Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([NH:6][N:7]([CH:10]([CH3:12])[CH3:11])[C:8]#[N:9])=O)C.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:10]([N:7]1[C:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:9][C:4]([OH:3])=[N:6]1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)NN(C#N)C(C)C
Reactant: C1CCNC1
Product: CC(C)n1nc(O)nc1N1CCCC1
Temperature: 30 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
26,6 g (0,15 mole) of 2-isopropyl-2-cyanohydrazinecarboxylic acid ethyl ester is added dropwise to 100 ml of pyrrolidine. The temperature raises to 30° C during the dropwise addition. The whole mixture is then stirred for 12 hours at room temperature and subsequently for 1 hour at 70° C. Then excess pyrrolidine is distilled off in vacuo. To the crystalline residue ethyl acetate is added and the crystals are filtered with suction. There is obtained 21,6 g (70% of theory) of 1-isopropyl-3-hydroxy-5-pyrrolidino-1,2,4-triazole, mp. 123°-125° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[N:17]=2)[CH:12]=1)=[O:6]>O.O1CCOCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[N:17]=[C:13]([C:11]3[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[C:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=3)[S:14][CH:15]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2nc(-c3ccc(F)c(Cl)c3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
Sodium hydroxide (100 mg, 2.5 mmol) was added to a suspension of 4-[4-(3-chloro-4-fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid methyl ester (100 mg) in a mixture of water (2 mL) and dioxane (4 mL). The reaction mixture was stirred at 50° C. for 2 h. An additional portion of water (2 mL) was added and the reaction mixture was stirred at 50° C. for a further 2 h. The reaction mixture was evaporated to dryness and water (5 mL) was added. The mixture was filtered and the filtrate was made acidic to pH 3-4 by the addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4-[4-(3-chloro-4-fluoro-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (60 mg, 41% for two steps). 1H NMR (300 MHz, DMSO-d6) δ 13.18 (br s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 8.27 (d, J=8.3 Hz, 1H), 8.08-8.16 (m, 2H), 7.79 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.9 Hz, 1H), 7.41-7.58 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][C:15](=[CH:18][O:19]C)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl.O1CCCC1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC=C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
420 mg of 1-[2-bis(4-fluorophenyl)methoxyethyl]-4-methoxymethylidenepiperidine (prepared as described in Preparation 5) were added to a mixture of 1.5 ml of 10% w/v aqueous hydrochloric acid and 3 ml of tetrahydrofuran, and the resulting mixture Was then stirred for 2 hours at room temperature. At the end of this time, water was added to the reaction mixture, and it was neutralized by the addition of a 5% w/v aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract was purified by silica gel column chromatography. Elution with 3% by volume methanol in methylene chloride afforded 434 mg (a quantitative yield) of the title compound as an oil, whose properties were the same as those of the product of step (a).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([N:9](C2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)[C:10](=O)C)[C:3]=1[OH:28].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[O:28]1[C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=2[N:9]=[CH:10]1
Reactant: CC(=O)N(c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)c1cc(Cl)cc(Br)c1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1ccc2ocnc2c1
Yield: 368 %

Procedure:
A solution of 2-bromo-4-chloro-6-(3,5-di-t-butyl-4-hydroxy-phenyl acetyl-amino)-phenol (35.67 g, 76.1 mmol) and phosphorus oxychloride (41.8 ml, 457 mmol) in toluene was heated under reflux for 1 hour. Volatiles were removed in-vacuo and residual amounts of phosphorus oxychloride removed by azeotropic distillation with toluene (2×50 ml). The residue was taken up in acetone (50 ml) and ether (100 ml), and treated with water (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The organic solvents were removed in-vacuo and the precipitate collected to give 33.36 g (93.6%) of crude benzoxazole. The crude benzoxazole was dissolved in dichloromethane (100 ml), filtered, and the filtrate diluted with methanol (100 ml). The dichloromethane was removed by distillation and the resulting crystals collected, washed, and dried in-vacuo to give 28.86 g (80.9%) of the title compound (mp 133-6 EC).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH:23]4[CH2:25][CH:24]4[C:26](OC)=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH2:22][CH:23]4[CH2:25][CH:24]4[CH2:26][OH:27])([CH2:20][CH2:21]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC1CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC1CC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of methyl 2-((1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)cyclopropanecarboxylate (110 mg, 0.280 mmol) in THF (1 mL) at 0° C. was added LAH (0.280 ml, 0.280 mmol) dropwise. The reaction was stirred at rt for 3 h, added CELITE® (200 mg), cooled to −78° C., and then quenched with sat′d aqueous NH4Cl (0.5 mL). The mixture was stirred at rt for 30 min, added MgSO4 (200 mg), and stirred at rt for another 1 h. The mixture was filtered. The solid was washed with DCM. The combined filtrates were concentrated in vacuo and the residue was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (101 mg, 99% yield) as a clear oil. LCMS, [M+NH4]+=382.2. 1H NMR (500 MHz, CDCl3) δ 7.34-7.24 (m, 3H), 7.16-7.10 (m, 2H), 7.09-7.05 (m, 1H), 7.00-6.96 (m, 2H), 6.85-6.81 (m, 1H), 3.87 (s, 2H), 3.55 (dd, J=11.0, 6.6 Hz, 1H), 3.41 (dd, J=11.0, 7.2 Hz, 1H), 2.05-1.99 (m, 4H), 1.76-1.69 (m, 4H), 1.14 (dd, J=6.9, 4.7 Hz, 2H), 0.84-0.76 (m, 1H), 0.62-0.54 (m, 1H), 0.45-0.39 (m, 1H), 0.28 (dt, J=8.3, 4.8 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>CC#N>[CH2:19]([CH:18]([CH2:21][CH3:22])[CH2:17][O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:20]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CCC(CC)CBr
Solvent: CC#N
Product: CCC(CC)COc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 0.38 h

Procedure:
Dimethyl 5-hydroxyisophthalate (0.44 g, 2.10 mmol) cesium carbonate (1.37 g, 4.20 mmol) and CH3CN (20 mL) were added to a round-bottom flask and stirred for 15-30 min. 3-(Bromomethyl)pentane (0.42 g, 2.52 mmol) was added and the reaction was stirred for 16 h. The solvent was removed under reduced pressure and the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[N:28]#[C:29][NH2:30].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([NH:30][C:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:24]=1)=[O:26])#[N:28]
Reactant: N#CN
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NC#N)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 68.5 %

Procedure:
Under an argon atmosphere, to a suspension of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (100 mg) in dichloromethane (2.8 mL) were added cyanamide (12.9 mg), 4-dimethylaminopyridine (75 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg) successively, and this mixture was stirred at room temperature for 60 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (73.1 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 4.47 (2H, s), 6.64 (1H, dd, J=2.3, 8.8 Hz), 6.89 (1H, d, J=2.3 Hz), 7.18-7.39 (3H, m), 7.42-7.52 (2H, m), 7.56-7.68 (2H, m), 7.84-7.99 (2H, m), 11.24 (1H, s). ESI-MS (m/z): 383 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:21]([OH:23])=O)[CH3:2].C(N1C=CN=C1)([N:26]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:21]([NH2:26])=[O:23])[CH3:2]
Reactant: CCOc1c(C(=O)O)n(-c2ccccc2)c2ccc(OC)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1c(C(N)=O)n(-c2ccccc2)c2ccc(OC)cc12
Yield: 75.5 %

Procedure:
A mixture of 3-ethoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid (0.11 g, 0.35 mmol; Unangst PC, et al., J. Med. Chem. 1989;32:1360) and 1,1'-carbonyldiimidazole (0.065 g, 0.40 mmol) in 5.0 mL of tetrahydrofuran is stirred at reflux for 90 minutes. The mixture is cooled slightly and 5.0 mL of concentrated ammonium hydroxide is added. After stirring for an additional 90 minutes, the mixture is partitioned between ethyl acetate and brine. The organic layer is washed several times with fresh brine, dried (anhydrous sodium sulfate) and evaporated. Recrystallization of the residue from ethyl acetate-hexane yields 0.082 g (75%) of product; mp 143°-144° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].C(=O)([O-])[OH:33].[Na+].ClC1C=CC=C(C(OO)=O)C=1.S([O-])(O)(=O)=O.[Na+]>ClCCl>[C:1]([C:4]1[C:12]2[S:11](=[O:33])[CH2:10][CH:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1SCC2c1ccc(C(C)C)cc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1S(=O)CC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
To a mixture of N-(7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzothien-5-yl)-3,3-dimethylbutanamide (960 mg, 2.19 mmol) obtained in Example 166 and sodium hydrogen carbonate (276 mg, 3.29 mmol) in dichloromethane (20 mL) was added m-chloroperbenzoic acid (530 mg, 3.07 mmol) at 0° C. and the resulting mixture was stirred at room temperature for two hours. To reaction solution was added an aqueous sodium hydrogensulfate solution, the organic layer separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 123 mg (yield: 12%) of the title compound as a low polarity isomer. Melting point: 214-216° C. (hexane-ethyl acetate).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:23][N:24]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:35]3[CH2:36][CH2:37][CH:32]([N:24]([CH3:23])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:33][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CN(Cc1cccnc1)C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Product: CN(Cc1cccnc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and methyl-piperidin-4-yl-pyridin-3-ylmethyl-amine, hydrochloride, preparative HPLC (Method C) (31%, orange oil). HPLC-MS m/z=487.1 (M+1), Rt: 2.64 min.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[C:6]=2[N:5]=[C:3]1[NH2:4].[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(Cl)Cl>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][O:17][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[N:5]=[C:3]1[NH2:4]
Reactant: Cn1c(N)nc2c(ncn2COC(CO)CO)c1=O
Reactant: CCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)n(C)c(N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
1-Methyl-9-(1,3-dihydroxy-2-propoxymethyl) guanine (340 mg, 1.26 mmol) was suspended in dry DMF and dry pyridine (approximately 20 ml total) and evaporated to dryness. This process was repeated twice, the final time concentrating the suspension down to 10 ml. This suspension was cooled to 0°, under N2, and a solution of octanoyl chloride (822 mg, 5.05 mmol) in dry DMF (1 ml) was added. This reaction was stirred overnight at room temperature. Methylene chloride was then added and the mixture was extracted with saturated aqueous NaHCO3 solution. The organic phase was then washed three times with H2O, dried over MgSO4, filtered and evaporated to dryness. The residual oil was dissolved in CH2Cl2 and applied to a column of silica gel, packed in CH2Cl2. Elution was first performed with CH2Cl2 followed by 1% MeOH in CH2Cl2 (200 ml), 2% MeOH in CH2Cl2 (200 ml), 3% MeOH in CH2Cl2 (100 ml) and finally 5% MeOH in CH2Cl2 (100 ml). Fractions containing the required product were pooled and evaporated to dryness to give 529 mg of product. It was recrystallized from ether/petroleum ether. The PMR spectrum was in accord with the structure.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.Cl>O1CCCC1.O>[CH2:1]([O:5][C:6]1[CH:29]=[C:28]([O:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:26][C:7]=1[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[C:14]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc(C(=O)c2ccc(OCC(C)C)c(C=CC(=O)O)c2)c(OCC(C)C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)COc1ccc(C(O)c2ccc(OCC(C)C)c(C=CC(=O)O)c2)c(OCC(C)C)c1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
In 2 ml of tetrahydrofuran is dissolved 150 mg of 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-2-propenoic acid. After adding 14 mg of lithium aluminum hydride at 5-10° C., the mixture thus obtained is stirred for one hour. The reaction mixture is added to a mixture of chloroform and water, pH is adjusted to 3.0 with 2 mol/L hydrochloric acid, and the organic layer is separated. After successively washing the organic layer with water and saturated aqueous solution of sodium chloride and drying it over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=4:1] to obtain 80 mg of 3-[5-[(2,4-diisobutoxyphenyl)(hydroxy)methyl]-2-isobutoxyphenyl]-2-propenoic acid as a colorless foaming product.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C1COCC1.O.CO.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(C(=O)O)[nH]1
Temperature: 75 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (Aldrich) (504 mg, 3 mmol) in THF/H2O/MeOH (5:1:1, 30 ml) was added NaOH (480 mg, 12 mmol) in H2O (12 ml). The mixture was stirred at 75° C. overnight. The homogeneous mixture was washed with ether. To the aqueous layer was added a saturated aqueous KHSO4 solution until the pH was about 3. The solution was then extracted with dichloromethane. The extracts were dried over MgSO4 and evaporated. The residue was purified on silica (ethylacetate/methanol 90/10) to give the title compound (375 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[CH2:17]=O.S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH2:7][N:8]([C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:17]2)=[CH:15][CH:16]=1
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Reactant: C=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(4-bromophenethyl)-2,2,2-trifluoroacetamide (8.88 g, 30 mmol) and paraformaldehyde (13.5 g, 0.45 mol) in 45 mL of glacial acetic acid at room temperature was slowly added 30 mL of sulfuric acid (96.6%). After stirring at room temperature overnight, the reaction mixture was quenched with ice water and extracted with EtOAc, washed with brine and Sat. NaHCO3 and dried over Na2SO4. After concentration, flash chomatography (SiO2, hexane/DCM=1:1) gave 1-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[C:16]([C:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])C)=[C:15]([C:25]#[N:26])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([N:12]2[C:16]([CH:17]3[O:22][CH2:23][CH:24]=[CH:21][CH2:20][O:19]3)=[C:15]([C:25]#[N:26])[CH:14]=[N:13]2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:9])[F:10]
Reactant: CCOC(C)(OCC)c1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(-n2ncc(C#N)c2C2OCC=CCO2)c(Br)c1OC(F)F

Procedure:
3.0 g (7.1 mmol) of 1-(4-bromo-5-difluoromethoxy-1-methyl-3-pyrazolyl)-5-(1,1-diethoxyethyl)-1H-pyrazole-4-carbonitrile are dissolved in 50 ml of toluene, and 6.3 g (71 mmol) of cis-2,3-butene-1,4-diol and a catalytic amount of p-toluenesulfonic acid are then added. The mixture is kept at the boil for half an hour under a water separator, and the cooled solution is washed with sodium chloride solution, dried with magnesium sulfate and concentrated. The residue is purified by column chromatography.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CC[C@H]2CC[C@H](O)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(CC[C@H]2CC[C@H](O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7.5 g trans-4-(2-[4-methoxyphenyl]ethyl)cyclohexanol and 100 ml of dichloromethane was treated at 0° C. with 27 ml of a 1M solution of boron tribromide in dichloromethane. The reaction mixture was stirred at room temperature for a further 2 hours and then poured on to ice-water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with water, sodium hydrogen carbonate solution and again with water and then dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from hexane and gave 5.2 g of trans-4-(2-[4-hydroxyphenyl]ethyl)cyclohexanol.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH2:6]([OH:10])[CH:7]([CH3:9])[CH3:8].CN(C)C1C=CC=CC=1.CCOCC>O>[Br:1][CH2:2][C:3]([O:10][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)CO
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CC(C)COC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Over a period of 6-8 hours there was added dropwise 1 M of bromoacetyl bromide to a stirred solution of 1 M of isobutyl alcohol, 1 M of dimethylaniline and 200 ml of anhydrous ether. The solution was kept just below boiling by adjusting the rate of addition and by occasional cooling in an ice bath. After complete addition, the mixture was stirred overnight at room temperature. Water (100 ml) was added and the mixture stirred until all of the precipitate had dissolved. The layers were separated and the ether layer was washed with 100 ml portions of 10% sulfuric acid until neutralization of the washings resulted in a clear solution. The washed ether solution was dried over anhydrous sodium sulfate and after removal of the drying agent and solvent the residue was distilled in vacuo. The recovered product had a bp / 14 mm = 72° - 76° C, n25 = 1.4468.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][NH:21][C:22]3[CH:23]=[CH:24][C:25]([F:32])=[C:26]([CH:31]=3)[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure A using 4-[(4-butylphenyl)ethynyl]benzaldehyde and methyl 5-amino-2-fluorobenzoate as a white powder (74%). 1HNMR (CDCl3, 300 MHz) δ 7.51 (d, J=7.9 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.17 (m, 3H), 6.97 (m, 1H), 6.76 (m, 1H), 4.35 (s, 2H), 3.92 (s, 3H), 2.63 (t, J=7.8 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). M+ (ESI): 414.0. HPLC, Rt: 5.78 min (Purity: 98.2%).