Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:22])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-])=O)=[O:5])[CH3:2]>CO.C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:22])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH2:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(C)c1Nc1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
Zinc powder (26.17 g, 400 mmol) was added to a suspension of 5-(4-chloro-2-nitro-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E1.1 (26.0 g, 80 mmol) in methanol/acetic acid (10:1, 330 ml) at room temperature. After the exothermic reaction which followed, the resulting suspension was stirred at room temperature for 18 h before being filtered through Celite® filter agent. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc, and the solution was washed with saturated NaHCO3 and brine, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 65% EtOAc:35% pet ether to 80% EtOAc:20% pet ether) to yield the title compound (18.41 g, 78.0%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:22]=[CH:21][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1.O>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium azide (210 mg, 1.15 eq) was added to a solution of 4-(4-bromomethylbenzyl)-nitrobenzene (901 mg) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature for 2 hours, poured into water, and extracted with diethyl ether (3×). The organic phase was washed with water (3×), dried (MgSO4), and evaporated to dryness. Chromatography on silica gel, eluting with hexane/ethyl acetate, gave 4-(4-azidomethylbenzyl)-nitrobenzene (492 mg, 62%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][NH2:6].C([O-])([O-])=O.[K+].[K+].[C:13]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35])([F:31])[F:30])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])([F:15])[F:14]>COCCOC>[C:13]([C:17]([C:20]([C:23]([C:26]([C:29]([CH2:32][CH2:33][S:34]([NH:6][CH2:5][CH2:4][CH2:3][Cl:2])(=[O:36])=[O:35])([F:30])[F:31])([F:28])[F:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])([F:15])[F:14]
Reactant: O=S(=O)(Cl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=S(=O)(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)NCCCCl
Temperature: 75 °C

Procedure:
3-chloropropyl amine hydrochloride (4.7 g), K2CO3 (6.9 g) and 1,2-dimethoxyethane (19.3 g) solvent were placed in the round bottom flask equipped with mechanical stirring under nitrogen. Solution of 2-(perfluorohexyl)ethanesulfonyl chloride CF3(CF2)5(CH2)2SO2Cl (10.1 g), in 1,2-dimethoxyethane (10 g) solvent was added dropwise during 1 hour at room temperature while stirring at 250 rpm. After the addition was completed, the reaction was gradually heated to 75° C. and reacted for 12 h. The reaction was monitored by GC to ensure the complete conversion of CF3(CF2)5(CH2)2SO2Cl. The final reaction mixture with pH=3.5 was cooled down and filtered from solids through 2 mm layer of CELITE 545. The solids were washed with 1,2-dimethoxyethane (10 mL) and combined filtrate was evaporated in vacuum to obtain 8.2 g of CF3(CF2)5(CH2)2SO2NH(CH2)3Cl. The product was additionally dissolved in hot toluene (8 g) and washed with 15.5 mL of 1 wt % HCl aqueous solution.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)=[O:9].CN([CH:22]=[O:23])C>>[CH:22]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[NH:15][CH:14]=1)=[O:23]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Place anhydrous DMF (25 mL) in a flask under an atmosphere of nitrogen, cool to 10° C. and treat dropwise with POCl3 (8.22 g, 54 mmol) while keeping the temperature below 15° C. Add a solution of 5-methoxycarbonyl-1H-indole in 30 mL DMF portionwise keeping the temperature below 20° C. Remove the cooling bath and stir the mixture at ambient temperature for 1 hour then pour onto ice. Addition of 50 mL 5N NaOH precipitated a solid which is filtered and rinsed with water and EtOAc to give the title compound: 1H NMR (DMSO-d6) 9.95 (s, 1H), 8.76 (s, 1H), 8.4 (s, 1H), 7.9–7.8 (m, 1H), 7.5–7.7 (d, 1H), 3.85 (s, 3H), 1.7 (s, 1H); ISMS 204 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32]#[N:33])[CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]([C:20]3[N:29]([CH3:30])[C:28](=[O:31])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:32]5[NH:36][N:35]=[N:34][N:33]=5)[CH:26]=4)[N:21]=3)[CH3:19])[CH2:16][CH2:17]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(C#N)cc4c(=O)n3C)CC2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccc(-c5nnn[nH]5)cc4c(=O)n3C)CC2)cc1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
To the 1 ml DMF solution of 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (10.0 mg, 0.02 mmol) was added sodium azide (16.7 mg, 0.24 mmol) and ammonium chloride (12.8 mg, 0.24 mmol). The reaction test tube was flushed with N2 and was irradiated at 200° C. for 40 minutes in the SmithSynthesizer Microwave Reactor with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, the solvent was removed by reduce pressure and extracted with water and ethyl acetate, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3-methyl-6-(1H-tetrazol-5-yl)-3H-quinazolin-4-one (Yield 3.09 mg, 9.8%). 1H NMR (400 MHz, MeOD-d4): δ 1.79 (d, 3H, J=6.57 Hz), 3.39-3.12 (m, 8H), 3.70 (s, 3H), 3.92 (s, 3H), 4.70 (s, br, 1H), 7.17 (d, 2H, J=9.09 Hz), 7.76 (d, 2H, J=9.09 Hz), 7.87 (d, 1H, J=8.59 Hz), 8.47 (dd, 1H, J=8.59, 1.77 Hz), 8.89 (d, 1H, J=1.77 Hz). MS m/z calc. 510.18 found (ESI); 511.4 (M+1)+. Retention time 2.2 minutes.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:11])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[CH3:20].C([Li])CCC.[CH3:26][CH:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([CH3:37])=[O:36])=[CH:31][CH:30]=1)[CH3:28].O>C1COCC1>[OH:36][C:35]([C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:11])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:3]=1[CH3:20])([C:32]1[CH:33]=[CH:34][C:29]([CH:27]([CH3:28])[CH3:26])=[CH:30][CH:31]=1)[CH3:37]
Reactant: CC(=O)c1ccc(C(C)C)cc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)OC(C)(C)C)CCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2c(c(C(C)(O)c3ccc(C(C)C)cc3)c(C)c1NC(=O)OC(C)(C)C)OCC2
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To a mixed solution of tert-butyl (7-bromo-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 222 (500 mg, 1.46 mmol) and cerous chloride (360 mg, 3.21 mmol) in THF (8 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.6 M hexane solution, 2.0 mL, 3.21 mmol). The mixture was stirred at the same temperature for 30 minutes, and then to the reaction solution was added dropwise a solution of 4-isopropylacetophenone (261 mg, 1.61 mmol) in THF (4 mL) and the resulting mixture was stirred for 30 minutes and elevated to room temperature. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 118 mg (yield: 19%) the title compound. Melting point: 185-186° C. (ethyl acetate-hexane).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[CH2:9]2)[O:7][NH:31]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(F)(F)F)nc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)nc1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (1.085 g, 2.70 mmol) was dissolved in MeOH (12 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (0.793 mL, 2.70 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.165 mL, 2.70 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (13.89 mL, 83.32 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1-carboxylate (160 mg, 16%) was isolated. MS m/z 372 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[N:7](CC3C=CC(OC)=CC=3)[C:8](=[O:16])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[C:14]=3[C:5]=2[CH:4]=1.[OH-].[Na+].Cl>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]2[NH:7][C:8](=[O:16])[C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc(Cn2c(=O)c3c(c4cc(OC)ccc42)N(C)CCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2[nH]c(=O)c3c(c2c1)N(C)CCC3
Temperature: 100 °C
Yield: 88.7 %

Procedure:
The compound (440 mg, 1.20 mmol) prepared in step 1 was dissolved in excess trifluoroacetic acid (3 ml), and the resulting mixture was heated at 100° C. for 18 hours in sealed-tube. The mixture was poured into ice water and acidified with 2 N sodium hydroxide aqueous solution. After neutralizing with 2 N hydrochloric acid aqueous solution, the crude solution was extracted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness. The residue was then purified by flash column chromatography (dichloromethane:methanol=10:1) to obtain the title compound (260 mg, yield: 88%, white solid).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[S:21](N)([NH2:24])(=[O:23])=[O:22].[H-].[H-].[H-].[H-].[Li+].[Al+3]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH:12]2[C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[N:10][CH:9]=[CH:8][CH:7]=4)[C:2]=3[NH:1][S:21](=[O:23])(=[O:22])[NH:24]2)=[CH:15][CH:16]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc2cccnc12
Reactant: NS(N)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=S1(=O)Nc2c(ccc3cccnc23)C(c2ccc(F)cc2)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
(8-Amino-quinolin-7-yl)-(4-fluoro-phenyl)-methanone 367 (100 mg, 0.38 mmol) and sulfamide (361 mg, 3.76 mmol) in pyridine (3 ml) and were heated in a microwave at 140° C. for 2 h. After cooling, the mixture was concentrated in vacuo. The residue was dissolved in anhydrous THF (5 ml). LiAlH4 (26 mg, 0.75 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 ml) and the resulting precipitate was collected by filtration and dried. The crude solid was purified by preparative HPLC (acidic conditions 1) to give the title compound (27 mg, 22%).
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Solvent: Cc1ccccc1
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (3.29 g.) in toluene (200 ml.) is added p-nitrobenzoyl chloride (1.86 g.). The mixture is refluxed for 18 hours and then cooled to room temperature. The precipitate is collected by filtration, washed with hexane and dried to afford 4.15 g. (87% yield) of 3-(3-carbomethoxythioureido)-4-p-nitrobenzamidobenzophenone, m.p. 205° C., dec. at 210° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]=[CH:5][CH2:6][O:7][C:8]1[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:22][C:21]=3[NH:20][C:19]([CH3:31])=[C:18]2[C:32]#[N:33])=[CH:10][C:9]=1[Br:34].O.Cl>O1CCOCC1.[OH-].[Na+]>[Br:34][C:9]1[CH:10]=[C:11]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:22][C:21]=3[NH:20][C:19]([CH3:31])=[C:18]2[C:32]#[N:33])[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:8]=1[O:7][CH2:6][CH:5]=[CH:4][C:3]([OH:35])=[O:2]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)OC)c(OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)O)c(OCC)c1

Procedure:
A solution of 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid methyl ester (1.2 g) in dioxane (100 ml) and 2N sodium hydroxide (2.2 ml) was stirred for 5 days. The mixture was poured into water and the pH was adjusted to 2 using 4N aqueous HCl. The resulting mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Yield: 1.5 g. MS-ESI: [M+H]+=529.2/531.2
Reaction SMILES: [CH:1]1([C@@:7]([OH:47])([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:8]2[N:12]=[CH:11][N:10]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]5C(=O)C6C(=CC=CC=6)C5=O)=[CH:24][CH:23]=4)[CH2:16][CH2:15]3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>C(O)C>[NH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][N:17]2[CH2:16][CH2:15][CH:14]([CH2:13][N:10]3[CH:11]=[N:12][C:8]([C@@:7]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[OH:47])=[N:9]3)[CH2:19][CH2:18]2)=[CH:27][CH:26]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1ccc(CCN2CCC(Cn3cnc([C@](O)(c4ccccc4)C4CCCCC4)n3)CC2)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
2-[2-(4-{2-[4-({3-[(R)-cyclohexyl(hydroxy)phenylmethyl]-1H-1,2,4-triazol-1-yl}methyl)piperdin-1-yl]ethyl}phenyl)ethyl]-1H-isoindole-1,3(2H)-dione (Preparation 12, 3.4 g, 5.38 mmol) was suspended in ethanol (20 ml) and hydrazine monohydrate (2.61 ml, 53.8 ml) added. After stirring at reflux for 2 hours, the reaction was cooled to room temperature and the precipitate collected by filtration and washed with ethanol (200 ml). The filtrate was concentrated in vacuo to furnish the title compound as a white solid, in 81% yield, 2.57 g.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12](Br)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH2:2][CH3:3].[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]>>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH2:2][CH3:3]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCCc1cc(Br)c2ncccc2c1
Product: CCCc1cc(-c2cccc([N+](=O)[O-])c2)c2ncccc2c1

Procedure:
6-propyl-8-bromoquinoline and 3-nitrobenzene boronic acid can be combined to form 6-propyl-8-(3-nitrophenyl)quinoline,
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.N[C:11](N)=[O:12].[OH-].[Na+]>O.C1(C)C(C)=CC=CC=1>[OH:12][C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: NC(N)=O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1nc2ccccc2[nH]1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Into a four-necked flask of 1 l capacity were charged 64.8 g (0.6 mol) of o-phenylenediamine, 31.3 g (0.5 mol) of hydrochloric acid, 36.0 g (0.6 mol) of urea and 50 ml of xylene, and a reaction was effected at 140°-150° C. for 5 hours while distilling out 20 ml of water. Then, the reaction product was charged into a four-necked flask of 1 l capacity, into which 30 g (0.75 mol) of sodium hydroxide and 600 ml of water had been previously charged, and the resulting mixture was stirred at 80° C. for 15 hours. Then, thus treated mixture was filtered while it was hot, and the filtrate was cooled to form a precipitate. The resulting precipitate was filtered, and the filter cake was washed with water to obtain the aimed 2-hydroxybenzimidazole having a melting point of 316°-317° C. in an yield of 53.6 g (66.6%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:23][CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: NCc1cccnc1
Solvent: c1ccncc1
Product: O=C(NCc1cccnc1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a flask containing 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (300 mg, 0.95 mmol) dissolved in pyridine (4 mL) was added 3-aminomethyl pyridine (106 μl, 1.05 mmol). The reaction was allowed to stir under a nitrogen atmosphere overnight. LCMS indicated the reaction was complete. Solvent was removed and water was added to the flask. A solid crashed out of solution that was collected by filtration. The solid was taken up in a 3% ammonia in methanol solution (8 mL) and allowed to reflux at 60° C. for three hours. The reaction was neutralized with 1 N HCl solution and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the title compound (134 mg, 41% yield). 1H NMR (DMSO-d6) δ 13.5 (s, 1H), 9.2 (s, 1H), 8.6 (m, 2H), 8.5 (s, 1H), 8.1 (m, 2H), 7.95 (d, 1H), 7.65 (d, 1H), 7.6 (m, 1H), 7.4 (m, 3H), 4.6 (m, 2H) ES-MS m/z 347 [M+1]+.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: N#CNC(=NCc1ccc(C(F)(F)F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4-(trifluoromethyl)benzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.53 g, 1.7 mmol, yield: 66%) as colorless crystals.
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([C:12]2[CH2:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CI>C1COCC1>[CH3:1][CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1=C(c2ccccc2)Cc2ccccc21
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1C(c2ccccc2)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Butyllithium (2.5 M in hexanes, 3.0 mL, 7.6 mmol was added dropwise to a suspension of 2-phenylindene (1.382 g, 7.2 mmol) in THF (50 mL) at −78 C. Upon addition of n-butyllithium the reaction mixture turned a dark orange color and 2-phenylindene dissolved. When the addition of the reagents was complete the solution was allowed to warm to room temperature and stirred for 30 minutes. CH3I (1.3 mL, 22 mmol) was added to this solution dropwise and the light brown reaction mixture was heated to 40° C. and stirred for 24 hours. After that the solvents were removed in vacuo and the light brown solid was recrystallized from EtOH (25 mL) at room temperature affording white needles (1.075 g, 75% yield). 1H NMR (CDCl3, 20° C., 300 MHz): Λ 7.52-7.19 (overlapping signals from aromatic protons, 9H), 3.74 (s, 2H), 2.31 (s, 3H). 13C {1H} NMR (CDCl3, 20° C., 75 MHz): δ□1147.49 (C), 142.42 (C), 140.31 (C), 137.56 (C), 134.70 (C), 128.37 (CH), 128.24 (CH), 126.63 (CH), 126.40 (CH), 124.74 (CH), 123.32 (CH), 119.11 (CH), 40.96 (CH2), 11.94 (CH3).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])[CH:11]=2)=[O:9])[CH2:4]1>CC(O)=O.Cl.[Fe]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:11]=[C:10]([C:8]([N:5]4[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:30])[CH3:1])[CH2:4]4)=[O:9])[S:18][C:17]=23)=[C:21]([F:29])[CH:22]=1
Reactant: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reaction time: 0.33 h
Yield: 77 %

Procedure:
To a solution of the nitro compound 25 (708 mg, 1.64 mmol) in AcOH (16 mL) at 90° C., was added iron powder (928 mg, 16.6 mmol) and the reaction mixture was stirred vigorously for 20 min. The grey suspension was dissolved in 1N HCl (50 mL) and washed with CHCl3 (50 mL). The aqueous phase was basified with NH4OH to pH-10, extracted with CHCl3. The organic phase was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound 26 (506 mg, 77%) as a white solid. MS (m/z): 401.1 (M+H).