(CC)CC)C>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:12]1[C:11]([NH:10][C:9]2[C:6]([C:7]#[N:8])=[CH:5][N:4]=[CH:3][C:2]=2[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2
Reactant: Cc1c(Nc2c(I)cncc2C#N)ccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1c(Nc2c(C#N)cncc2-c2nccs2)ccc2[nH]ccc12

Procedure:
A mixture of 5-iodo-4[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile (120 mg, 0.32 mmol), 2-(tributylstannyl)-1,3-thiazole (340 mg, 0.91 mmol), dichlorobis(triphenylphosphine)palladium(II) (28 mg, 0.04 mmol), and triethylamine (36 mg, 0.35 mmol) in dioxane (4 mL) was heated at reflux for 24 h. 4-[(4-Methyl-1H-indol-5-yl)amino]-5-(1,3-thiazol-2-yl)nicotinonitrile was obtained following the work-up and purification procedures as described for the preparation of 5-(2-formyl-1-methyl-1H-imidazol-5-yl)-4-[(4-methyl-1H-indol-5-yl)amino]nicotinonitrile 541. HPLC retention time: 10.1 min.(g); MS: 332.2 (M+H); melting range: 245-247° C.; and HRMS: 332.0964.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2=[O:12].[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:26](=[O:27])[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([CH2:18][C:17]4[CH:16]=[CH:15][C:14]([F:13])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)=[O:29])=[CH:10][CH:9]=2)[C:5](=[O:12])[NH:6]1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: CCOCC
Product: O=C(Nc1ccc2c(c1)C(=O)NC2=O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 5-amino-isoindole-1,3-dione [Tetrahedron 54, 7485. (1998)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic-acid (Example 1b) according to the method described in Example 1c. Melting Point: 226-228° C. (diethylether)
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>ClCCl>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Yield: 47.2 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-tetradecanol (96.3 grams, 449 mmol), pyridine (40 milliliters), and dichloromethane (1000 milliliters) was heated to 30° C. 4-Nitrobenzoyl chloride (100 grams, 539 mmol) was added in portions over a twenty minute period. The reaction mixture was heated to reflux for sixteen hours. The reaction mixture was washed with water (2×500 milliliters). The organic layer was concentrated under reduced pressure to a yellow solid. 1000 milliliters of hexane was added and the mixture was heated to reflux. The mixture was cooled and filtered. The filtrate was concentrated to yield a yellow solid. The yellow solid was recrystallized twice from ethanol to obtain 77.0 grams of tetradecyl 4-nitrobenzoate as yellow crystals.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19](Cl)[C:18]([C:22]#[N:23])=[CH:17][N:16]=1)[CH3:13]>CN(C=O)C.O>[CH2:12]([S:14][C:15]1[N:16]=[C:17]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[C:18]([C:22]#[N:23])=[CH:19][N:20]=1)[CH3:13]
Reactant: CCSc1ncc(C#N)c(Cl)n1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ncc(C#N)c(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
To a suspension of sodium hydride (31 mg, 0.78 mmol) in DMF (2.5 mL) at 0° C. was added benzimidazole (86 mg, 0.72 mmol). After stirring for 5 min, the reaction mixture was warmed to room temperature. To this was added 2-ethylthio-4-chloro-5-cyanopyrimidine (130 mg, 0.65 mmol) dissolved in DMF (1.0 mL), then the mixture was heated at 100° C. for 1 h. The reaction mixture was cooled and carefully diluted with H2O. The aqueous layer was extracted with EtOAc several times, and the combined extracts were washed with brine. After drying over Na2SO4, the crude material was purified by flash chromatography using 1:7 acetone:hexane system to give 126 mg of the title compound. Mass spectrum 282.2 (ESI, M+1).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:30]=[N+:31]=[N-:32].[Na+].Cl.C(N(CC)CC)C>CN1CCCC1=O>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[NH:32][N:31]=[N:30][N:20]=3)[CH:10]=[C:9]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCCCCOc1cc(-c2ccc3c(c2)OCO3)cc(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: c1ccc(-c2cc(-c3ccc4c(c3)OCO4)cc(OCCCCCc3nnn[nH]3)n2)cc1

Procedure:
By using a similar procedure to that described in example 9 but with 2.4 g 6-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}hexanonitrile, 1.65 g of sodium azide, 1.3 g of triethylamine hydrochloride (in place of ammonium chloride) and 90 cc of N-methylpyrrolidone (in place of dimethylformamide) as the starting material (70 hours; 150° C.), and after purification by flash chromatography on silica gel (30-60 mm; eluent: ethyl acetate) and recrystallization from 18 cc of acetonitrile gives 5-{5-{[6-phenyl-4-(3,4-methylenedioxyphenyl)-2-pyridyl]oxy}pentyl }-1H-tetrazole (m.p.=150° C.)
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.O1CCCC1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:9][CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[O:24])=[CH:18][CH:17]=1
Reactant: NCCCn1cncn1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCCn1cncn1)Nc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A 1.26 g. portion of 1H-1,2,4-triazole-1-propanamine was suspended in 15 ml. of toluene and 5 ml. of tetrahydrofuran was added to produce solution. A solution of 1.55 g. of freshly distilled p-chlorophenyl isocyanate in 15 ml. of toluene was added and the mixture was stirred overnight. The resulting crystals were recrystallized from toluene, giving 2.06 g. of the desired product, mp. 137°-139° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:22][C:19]3[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH2:6][CH3:7])[C:4]([OH:3])=[O:23])=[CH:17][CH:18]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCC(Cc1ccc(OCCc2nc(C3CCCCC3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared from 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the method of Example 46. 1H NMR (400 MHz, CDCl3) δ 8.01 (bs, 1H), 7.31-7.26 (m, 2H), 7.06-6.96 (m, 5H), 6.72 (d, 2H, J=8.8 Hz), 4.08 (t, 2H, J=6.4 Hz), 3.28 (s, 2H), 2.91 (t, 2H, J=6.4 Hz), 2.81 (tt, 1H, J=11.6, 3.6 Hz), 2.26 (s, 3H), 2.18-1.98 (m, 4H), 1.82-1.77 (m, 2H), 1.72-1.67 (m, 1H), 1.58-1.48 (m, 2H), 1.39-1.18 (m, 3H), 0.92 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:19][CH3:20])=[C:6]([F:11])[CH:5]=1
Reactant: CCI
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)OC)cc1F
Yield: 100.7 %

Procedure:
A solution of 3-fluoro-4-hydroxy-benzoic acid methyl ester (1.5 g, 8.82 mmol), K2CO3 (2.43 g, 17.6 mmol) and ethyliodide (2.75 g, 17.6 mmol) in DMF (15 ml) was heated to 80° C. for 2 hrs. Addition of excess Na2CO3 and extraction with EtOAc followed by washing with satd. NaCl, then drying with Na2SO4 and evaporation afforded the title compound (1.76 g, 101% yield) as an orange oil. MS: m/e=170 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:20]=4[C:21]=3[CH3:22])=[CH:11][C:9]=2[CH:10]=1)=O)C.[C-]#[N:40].[Na+].C(Cl)Cl.CO>N>[CH3:22][C:21]1[C:20]2[C:23]([O:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([NH2:40])=[O:3])=[CH:10][C:9]=2[CH:11]=1
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2cc(OCc3oc4cccc(OCCCNCc5cccnc5)c4c3C)ccc2o1
Agent: N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1c(COc2ccc3oc(C(N)=O)cc3c2)oc2cccc(OCCCNCc3cccnc3)c12
Yield: 100.9 %

Procedure:
The compound in Example 36 (12 mg, 0.022 mmol) and NaCN (1 mg) in saturated NH3 anhydrous MeOH solution was heated at 70° C. in a sealed flask overnight. Silica gel column chromatography (CH2Cl2/MeOH=20/1 to 10/1) gave desired product (10 mg, 88%) as a colorless solid. FAB-MS: m/z 486 (MH+); 1H-NMR (CD3OD): δ 2.01 (2H, m); 2.26 (3H, s), 2.80 (1H, t, J=6.9 Hz), 3.78 (2H, s), 4.10 (1H, t, J=5.9 Hz), 5.04 (2H, s), 5.80 (1H, brs), 6.50 (1H, brs), 6.52 (1H, d, J=7.6 Hz), 7.04-7.20 (5H, m), 7.33 (1H, d, J=8.9 Hz), 7.39 (1H, s), 8.41 (1H, brd, J=4.5 Hz), 8.49 (1H, brs).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=1>>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([OH:14])=[C:8]([C:2]2([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:9]=1
Reactant: C=C1CCCCC1
Reactant: Oc1ccc(Br)cc1
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
A mixture of methylene cyclohexane (0.96 g, 10 mmoles), p-bromophenol (1.73 g, 10 mmoles) and acid resin (Dowex 50x12-150 mg) is heated at 80° C. for 16 hours. The residue is purified by silica gel chromatography (eluant: 50/50 mixture of CH2Cl2 /hexane). On evaporation of the solvents 0.50 g (19% yield) of 4-bromo-2-(1-methylcyclohexyl) phenol in the form of a yellowish oil is obtained.
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)C1C=CC=CC=1)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([O:12][CH2:13][CH3:14])[CH:6]=[CH:5][C:3]=1[NH:4][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(N)c(F)c1OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)c(F)c1OCC
Temperature: 0 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
2-Fluoro-3,4-diethoxyaniline (0.17 g) and N,N-diethylaniline (0.13 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.11 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(2-fluoro-3,4-diethoxyphenyl)carbamate (Compound No. 1) (0.23 g) in a yield of 94.4%. M.P., 79°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]1[N:18]=[CH:17][N:16]([C:19](N2C=NC=C2)=O)[CH:15]=1>C1COCC1.CN(C)CCN>[CH3:17][N:16]([CH2:15][CH2:14][NH:18][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73610.6 %

Procedure:
A solution of 10 g (0.050 mmol) of 2-chloro-5-nitrobenzoic acid in 60 ml of THF was cooled over an ice bath, followed by the addition of 10 g (0.064 mmol) of CDI. The thus-obtained mixture was stirred at room temperature for 1 hour. To the solution, 12 ml (0.11 mmol) of N,N-dimethylethylenediamine were added dropwise, followed by stirring at room temperature for 3 hours. After the solvent was distilled out, the residue was dissolved in ethyl acetate. After the solution so obtained was washed with a 10% aqueous solution of sodium hydrogencarbonate, magnesium sulfate was added to the solution to dry the same. The ethyl acetate was distilled out under reduced pressure and the residue was purified by chromatography on a silica gel column (ethyl acetate), whereby 10 g of the title compound were obtained as a colorless oil (yield: 74%).