Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:11]1.[Br:20]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:20])[C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:11]1
Reactant: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reaction time: 1 h
Yield: 83.9 %

Procedure:
54.5 g (0.17 mol) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-5-oxo-2-pyrazoline was dissolved in 300 ml of acetic acid, to which there was then gradually added dropwise 27.2 g (0.17 mol) of bromine. After stirring for 1 hour, the reaction mixture was poured into 900 ml of water and the crystals thus-separated were collected by filtration to obtain 57 g (84% yield) of 1-(2,4,6-trichlorophenyl)-3-acetylamino-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=1.[Cl:10][C:11]1[C:12]([O:34][CH3:35])=[CH:13][C:14]([O:32][CH3:33])=[C:15]([CH2:17][CH2:18][C:19]2([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH:16]=1>>[Cl:10][C:11]1[C:12]([O:34][CH3:35])=[CH:13][C:14]([O:32][CH3:33])=[C:15]([CH2:17][CH2:18][C:19]2([CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[O:24][C:23](=[O:25])[C:22]([CH2:2][C:3]3[O:7][N:6]=[C:5]([CH2:8][CH3:9])[N:4]=3)=[C:21]([OH:26])[CH2:20]2)[CH:16]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: CCc1noc(CCl)n1
Product: CCc1noc(CC2=C(O)CC(CCc3cc(Cl)c(OC)cc3OC)(C3CCCC3)OC2=O)n1
Yield: 7 %

Procedure:
The title compound was prepared as described in Example B(53), using 5-(chloromethyl)-3-ethyl-1,2,4-oxadiazole (Step 1, below) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 7%. 1H NMR (300 MHz, DMSO-d6) δ 1.10 (t, J=7.8 Hz, 3H), 1.25-1.73 (m, 8H), 1.89 (m, 2H), 2.33 (m, 1H), 2.43-2.53 (m, 2H, overlap with DMSO-d5), 2.58 (q, m, overlap, 3H), 2.76 (d, J=18 Hz, 1H), 3.75 (ABQ pattern, J=16 Hz, 2H), 3.77 (s, 3H), 3.84 (s, 3H), 6.71 (s, 1H), 7.10 (s, 1H), 11.31 (br s, 1H). LC-MS (APCI) calcd for C25H31ClN2O6: 490.19; found (M+H+) 491.0 m/z.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][Si](C(C)(C)C)(C)C)=[CH:7][C:6]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[NH:20][C:21](=[O:39])[CH2:22][CH:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:37])([F:38])[F:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C(C)(C)C)c1ccccc1C(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CO)ccc1C(C)(C)C)c1ccccc1C(F)(F)F

Procedure:
Following a procedure similar to that described in Preparation 9, but using N-[2-t-butyl-5-(t-butyldimethylsilyloxymethyl)phenyl]-3-(2-trifluoromethyl-phenyl)octanamide (prepared as described in Preparation 18) as a starting material, the title compound was obtained as crystals, melting at 147°-147.5° C. (from ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[N:21]=[C:5]2[C:6]([C:10]3[C:18]4[O:17][C:16]([F:20])([F:19])[O:15][C:14]=4[CH:13]=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH2:40])=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([NH:40][C:2]3[N:21]=[C:5]4[C:6]([C:10]5[C:18]6[O:17][C:16]([F:20])([F:19])[O:15][C:14]=6[CH:13]=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:39][C:32]=2[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: FC1(F)Oc2cccc(-c3cccn4nc(Cl)nc34)c2O1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Nc3nc4c(-c5cccc6c5OC(F)(F)O6)cccn4n3)cc2CC1

Procedure:
7-[8-(2,2-difluoro-1,3-benzodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2,2-difluoro-1,3-bezodioxol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (0.78 g, 2.5 mmol), and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.99 g, 3.778 mmol), in a manner analogous to Example 2d. Product was isolated as a foam (0.78 g, 58%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (d, J=6 Hz, 1H), 7.61 (d, J=6 Hz, 1H), 7.51-7.42 (m, 4H), 7.00-6.89 (m, 3H), 6.79 (s, 1H), 3.62-3.45 (m, 4H), 2.84-2.74 (m, 4H), 1.52 (s, 9H). MS=536 (MH)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[CH2:25]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:42](=O)[NH2:43])[CH:39]=2)[CH2:34]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:25]([CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:42]#[N:43])[CH:39]=2)[CH2:34]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC1Cc2ccc(C(N)=O)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Subsequently, 8.71 g (33.2 mM) of triphenylphosphine, 25 ml of carbon tetrachloride and 15 ml of THF were placed in 200 ml-three necked flask. Under stirring at room temperature, 4.55 g (16.6 mM) of the above-prepared 2-octyl-5-carbamoylindan was gradually added to the above mixture, followed by washing with 10 ml, of THF and stirring for 3 hours at 45°-50.4° C. to precipitate a crystal. After the reaction, the crystal was removed from the reaction mixture by filtration and the filtrate was evaporated under reduced pressure to obtain a residue. The residue was purified silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized from methanol to obtain 4.24 g of 2-octyl-5-cyanoindan (Yield: 99.8%).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]([OH:20])(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([O:10][C@H:2]1[C@H:3]2[O:8][CH2:7][C@H:6]([O:9][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:20])[C@H:4]2[O:5][CH2:1]1)=[O:20]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC(=O)O[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OC(=O)CCCCCCC
Temperature: 180 °C

Procedure:
In a stirred 1 liter apparatus under a stream of nitrogen, 219.0 g (1.5 mol) of isosorbide and 461.4 g (3.2 mol) of caprylic acid are heated with stirring and under a stream of nitrogen to 180° C. The reaction mixture is heated at 180° C. until no more water of reaction distills off (about 28 h). The temperature is then gradually increased to 210° C. (altogether over about 30 h). The reaction has ended when a residual acid value of <2 mg KOH/g is reached. This gives a clear red-brown liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:17])=[C:4]([NH:9]C(=O)OC(C)(C)C)[C:5]([F:8])=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:17])=[C:4]([C:5]([F:8])=[CH:6][CH:7]=1)[NH2:9]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(Br)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a round bottom flask containing tert-butyl 3-bromo-2,6-difluorophenylcarbamate (1 g, 3.3 mmol) was added DCM (3 mL) and TFA (3 mL). The reaction was stirred for 2 hours at room temperature. The volatiles were removed in vacuo, and the resulting residue was neutralized with saturated aqueous NaHCO3 solution to pH 8. The aqueous mixture was extracted with EtOAc. Organic phase was washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica. Purification by flash chromatography (SiO2; 0-50% EtOAc in heptane) afforded 425 mg (63%) of 3-bromo-2,6-difluoroaniline: LCMS (m/z) 208.0 (MH+); tR=0.80 minute; 1H NMR (400 MHz, DMSO-d6) δ 5.54 (s, 2H) 6.78 (ddd, J=9.0, 7.4, 5.5 Hz, 1H) 6.85-6.95 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C(O)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCO
Product: CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 5 °C

Procedure:
A 500 ml. 3-neck, r.b. flask fitted with y-tube and condenser and thermometer, stirrer and addition funnel was charged with a mixture of 2-chloro-5-nitropyridine (15.8 g. 0.1 mole) in ethanol (300 ml.). To this was added N-methylpiperazine (20 g. 0.2 mole) dropwise while stirring. After the addition (ca. 5 min.), the mixture was heated at reflux for 3 hr. while stirring continued. The solution was chilled to 5°C and the crystals were collected by filtration and dried at 60°C to yield 12 g. yellow crystals, m.p. 94°-96°C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:7](=O)[C:8](OC)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH2:23][CH2:24][CH2:25][C:21]=2[C:20]([C:26](=[NH:29])[NH:27][NH2:28])=[N:19]1>C(O)C>[F:14][C:15]1[CH:33]=[CH:32][CH:31]=[CH:30][C:16]=1[CH2:17][N:18]1[C:22]2[CH2:23][CH2:24][CH2:25][C:21]=2[C:20]([C:26]2[N:27]=[N:28][C:7]([C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[C:8]([OH:9])[N:29]=2)=[N:19]1
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1O
Yield: 15.6 %

Procedure:
218 mg (1.13 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate were initially charged in 5 ml of ethanol and heated to reflux. Subsequently, 205 mg (0.75 mmol) of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidohydrazide suspended in 5 ml of ethanol were added and the mixture was boiled under reflux overnight. After cooling, the mixture was filtered, the filtercake was washed with a little ethanol and the filtrate was concentrated. The residue was purified by means of preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 48 mg of the target compound were obtained (purity 54%; 8% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](C=O)[C:5]([Cl:10])=[CH:4][N:3]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>CO.CC1C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: O=Cc1cc(Br)ncc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)c1cc(Br)ncc1Cl
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-TsOH (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt, and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2, and the mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the crude title compound (51.7 g, 97%) that was used further without purification. LC-MS: tR=0.92 min; ES+: 309.06.
Reaction SMILES: N([O-])=O.[Na+].[ClH:5].[CH3:6][S:7][C:8]1[N:9]=[CH:10][C:11](N)=[N:12][CH:13]=1>O>[Cl:5][C:11]1[CH:10]=[N:9][C:8]([S:7][CH3:6])=[CH:13][N:12]=1
Reactant: Cl
Reactant: CSc1cnc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CSc1cnc(Cl)cn1
Reaction time: 1 h
Yield: 26 %

Procedure:
Sodium nitrite (50.9 g, 0.74 Mop was dissolved in water (150 mL), followed by dropwise addition into a 5N aqueous hydrochloric acid solution (1.0 L) at 0° C. over 1 hour. Subsequently, 5-(methylsulfanyl)pyrazine-2-amine (40.4 g, 0.28 mol) synthesized in Example (97a) was added at 0° C. over 40 minutes, and stirring was carried out at 0° C. for 1 hour. The reaction solution was brought back to room temperature, and water (500 mL) was added, followed by extraction with ethyl acetate (1.0 L). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-20%) to afford the desired compound (11.9 g, yield 26%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[C:14]1([C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:21]2[CH:25]=[C:24]([CH:26]=[O:27])[N:23]=[CH:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:10][C:7]1([CH3:11])[O:6][C:5]2[CH:12]=[CH:13][C:2]([CH:26]([C:24]3[N:23]=[CH:22][N:21]([C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:25]=3)[OH:27])=[CH:3][C:4]=2[CH2:9][O:8]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Product: CC1(C)OCc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2O1
Yield: 54.5 %

Procedure:
Starting from 6-bromo-2,2-dimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The temperature of the reaction mixture does not exceed 40° C. Yield: 54.5% of theory; M.P.: 155°-162° C. (recrystallized from acetonitrile).
Reaction SMILES: [ClH:1].C([NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.O.[Pd]>[ClH:1].[NH2:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=2)[CH2:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)CC(NCc1ccccc1)CC2
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)COc1ccc2c(c1)CC(N)CC2
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A solution of 27 g of 2-benzylamino-7-carbethoxymethoxytetraline hydrochloride, EXAMPLE 1, in 300 ml of 95% ethanol and 25 ml of water, is hydrogenated under ordinary pressure and at temperature of 50° C. by using 3 g of 10% palladium on charcoal as a catalyst. After 3 hours, the mixture is filtered, the residue is taken up twice with 100 ml of absolute ethanol and dried every time. The product so obtained is triturated in 150 ml of acetone, filtered and crystallized from 100 ml of isopropanol to give 19 g of 2-amino-7-carbethoxymethoxytetraline hydrochloride; m.p. 143°-145° C. The product thus obtained may be used for the preparation of the compound of formula (XV) above, in which X is hydrogen and O-R' is a carbethoxymethoxy group (COMPOUND 1), as follows: A solution of 1.8 g of phenyloxirane and 3.7 g of 2-amino-7-carbethoxymethoxytetraline base, obtained by neutralization of the hydrochloride described above, in 40 ml of n-butanol is heated under reflux for 6 hours. The mixture is concentrated to dryness, the residue is purified by flash chromatography, by eluting with a mixture of ethyl acetate/methanol 9/1. The purified oil is left to react overnight with an excess of oxalic acid in 5 ml of isopropanol. Thus, 1.9 g of N-(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-2-phenylethanamine oxalate is obtained; m.p. 159°-162° C., identical with the compound of Example 5 of the European patent 211 721.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23][NH2:24])=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23]/[N:24]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(CNN)cc1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN/N=C(/c2ccccc2)c2ccc(C)cc2)cc1

Procedure:
To a solution of (4-methylphenyl)(phenyl)methanone (12) (1.9 g, 0.01 mol) in methanol was added 4-methoxybenzyl hydrazine (4.5 g, 0.035 mol) and acetic acid (0.5 mL). The mixture was reflux for 2 h. After cooling, the mixture was concentrated and the residue was extracted with CHCl3, washed with dil. HCl, followed by water, dried over MgSO4 and concentrated in vacuo, to give (Z)-(4-methylphenyl)(phenyl)methanone (4-methoxybenzyl)hydrazone (13). Next, a solution of above benzylhydrazone was dissolved in CH2Cl2 (50 ml) was added dropwise to a solution of Pb(OAC)4 (14.1 g, 0.03 mol) in CH2Cl2 (200 mL). After addition was completed, the mixture was reacted at 30±2° C. for 30 min, the BF3.Et2O (containing 47% of BF3 61 mL) was added. The mixture was reflux for 30 min before quenched into ice water. The organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel-toluene) produce compound 24 (0.6 g). This product was confirmed by comparison of its IR and NMR spectra with that of a sample from the method A.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1.Cl([O-])=[O:25].[Na+].CC(=CC)C.P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:25])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[C:15]([F:23])[CH:14]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCO)c(F)c3)cc12
Temperature: 25 °C
Reaction time: 10 h
Yield: 47.7 %

Procedure:
To a solution of 6-chloro-5-[3-fluoro-4-(2-hydroxyethoxy)phenyl]-1H-indole-3-carbaldehyde (40 mg, 0.12 mmol) in water (1 mL) and t-butanol (1 mL) was added sodium chlorite (210 mg, 2.30 mmol), 2-methyl-2-butene (0.5 mL) and sodium dihydrogen phosphate (350 mg, 2.90 mmol). The reaction solution was stirred at room temperature for 10 hrs. The reaction was diluted with water (5 mL) and extracted with dichloromethane (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL), dried over sodium sulfate and concentrated to give a crude product. The crude was purified by preparative HPLC to give the title compound (20 mg, 49% yield) as off-white solid. MS (AP−) 348.0 (M−H)−. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.60 (s, 1H), 7.20 (m, 3H), 4.21 (t, 2H), 3.95 (t, 2H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([OH:8])[C@@H:6]([OH:9])[CH:5]=[CH:4]1.N1C=CN=C1.Cl[Si:16]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:17][Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>CN(C=O)C>[CH:22]([Si:18]1([CH:19]([CH3:21])[CH3:20])[O:8][C@H:7]2[C@@H:6]([OH:9])[CH:5]=[CH:4][C@@H:3]2[CH2:2][O:1][Si:16]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:31])[CH3:30])[O:17]1)([CH3:24])[CH3:23]
Reactant: OC[C@H]1C=C[C@H](O)[C@@H]1O
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C=C[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
To a stirred mixture of triol 10 (5.8 g, 44.6 mmol) and imidazole (21.2 g, 312.3 mmol) in DMF (300 mL), 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (14.7 mL, 46.8 mmol) was added drop wise at 0° C. under nitrogen. The mixture was stirred at room temperature for 2.5 h, quenched with water (200 mL) and extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with brine (2×100 ml), followed by with water and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc: Hexane 1:30 to 1:5) to give 11 (13.7 g, 82%) as an oil. [α]24D +45.87° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.93-1.04 (m, 28H), 2.90 (m, 1H), 3.16 (d, J=2.0 Hz, 1H), 3.51 (m, 1H), 4.01 (dd, J=3.0, 11.0 Hz, 1H), 4.21 (t, 5.6 Hz, 1H), 4.47-4.45 (m, 1H), 5.60 (dd, J=1.5, 6.0 Hz, 1H), 5.86 (dd, J=3.0, 6.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 12.6, 12.7, 12.9, 13.2, 13.3, 13.4, 17.0, 17.1, 17.2, 17.3, 17.4, 17.6, 54.6, 66.7, 74.7, 76.3, 132.5, 134.4; HR-MS Calcd. For (C18H36O4Si2+Na)+ 395.2152. found 395.2052.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:39][Cl:40]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([O:15][CH2:39][Cl:40])=[O:14])=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: ClCI
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(=O)OCCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-methoxybenzyloxy) benzoic acid (5.16 g, 20 mmole) in 100 ml 1,4-dioxane was added a 40% solution of tetrabutylammonium hydroxide (14.27 g, 22 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (35.3 g 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl acetate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 4.48 g=73%
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[N:31][NH:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[CH:30]=[N:31][N:32]([C:20]2[CH:21]=[CH:22][C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=4[CH3:1])[CH2:10][CH2:11]3)=[O:16])=[CH:18][CH:19]=2)[CH:33]=1)=[O:28])[CH3:25]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CCOC(=O)c1cn[nH]c1
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)N3CCN(c4ccc(C)cc4C)CC3)cc2)c1

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (840 mg) described in Preparation Example 108 and 1H-pyrazole-4-carboxylic acid ethyl ester (320 mg) and by the reaction and treatment in the same manner as in Example 1, 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-1H-pyrazole-4-carboxylic acid ethyl ester was obtained. Using this compound and 1-methylpiperazine (230 μL) and by the reaction and treatment in the same manner as in Example 109, the title compound (88 mg) was obtained.