Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=C([C:11]3[C:12]4[C:17]([C:18](Br)=[C:19]5[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]5)=[CH:16][CH:15]=[CH:14][CH:13]=4)C=2)C=CC=1C1C=CC2C(=CC=CC=2)C=1.C1(C2C=CC=CC=2)C(B(O)O)=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O.C(O)C>[CH:13]1[C:12]2[C:17](=[CH:18][C:19]3[C:24]([CH:11]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=1
Reactant: Brc1c2ccccc2c(-c2ccc3ccc(-c4ccc5ccccc5c4)cc3c2)c2ccccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc2cc3ccccc3cc2c1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
Under the nitrogen atmosphere, [9-([2,2′-binaphthalen]-7-yl)-10-bromoanthracene (2.0 g) as the tenth intermediate compound, p-biphenylboronic acid (0.9 g), Pd(dba)2 (0.05 g), tricyclohexyl phosphine (0.05 g), potassium phosphate (1.7 g), and a mixture solvent of toluene and ethanol (15 ml) (toluene/ethanol=4/1 (volume ratio)) were added to a flask and then refluxed for 3 hours. Once the heating is completed, it was cooled to room temperature and added with water. The precipitates were collected by suction filtration. The obtained solid was washed with water followed by methanol and purified by silica gel column chromatography (solvent: toluene) and further by active carbon column chromatography (solvent: toluene) to give 9-([1,1′-biphenyl]-4-yl)-10-([2,2′-binaphthalen]-7-yl)]anthracene (0.6 g) as the target compound represented by Formula (1-129). The scheme is shown in the following “Reaction 20”.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C(O[CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH3:7][C:4]1[C:3]2[C:2](=[N:1][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=2)[O:6][N:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cc(N)on1
Product: CCOC(=O)c1cnc2onc(C)c2c1
Temperature: 120 °C

Procedure:
A mixture of 5-amino-3-methyl-isoxazole (5.26 g) and diethyl ethoxymethylenemalonate (10.9 ml) was heated at 120° C. for 3 hrs. The mixture was cooled to room temperature. The precipitated solid was collected, washed with n-hexane and dried under high vacuum. A portion of this solid (11.37 g) was dissolved in phosphoryl chloride (55 ml), heated at reflux for 11 hrs, and then cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified with the column chromatography (ethyl acetate:n-hexane=1:9) to give ethyl 3-methylisoxazolo[5,4-b]pyridine-5-carboxylate as a white solid. Zinc powder (2.75 g) was added to a solution of a portion of the solid (2.43 g) in acetic acid (24 ml), the mixture was stirred at 80° C. for 1.5 hrs, and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of 5N NaOH (10 ml) and ethanol (10 ml), the solution was refluxed for 1.5 hrs, cooled to room temperature, and acidified with concentrated HCl. The precipitated solid was collected by the filtration, washed with water, and dried under high vacuum.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH2:22])=[O:21])=[N:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([NH2:22])=[O:21])=[N:18][CH:19]=1
Reactant: OB(O)c1cc2ccccc2s1
Reactant: NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(-c2cc3ccccc3s2)cn1
Yield: 3.6 %

Procedure:
2-Benzothienylboronic acid (1.8 mmol), 5-bromopyridine-2-carboxamide (1.2 mmol), 2M K2CO3 (2.4 mL), Pd(dppf)Cl2 (0.12 mmol) were mixed and stirred at 80° C. in DMF for 3 h. The reaction mixture was filtered and to the filtrated was added EtOAc and H2O. The layers were separated and the aqueous phase was extracted twice with EtOAc. The organic extracts were dried over Na2SO4. The solvent was evaporated in vacuo to give a brown solid. The crude was subjected to reverse phase HPLC to afford the title compound as a light brown solid (11 mg). 1H NMR δ ppm 9.07 (d, 1 H) 8.34 (dd, 1 H) 8.24-8.02 (m, 5 H) 7.73 (s br, 1 H) 7.54-7.37 (m, 2 H); MS m/z 255 (M+H).
Reaction SMILES: P(=O)(O)(O)O.[CH2:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]1([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([C:35]([NH2:37])=[O:36])[CH:34]=2)[NH:31][CH:30]=[CH:29]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)(=O)C>[C:20]1([C:26]2[CH:27]=[C:28]3[C:32](=[C:33]([C:35]([NH2:37])=[O:36])[CH:34]=2)[NH:31][CH:30]=[C:29]3[C:16]2[CH2:15][CH2:14][N:13]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2cc[nH]c12
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c12
Temperature: 90 °C

Procedure:
To a 5 L three necked flask was charged 85% wt Phosphoric acid (423 mL, 6.16 moles, 25 eq), benzyl piperidone (142 mL, 0.733 mole, 3 eq) and glacial acetic acid (400 mL). The resulting mixture was heated to 90° C. A solution of 5-phenyl-1H-indole-7-carboxamide (57.69 g, 0.244 mole, 1 eq) in glacial acetic acid (755 mL) was then added portionwise. The reaction was then maintained at 90° C. overnight. The reaction mixture was cooled to room temperature. It was then divided into two equal portions and each was added slowly to separate stirring mixtures of ice/0.88 ammonia (1 L/1 L). A dry ice/acetone bath was also used to control the exotherm. Ethyl acetate (600 mL) was then added to the mixture with stirring. It was then filtered and the solid washed well with ethyl acetate. The filtrate was then separated and the aq was re-extracted with ethyl acetate. The organics were then dried over magnesium sulfate and filtered before the two batches were combined and evaporated under reduced pressure. The residue was then dissolved in 3% (3.5M ammonia in methanol) in DCM (300 mL). The solid precipitate was then collected by filtration and was then dried in vacuo to yield the desired product. (42.25 g) MS: (M+H): 408.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[CH:10]([CH:12]=O)=O>CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: O=CC=O
Reactant: Cc1ccc(N)c(N)c1
Solvent: CO
Product: Cc1ccc2nccnc2c1
Reaction time: 16 h
Yield: 25 %

Procedure:
A solution of 4-methyl-1,2-phenylenediamine (5.0 g, 41 mmol) in methanol (250 mL) was treated with a solution of 40% aqueous glyoxal and stirred for 16 h. The solvent was evaporated and the residue was distilled under vacuum (2 mm Hg, 85-88° C.) to leave a colorless oil (1.5 g, 25%). LC/MS (Method A): r.t.=1.02 min., purity=99.5%.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].C([O-])(=O)C.[Na+].[C:16](OCC)(OCC)(OCC)[O:17][CH2:18][CH3:19]>C(O)C>[CH2:18]([O:17][C:16]1[O:10][C:4]2[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=2[N:2]=1)[CH3:19]
Reactant: CCOC(OCC)(OCC)OCC
Reactant: Nc1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2ccc(O)cc2o1
Yield: 60 %

Procedure:
A mixture of equivalent amounts of 4-aminoresorcinol hydrochloride and anhydrous sodium acetate in anhydrous ethanol was stirred for 16 hours at room temperature with a slight excess of tetraethyl orthocarbonate to give 2-ethoxy-6-hydroxybenzoxazole in 60% yield.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.Cl([O-])(=O)(=O)=O.[Li+].CCN(C(C)C)C(C)C.[CH3:50][C:51]1([CH3:54])[CH2:53][O:52]1>C1COCC1.O>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:50][C:51]([CH3:54])([OH:52])[CH3:53])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: CC1(C)CO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride (100 mg, 0.21 mmol), lithium perchlorate (22 mg, 0.21 mmol) and DIPEA (72 μL, 0.41 mmol) in THF (3 mL) was treated with 2,2-dimethyl-oxirane (183 μL, 2.06 mmol) and then water (150 μL). The reaction mixture was stirred at RT for 18 h before being concentrated in vacuo. The resultant residue was partitioned between DCM and water, the organic layer separated and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 40 to 100% ethyl acetate in cyclohexane) followed by trituration in a mixture MeOH and water to give 177 as a white solid (58 mg, 54%). 1H NMR (400 MHz, DMSO-d): δ 8.44 (s, 1H); 8.28 (s, 1H); 7.85 (td, J=8.76, 5.90 Hz, 1H); 7.61 (ddd, J=10.27, 8.88, 2.78 Hz, 1H); 7.36-7.30 (m, 1H); 7.22 (d, J=2.31 Hz, 1H); 7.08 (dd, J=8.38, 2.35 Hz, 1H); 6.89 (d, J=8.34 Hz, 1H); 4.21 (t, J=5.02 Hz, 2H); 4.06 (s, 1H); 3.12-3.02 (m, 4H); 2.31-2.19 (m, 5H); 1.60-1.48 (m, 4H); 1.15 (s, 6H). LCMS: RT=7.75 min, M+H+=521
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10]1[CH2:16][S:13](=[O:15])(=[O:14])[O:12][CH2:11]1>O1CCOCC1.O>[C:3]([C:2]([NH:1][CH2:11][CH2:10][CH2:16][S:13]([OH:15])(=[O:14])=[O:12])([CH3:7])[CH3:6])([OH:5])=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: O=S1(=O)CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(NCCCS(=O)(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (5° C.) mixture of 2-aminoisobutyric acid (2.0 g, 19.4 mmol), NaOH (776 mg, 19.4 mmol) in 1,4-dioxane (10 mL) and water (4 mL) was added via syringe pump (over a 4-hour period), a solution 1,3-propane sultone (2.02 g, 16.2 mmol) in 1,4-dioxane (total: 4 mL). The solution was stirred at room temperature for 2 hours before it was allowed to warm up to room temperature. The reaction mixture was stirred under these conditions overnight. The solvent was evaporated under reduced pressure. The resultant solid material was recrystallized from 5% water/EtOH. The resulting solid was dissolved in water; and the aqueous solution was passed through an ion exchange column (Dowex 50WX 8, 100 g, solvent: water). The solvent was evaporated under reduced pressure. The product was lyophilized to afford Compound DI (880 mg, 28%). 1H NMR (D2O, 500 MHz) 8 ppm 3.00 (t, 2H, J=7.6 Hz), 2.91 (t, 2H, J=7.3 Hz), 2.01 (m, 2H), 1.34 (s, 6H). 13C NMR (D2O, 125 MHz) 8 ppm 176.93, 63.89, 48.13, 42.04, 22.15, 21.86. ES-MS 224 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][OH:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OCC)C.Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][O:17][CH2:18][CH2:19][O:20][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCOCC(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc(OCc3ccccc3)cc2)cc1
Temperature: -20 °C
Reaction time: 15 h
Yield: 58.8 %

Procedure:
22.7 g of 1-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanol was dissolved in 140 ml of pyridine. The solution was cooled to -20° C. To the solution was added 19 g of p-toluenesulfonyl chloride. The resulting mixture was heated to 0° C. and stirred for 15 hours at the same temperature. The reaction mixture was added to a mixture of 300 ml of ice water and 200 ml of diethyl ether. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with 1N hydrochloric acid., water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=3/1) to obtain 20.5 g of oily 1-(4-benzyloxyphenyl)-2-[2-(p-toluenesulfonyl)oxyethoxy]ETHANOL.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].C1C=C([O:15]O)C(C(O)=O)=C(C(O)=O)C=1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[N+:5]([O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: N#Cc1cccnc1
Solvent: ClCCl
Product: N#Cc1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 20.0 grams (0.194 mole) of 3-cyanopyridine and 142.5 grams (0.288 mole) of monoperoxyphthalic acid, magnesium salt, hexahydrate (80% pure) in 300 mL of methylene chloride is stirred at ambient temperature for about 24 hours. After this time, the mixture is filtered, and the filtrate is concentrated under reduced pressure, yielding 3-cyanopyridine N-oxide.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]=[CH2:12])=[CH:5][CH:4]=1)=[CH2:2].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C(O)(C)C>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=CCOc1ccc(C=C)cc1
Reactant: CO[SiH](OC)OC
Solvent: CC(C)O
Product: C=Cc1ccc(OCCC[Si](OC)(OC)OC)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 500 ml glass flask equipped with a stirring machine, a reflux condenser, a thermometer and a dropping funnel, there were added 48.0 g (0.3 mole) of 3-(4-vinylphenyloxy)propene, 0.1 g of a 4% isopropyl alcohol solution of H2PtCl6 and 0.2 g of BHT. To the mixture, there was dropwise added 36.6 g (0.3 mole) of trimethoxysilane through the dropping funnel at 60° to 70° C. over one hour, followed by ripening at 70° C. for 30 minutes. The reaction solution was distilled to give 66.1 g of a compound having a boiling point of 147°-151° C./3 mmHg. The yield thereof was found to be 78.0%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.[Pd].P.P.P.P>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: P
Solvent: COCCOC
Product: COc1ccccc1-c1ccnc(Cl)c1N
Yield: 78.3 %

Procedure:
2-chloro-4-iodo-N-(triphenylphosphoranylidene) pyridin-3-amine (12 g, 23 mmol), (2-methoxyphenyl) boronic acid (4.25 g, 28 mmol), 2M potassium carbonate solution (46.6 ml, 93 mmol) were poured in 120 mL DME and degassed with bubbling nitrogen for 15 min. To the stirred solution was added tetrakisphosphine palladium(0) (1.35 g, 1.12 mmol) and reaction mixture was degassed for another 10 min. Reaction mixture was then refluxed for 48 h. Cooled reaction mixture was partitioned between ethyl acetate and brine. Organic layer was isolated, dried over anhd. Na2SO4 and purified by silica gel column chromatography using 5-30% ethyl acetate/hexanes as eluent. 2-chloro-4-(2-methoxyphenyl)pyridin-3-amine (4.3 g, 18 mmol, 78% yield) was isolated as liquid oil which turns into white crystals upon standing at room temperature.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:11][C:12]([F:26])([F:25])[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[CH2:16]Br>CN(C)C=O>[C:1]([O:4][CH2:16][C:15]1[CH:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=[C:13]([C:12]([F:11])([F:25])[F:26])[CH:14]=1)(=[S:3])[CH3:2]
Reactant: CC(O)=S
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=S)OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Thioacetic acid (5.13 ml) was added to a suspension of caesium carbonate (11.7 g) in dimethylformamide (120 ml) at room temperature. The solution was stirred for 10 min and a solution of 3,5-bis(trifluoromethyl)benzyl bromide (20 g) in dimethylformamide (10 ml) was added. The resulting solution was stirred for 16 h, in the dark. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and the solvent was removed leaving an orange oil. The off was chromatographed on silica gel in 5% ethyl acetate/petrol giving 3,5-bis(trifluoromethyl)benzyl thioacetate (14.8 g) as a yellow oil. 1H NMR (360 MHz, CDCl3) δ 2.39 (3H, s), 4.17 (2H, s), 7.75 (3H, s); m/z (CI+) 303 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH:18]=[N:19][C:20]([C:25]#[N:26])=[C:21]([NH2:24])[C:22]#[N:23])[CH:15]=[N:14]1.O1CCCC1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:18][NH:19][C:20]([C:25]#[N:26])=[C:21]([NH2:24])[C:22]#[N:23])[CH:15]=[N:14]1
Reactant: N#CC(N)=C(C#N)N=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: N#CC(N)=C(C#N)NCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-2H-1,2,3-triazole (8 g) (prepared as in Example 1) was dissolved in methanol (50 ml) and tetrahydrofuran (75 ml) and then sodium borohydride (0.76 g) was added portionwise. This mixture was stirred for 20 minutes at room temperature and then poured into water to give a brown solid. This was purified by flash column chromatography to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylamino)methyl]-2H-1,2,3-triazole, m.p. 191°-192°. A mixture of this compound (1.8 g), nicotinamide (0.6 g), N-chlorosuccinimide (0.6 g) and dimethylformamide was heated at 65°-70° for 10 minutes. The mixture was poured into water and extracted with diethyl ether. Conventional work-up and purification by flash column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-(4,5-dicyano-4-imidazolin-2-yl)-2H-1,2,3-triazole, m.p. 219°-220° (dec). (Compound 10).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:32])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-methyl-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M39) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (113 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][C:26](O)([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+].CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40][CH3:41])=[CH:33][CH:34]=4)[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOc1ccc(C2(O)CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COCCCCOc1ccc(C2=CCN(c3ccc(N4CCN(C(=O)OCc5ccccc5)CC4)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a solution of 4-[4-[4-hydroxy-4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (3.41 g) in dichloromethane (50 ml) was added trifluoroacetic acid (8.5 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for further 6 hours. To the reaction mixture was added 1 mol/ml sodium hydroxide solution (170 ml), dichloromethane (136 ml) and methanol (14 ml). The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (50:1 dichloromethane-methanol elution) to give 4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylic acid benzyl ester (2.23 g).
Reaction SMILES: C1([OH:7])C=CC=CC=1.[OH:8][C:9]1[C:14]2[C:15]([CH3:27])=[C:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[O:17][C:13]=2[C:12]([Cl:28])=[CH:11][C:10]=1[CH2:29][CH2:30][CH2:31][OH:32].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O>[OH:8][C:9]1[C:14]2[C:15]([CH3:27])=[C:16]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[O:17][C:13]=2[C:12]([Cl:28])=[CH:11][C:10]=1[CH2:29][CH2:30][C:31]([OH:7])=[O:32]
Reactant: COc1ccc(Cc2oc3c(Cl)cc(CCCO)c(O)c3c2C)cc1
Reactant: Oc1ccccc1
Agent: O=[Cr](=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3c(Cl)cc(CCC(=O)O)c(O)c3c2C)cc1

Procedure:
To a solution of the silyated phenol derivative of (180) (Example 49) (400 mg, 0.84 mmol) in 10 mL acetone was added dropwise at 0° C. the Jones reagent. The reaction was monitored by tlc. The crude silylated acid after workup was treated with tetra-n-butyl ammonium fluoride as described before. The title compound was isolated by preparative tlc, mp 149°-151° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.N>O>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(NCc3ccccc3)c2c1
Agent: N
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]nc(NCc3ccccc3)c2c1
Yield: 28.1 %

Procedure:
5-Amino-3-benzylamino-1H-indazole can be obtained as described in Example 4 from 0.6 g of 3-benzylamino-5-nitro-1H-indazole, 22 ml of ethanol, 4.5 g of ferrous sulfate, 7 ml of water and 5.4 ml of 32% aqueous ammonia. 0.15 g of 5-amino-3-benzylamino-1H-indazole is thus obtained in the form of a brown powder melting at 196° C.