Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:15][CH2:16][CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:19]1=[O:27].C(N(C(C)C)CC)(C)C.O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Solvent: CCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 103.3 %

Procedure:
A mixture of 5.0 gm of 1-t-butoxycarbonyl piperazine, 6.26 gm of 1-(3-chloro propyl)-2,3-dihydro-1H-benzimidazol-2-one (available from Janssen) and 4.16 gm diisopropylethylamine in 150 ml ethanol is kept for 12 hours at 80° C. Upon cooling to ambient temperature, 100 ml water is added and the mixture is extracted with chloroform (CHCl3) and the extract is collected, washed with 20 ml water and dried over Na2SO4. After removing the solvents, 10 gm of a yellowish oil is obtained which is used without further purification.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH2:25][OH:26])[CH2:19]2)([CH3:15])([CH3:14])[CH3:13]>ClCCl.CCOCC>[C:12]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[CH2:21][CH:20]([CH:25]=[O:26])[CH2:19]2)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc2c(c1)CC(CO)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)CC(C=O)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a suspension of pyridinium chlorochromate (PCC, Fluka, 3.24 g, 15 mmole) in dichloromethane (20ml), there was added at room temperature, a solution of 5-tert-butyl-2-indanmethanol (2.04 g, 10 mmole) in dichloromethane (10 ml). The mixture was stirred for 5 h at room temperature. It was diluted in ether (50 ml), filtered on CELITE®, then on a FLORISIL® column (Fluka), and concentrated. Bulb-to-bulb distillation provided 5-tert-butyl-2-indancarbaldehyde (1.47 g, purity>99%, yield 72%) as a colorless oil.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]2[C:15]([CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[C:25]([CH2:24][CH3:23])[CH:26]=[CH:27][CH:22]=2)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cccc(C2C=CCC2)c1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of lithiumfluorene in 50 cm3 of tetrahydrofuran is added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated during this procedure was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)-ethylbenzene were obtained (correct elmemental analyses; 1H-NMR spectrum).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:10]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C1C=CC=CC=1>O>[CH3:2][C:1](=[N:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1
Yield: 93.7 %

Procedure:
solution of acetophenone (33.5 g), p-dodecyl aniline (73 g), benzene (50 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was purified by crystallizing it from ethanol to give N-(α-methyl benzylidene)-p-dodecyl aniline (V) (95 g). V had a melting point of 47° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=O)[NH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:17])=O>CN(C=O)C>[ClH:17].[Cl:17][C:8]1[C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=[CH:10][N:9]=1
Reactant: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Yield: 100 %

Procedure:
A mixture of 7-nitro-3,4-dihydroquinazolin-4-one (J. Chem. Soc. 1950, 1104-1111) (5 g, 26 mmol) in thionyl chloride (50 ml) and DMF (1 ml) was heated at reflux for 1.5 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The residue was suspended in ether, collected by filtration and dried under vacuum to give 4-chloro-7-nitroquinazoline hydrochloride (6.4 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4]([NH2:10])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>ClCCl>[CH3:1][O:2][C:3](=[O:11])[CH:4]([NH:10][C:27]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:28])[CH2:5][C:6]([CH3:7])([CH3:8])[CH3:9]
Reactant: COC(=O)C(N)CC(C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CC(C)(C)C)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Amino-4,4-dimethyl-pentanoic acid methyl ester (5.35 g, 27.4 mmol) was dissolved in 100 mL of dichloromethane. Hunig's base (7.07 g, 54.7 mmol) and 4-morpholinecarbonyl chloride (4.08 g, 27.4 mmol) were added and the reaction was stirred at ambient temperature 16 h. The reaction mixture was concentrated in vacuo and taken up in 150 mL EtOAc. A white precipitate formed and was filtered and washed with EtOAc. EtOAc solutions were combined and washed with 3×50 mL 1 N HCl (aq), 3×50 saturated NaHCO3 (aq), and 1×50 mL brine. The organic layer was dried over Na2SO4, decanted, and concentrated to a white solid (6.33 g). MS, m/z 273=M+1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:10]=O.CO[C:14](=[O:31])[C:15]([OH:30])=[CH:16][C:17](=[O:29])[N:18]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)[CH3:19]>CC(O)=O>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][N:18]([CH3:19])[C:17]([C:16]1[CH2:10][N:1]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[C:14](=[O:31])[C:15]=1[OH:30])=[O:29]
Reactant: C=O
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: NCCN1CCOCC1
Solvent: CC(=O)O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 23.9 %

Procedure:
To 0.5 mL of AcOH at 60° C. was added N-(2-aminoethyl)morpholine (0.066 mL, 0.5 mmol) and paraformaldehyde (15 mg, 0.5 mmol). After stirring for 5 min, 3-[(3,4-dichloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (159 mg, 0.5 mmol) was added and the resulting mixture stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc. The remaining aqueous layer was extracted with CH2Cl2, and dried over Na2SO4. Concentration yielded 51.1 mg (24% yield) of the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ: 10.52 (bs, 1H), 7.40 (d, 1H, J=10.61), 7.39 (s, 1H), 7.11 (dd, 1H, J=10.24, J=1.83), 4.60 (s, 2H), 4.23 (s, 2H), 3.64 (m, 6H), 3.01 (s, 3H), 2.63 (t, 2H, J=6.22), 2.54, (m, 4H), 2.05 (s, 3H). MS (M+H) calcd for C19H23N3O4Cl2: 427.1; found: 428.11.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:6]2[C:4](=[CH:3][C:2]([I:1])=[CH:8][CH:7]=2)[N:5]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1cccc(I)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(I)ccc2c1O
Temperature: 25 °C

Procedure:
3-Iodoaniline (8.50 mL) and diethyl ethoxymethylenemalonate (14.30 mL) are heated at 130° C. for 1 hour. The reaction is cooled to room temperature and 70 mL diphenyl ether is added. The solution is heated at 250° C. for 1.5 hours with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature and the resulting solid filtered, washed with hexanes, and dried. The solid is triturated in ethyl acetate to give 12.82 g of ethyl 4-hydroxy-7-iodoquinoline-3-carboxylate. A mixture of this ester (0.35 g) and 4-chlorobenzylamine (3.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to 70° C. and poured into 50 mL diethyl ether. A tan solid which crystallizes slowly out of diethyl ether is obtained. The solid is recrystallized from ethyl acetate/hexanes to give the desired product (0.22 g).
Reaction SMILES: C(C1[CH:5]=[C:6]([Cl:11])[C:7]([Cl:10])=[N:8][CH:9]=1)C=C.C[N+]1([O-])CC[O:16]CC1.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>O.[Os](=O)(=O)(=O)=O>[Cl:11][C:6]1[CH:5]=[C:22]([CH2:21][CH:20]([OH:16])[CH2:24][OH:23])[CH:9]=[N:8][C:7]=1[Cl:10]
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1cnc(Cl)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: OCC(O)Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 5-allyl-2,3-dichloropyridine 58 in THF (2 ml) and H2O (1 ml) was added NMO (280 mg, 2.393 mmol) and osmium tetraoxide (THF solution) (0.487 ml, 0.080 mmol) at 0° C. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with H2O, then extracted with EtOAc (3×10 mL). The organic layers were combined and washed with sat NaCl. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel chromatography column and was eluted with Hex/EtOAc 2:8. Collected fractions were evaporated to afford 59 (255 mg 1.148 mmol 72.0%) as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C:15](=[O:28])[N:14]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[OH:44][C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:14]2[C@H:13]([C:10]3[CH:11]=[CH:12][C:7]([C:48]4[CH:49]=[CH:50][C:45]([OH:44])=[CH:46][CH:47]=4)=[CH:8][CH:9]=3)[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[OH:20])[C:15]2=[O:28])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3ccc(O)cc3)cc2)N1c1ccc(F)cc1
Reaction time: 5 h
Yield: 76.9 %

Procedure:
4-{(2S,3R)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (162.5 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.3 mg, 0.015 mmol) were dissolved in toluene (2.5 mL). 2.0 M aqueous potassium carbonate (0.3 mL) and a solution of 4-hydroxyphenylboronic acid (57.9 mg, 0.42 mmol) in ethanol (1.0 mL) were added. The reaction was stirred vigorously for 5 h at refluxing temperature under a nitrogen atmosphere and then diluted with water (2.5 mL), extracted with ethyl acetate (3×10 mL), washed with brine (10 mL), dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 10% to 100% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4′-hydroxybiphenyl-4-yl)azetidin-2-one (112 mg, 77% yield) as a clear film; mp 110° C.; Rf 0.5 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.5 (d, J=9.0 Hz, 2H) 7.4 (d, J=9.0 Hz, 2H) 7.3 (m, 6H), 6.9 (m, 6H), 4.7 (m, 1H), 4.6 (s, 1H), 3.15 (m, 1H), 2.1-1.9 (m, 4H) ppm; MS [M+H] 486.5.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[CH3:13]
Reactant: CCO
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: CCOC(=O)CCC1CCC(=O)N1

Procedure:
Twenty-eight grams of dihydro 1H-pyrrolizine-3,5 (2H, 6H) dione is dissolved in 100 g of ethyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at reflux for 104 hours. The mixture is cooled and excess ethyl alcohol is distilled at reduced pressure. The oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from carbon tetrachloridepetroleum ether yields 5-oxo-2-pyrrolidinepropanoic acid ethyl ester with a melting point of 60°-61° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.Br[CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16].[Cl:22]C(C)C(N(C)C)=O>>[Cl:22][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:3]1[C:2]([CH3:1])=[CH:6][N:5]([CH:14]([CH2:20][CH3:21])[C:15]([N:17]([CH3:19])[CH3:18])=[O:16])[N:4]=1
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CCC(Br)C(=O)N(C)C
Reactant: CC(Cl)C(=O)N(C)C
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2Cl)n1

Procedure:
Following the procedure of Example 1, but substituting 3-(o-chlorophenyl)-4-methylpyrazole for 4-methyl-3-phenylpyrazole and 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide there was obtained 3-(o-chlorophenyl)-α-ethyl-N,N,4-trimethylpyrazole-1-acetamide having a boiling point of 180°/0.15 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])[CH:18]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(NC(=O)COc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Yield: 71.6 %

Procedure:
To solution of (2,4-dichloro-phenoxyacetic acid (0.200 g, 0.9 mmol), 2-amino isonicotinic acid methyl ester (207 mg, 1.36 mmol) and DMAP (0.222 g, 1.81 mmol) in DMF 13 mL was added PyBOP (946 mg, 1.81 mmol) at room temperature. Reaction mixture was stirred at room temperature. Resulting mixture poured onto ice cold water, was diluted by ethyl acetate. The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by flash silica gel column chromatography (EtoAC:Hexane=1:9-4:6) to give 2-[2-(2,4-dichloro-phenoxy)-acetylamino]-isonicotinic acid methyl ester as a colorless solid (0.229 g, 71% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:22])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH:15](O)[CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]([CH3:22])([CH3:12])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CC(OC(=O)Cc2ccc(O)cc2)CC(C)(C)C1
Yield: 106.1 %

Procedure:
A mixture of 4-hydroxyphenylacetic acid (6.08 g), 3,3,5,5-tetramethylcyclohexyl alcohol (6.24 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) was refluxed for 8 hours with continuous water separation. The mixture was cooled and washed with 10% Na2CO3, then with water. Drying over MgSO4 and evaporation in vacuo yielded 12.3 g of 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate. That product, which can be represented by the structural formula ##STR26## is characterized by the following NMR (CDCl3, TMS, ppm): 7.00 (d, J=8Hz, 2H), 6.60 (d, J=8Hz, 2H), 5.00 (broad, 1H), 3.40 (s, 2H) and 1.80-0.80 (m, 18H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[CH3:16])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:23]([Cl:33])(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[ClH:33].[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][N:13]([C:23](=[O:32])[CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH:11]2[CH3:16])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC1CNCCN1c1ccccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CN(C(=O)C=Cc2ccccc2)CCN1c1ccccc1C1CC1
Product: Cl
Reaction time: 4 h
Yield: 64 %

Procedure:
A flask containing a solution of 21.6 g (0.1 mole) of 1-(cyclopropyl phenyl)-methyl piperazine (boiling point: 147°-148°C), at a pressure of 1.8 to 2 mm of Hg in 100 ml of dry benzene was cooled to 5°C. 11 g of anhydrous Na2CO3 were added, and a solution of 16.6 g (0.1 mole) of cinnamoyl chloride in 50 ml of dry benzene was introduced dropwise, with stirring; this addition was effected at a rate such that the temperature of the mixture did not rise above 10°C. It was then left to return to the ambient temperature, it was stirred for another 12 hours, and the mixture was brought to a temperature between 40° and 50°C for 4 hours. It was then cooled, the mineral salts were filtered and the mother liquors were acidified with hydrochloric acid dissolved in isopropanol. 24.5 g of crude 1-(cyclopropyl phenyl)-methyl-4-cinnamoyl piperazine hydrochloride were thus obtained, having a melting point of 220°-222°C, and which can be recrystallized if desired.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2C(C(O)=O)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.CN(C)C=O>C(Cl)Cl>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:1]([C:2]([Cl:4])=[O:3])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
Oxalyl chloride (2.43 mL) was added dropwise to a mixture of 4′-trifluoromethylbiphenyl-2-carboxylic acid (5.06 g), dimethylformamide (catakytic amount) and methylene chloride (30 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 100 minutes, and concentrated to remove the solvent. The residue was evaporated azeotropically together with toluene, and dried in vacuo to give the title compound (5.40 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:31](O)=[O:32]>>[C:1]([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([OH:14])=[C:7]([C:6]=1[CH:15]([CH3:17])[CH3:16])[CH:31]=[O:32])(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)Oc1c(C(C)C)cc(O)cc1C(C)C
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)Oc1c(C(C)C)cc(O)c(C=O)c1C(C)C
Temperature: 0 °C
Yield: 70 %

Procedure:
1.00 g of 4-acetoxy-3,5-diisopropylphenol and 0.71 g of hexamethylenetetramine were dissolved in 4 ml of trifluoroacetic acid and the mixture was heated under reflux for 20 minutes. The reaction solution was cooled to 0° C., then combined with water and extracted with ethyl acetate. The organic layers were washed with a saturated aqueous sodium bicarbonate solution and then saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was dissolved in 10 ml of methanol, 13 ml of 1N hydrochloric acid was added, and the solution was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature, then combined with water and extracted with ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5%-10% ethyl acetate) to give 0.78 g of 5-acetoxy-2-hydroxy-4,6-diisopropylbenzaldehyde as a pale yellow oil (yield 70%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)=[CH2:2].[Br-].[C:17]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)CCC=C)C=CC=C[CH:18]=1.[CH3:40][C:41](C)([O-])C.[K+].O>C1COCC1>[CH:1](=[C:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][CH:12]([CH:40]=[CH2:41])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)[CH2:2][CH:17]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: C=CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CC1CCC(C2CCC(=O)CC2)CC1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC=C1CCC(C2CCC(C=C)CC2)CC1
Temperature: 10 °C

Procedure:
20.6 g of 4'-vinylbicyclohexyl-4-one and 39.7 g of triphenyl(3-butenyl)phosphonium bromide in 250 ml of THF were cooled to -10° C. under nitrogen with stirring. A solution of 11.44 g of potassium tert-butoxide in 150 ml of THF was then added dropwise at -10° C. with stirring, and the mixture was then stirred at RT for a further 2 hours. The yellow suspension was cooled to 10° C., and 500 ml of water were added. The organic phase was separated off, and the aqueous phase was extracted once with 100 ml of methyl tert-butyl ether. Combined organic extracts were washed once with 100 ml of water, dried using sodium sulfate, filtered and evaporated to give a residue, giving 4'-but-3-enylidene-4-vinylbicyclohexyl.
Reaction SMILES: [K].[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]([CH2:12][OH:13])=[C:9]([Cl:11])[N:10]=1)[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.O>[CH2:2]([C:6]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]([CH2:12][OH:13])=[C:9]([Cl:11])[N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 90.9 %

Procedure:
To a solution of 0.600 g of 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-methanol mono potassium salt in 40 ml of methylene chloride is added 0.218 ml of triethylamine and 0.381 g of trityl chloride. The solution is heated at reflux for 8 hours, cooled and diluted with 30 ml of water. The organic layer is separated and the aqueous layer extracted with methylene chloride. The combined extracts are washed with water, dried with potassium carbonate, filtered and concentrated in vacuo to give 0.785 g of the desired product as a solid. FAB MASS SPEC 665(M+H).