Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.O.C([O-])(O)=[O:13].[Na+]>OS(O)(=O)=O.C(OC(=O)C)(=O)C>[OH:13][CH2:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C)c(C#N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(CO)nc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3,6-dimethylpyridine-2-carbonitrile (4.44 g, 30.0 mmol) and conc. H2SO4 (2 drops) in acetic anhydride (30 mL) was stirred at 100° C. for 16 h, cooled to room temperature, poured into water (100 mL) and basified to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with EtOAc (3×25 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo. The residue was treated with MeOH (100 mL), water (40 mL) and K2CO3 (8.8 g), stirred at room temperature for 1 h, concentrated in vacuo and partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (2.4 g, 51%) as a yellow oil; NMR δH (400 MHz, CDCl3) 2.57 (3H, s), 4.78 (2H, s), 7.42 (1H, d, J 8.5 Hz) and 7.67 (1H, d, J 8.5 Hz); M/Z 149 (M+H)+
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH3:20])[O:14][N:13]=1.[C:21](OC)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][C:12]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:14][N:13]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: COC(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1noc(CC(=O)c2ccccc2)c1C(=O)O

Procedure:
A solution of lithium bis(trimethylsilyl)amide (10 g, 60 mmol, 3 eq) in toluene (60 mL) was added drop wise during 15 min to a solution of 3,5-dimethylisoxazole-4-carboxylic acid (2.82 g, 20 mmol) and methyl benzoate (2.5 mL, 1 eq) in THF (20 mL) at a temperature not exceeding 40 deg. After 1 h the reaction was quenched by the addition of a water solution of 0.1M HCl (0.3 L) leaving the water phase still basic and the phases was separated. The water phase was washed with toluene and then reduced in volume by evaporation until most of the residual organic solvents were removed. 1M HCl was added dropwise with stirring. The resulting crystals were filtered and dried in vacuum to yield the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.45 (s, 3H) 4.75 (s, 2H) 7.43-7.51 (m, 2H) 7.55-7.63 (m, 1H) 7.86-8.12 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC(C)([O-])C.[K+].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](Cl)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:17][C:18]1[CH:23]=[C:22]([O:8][C:6]2[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([NH2:1])[CH:7]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Clc1cncc(Cl)c1
Reactant: Nc1cc(O)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Oc2cncc(Cl)c2)c(F)cc1F
Temperature: 190 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5-amino-2,4-difluorophenol (0.3 g, 2.07 mmol) in DMSO (2 mL) was added potassium t-butoxide (0.23 g, 2.07 mmol) at RT. After stirring for 1 h, 3,5-dichloropyridine (0.37 g, 2.5 mmol) and potassium carbonate (0.14 g, 1 mmol) were added and the mixture was heated to 190° C. for 1 h in microwave reactor. Water (30 mL) was added, and the product was extracted with EtOAc (2×35 mL) and the combined organic layers were washed with brine solution, dried (Na2SO4), concentrated in vacuo and purified by chromatography (EtOAc/hexane) to afford 5-(5-chloropyridin-3-yloxy)-2,4-difluorobenzenamine (0.35 g, 66% yield) as a solid. 1H NMR (400 MHz, Acetone-d6) δ 8.33-8.30 (m, 2H), 7.44 (t, J=2.4 Hz, 1H), 7.13 (t, J=10.8 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.85 (brs, 2H); MS (ESI) m/z: 257.0 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O.C(N(CC)CC)C>C(#N)C>[Cl:15][C:7]1[N:6]2[N:10]=[CH:11][CH:12]=[C:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nc2ccnn2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)n2nccc2n1
Yield: 71 %

Procedure:
In a round bottom flask equipped with a magnetic stirbar, 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.0 eq, 10.43 g, 57.24 mmol) was suspended in acetonitrile (100 ml). Phosphorus oxychloride (4.0 eq, 21 ml, 229.4 mmol) and triethylamine (1.05 eq, 8.4 ml, 60.27 mmol) were added and the mixture stirred at reflux for 3.5 hours, at which time LCMS indicated completion of the reaction. The mixture was cooled down and slowly poured into crushed ice (final total volume of about 600 ml). The solid was filtered, washed with water and dried in a vacuum oven to afford 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine as a tan solid (8.15 g, 71% yield). LCMS (ES): >97% pure, m/z 201 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[N+:20]([O-])=O)(=[O:3])[CH3:2].N[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[N:8][N:7]([CH2:17][CH3:18])[C:6](=[O:19])[C:5]=1[NH:20][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cccc2cccnc12
Solvent: CCO
Product: CCn1nc(-c2cccc(Cl)c2)c(C(C)=O)c(Nc2cccc3cccnc23)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a stirred solution of 100 mg (0.311 mmol) of 5-acetyl-2-ethyl-4-nitro-6-(3-chlorophenyl)pyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 8-aminoquinoline (67 mg, 0.467 mmol) was added. The resulting mixture was stirred at room temperature for two hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to yield the title compound (65 mg, 50% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]=O)=[C:12]([Cl:19])[CH:11]=1.[BH3-]C#N.[Na+].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][CH2:17][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Clc1cc(-c2nc3ccccc3o2)ccc1CCN1CCOCC1

Procedure:
The crude aldehyde was treated with NaCNBH3 and morpholine in MeOH/CH2Cl2 (2 mL). The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 2-[3-chloro-4-(2-morpholin-4-ylethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 8.26–8.25 (d, 1H), 8.09–8.06 (m, 1H), 7.79–7.74 (m, 1H), 7.43–7.34 (m, 3H), 3.78–3.75 (m, 4H), 3.05–3.00 (m, 2H), 2.68–2.59 (m, 6H). MS (ESI) 343 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[OH:29][CH:28]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[O:23][CH:24]=[CH:25][C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 72.1 %

Procedure:
3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.200 g, 3.33 mmol) and ethyl formate (0.8 mL, 9.95 mmol) were dissolved in anhydrous ethanol (30 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (6.21 mL, 16.63 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a light yellow precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.931 g, 2.4 mmol, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13](O)=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:25])=O>C1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([Cl:25])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)Cl
Reaction time: 16 h

Procedure:
47.2 g (0.20 moles) of 4-t-butyl-2,6-dimethyl-3-hydroxyphenyl acetic acid, and 0.4 ml of dry N,N-dimethylformamide are dispersed in 325 ml of dry benzene. To this slurry was added dropwise with stirring under a nitrogen atmosphere 28.5 g (17.5 ml, 0.24 moles) of thionyl chloride at ambient temperature. The reaction mixture was allowed to stir for 16 hours, then evaporated under reduced pressure, yielding an orange-colored solid, which proved by analysis to be the desired acid chloride. The residue was dissolved in 500 ml of benzene, analyzed for chloride ion and used for subsequent reactions in solution.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[I:15]I>N1C=CC=CC=1.CCOCC>[I:15][C:10]1[C:11](=[O:14])[O:12][CH2:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: CSc1ccc(C2=CC(=O)OC2)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reaction time: 24 h

Procedure:
To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 5N Na2S2O3. The ether layer is dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Zr+2:13].[CH:14]1[C:27]2[C:18](=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1.[Mg]>C1COCC1>[CH:14]1[C:27]2[C:18](=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][CH:15]=1.[CH:3]1([Zr:13][CH:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: c1cc[cH-]c1
Reactant: [Zr+2]
Agent: [Cl-]
Agent: [Mg]
Agent: c1ccc2nc3ccccc3cc2c1
Solvent: C1CCOC1
Product: C1=CC([Zr]C2C=CC=C2)C=C1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a solution of 5.00 g (17.10 mmol) zirconocene dichloride in 100 ml THF were added 3.06 g (17.10 mmol) acridine and 0.41 g magnesium and the mixture was stirred at room temperature until the metal was fully reacted. The solvent was then removed to dryness in vacuo and the residue was extracted with 80 ml toluene. 4.29 g bis(cyclopentadienyl)zirconium acridine were isolated from the toluene extract as a red solid.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.O>CN(C)C=O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:1][CH:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
4.66 g (19.23 mmol) of methyl α-hydroxy-α-phenyl-p-toluate was dissolved in 50 ml of N,N-dimethylformamide. 0.77 g (19.23 mmol) of 60% sodium hydride was added thereto and the mixture was stirred at room temperature for 1 hour. 3.10 g (28.85 mmol) of 2-dimethylaminoethyl chloride was added thereto and the mixture was heated at 80° C. for 2.5 hours. After the reaction mixture was cooled and poured into water, the obtained mixture was extracted twice with ethyl acetate and the extract was washed with brine, and dried (MgSO4). The solvent was distilled off and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=40:1 (v/v)) to obtain 0.53 g (1.69 mmol) of methyl α-(2-dimethylaminoethoxy)-α-phenyl-p-toluate as a brown oily substance. Its spectroscopic data are as follows:
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][C:7]([CH3:11])=[CH:8][C:9]=1[SH:10].Cl.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19]Cl>CO>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][S:10][C:9]1[CH:8]=[C:7]([CH3:11])[O:6][C:5]=1[CH3:4]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(S)c(C)o1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(SCc2ccccn2)c(C)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 25 ml 3 neck round bottom flask equipped with magnetic stirrer, pot thermometer, Y tube, nitrogen inlet tube, reflux condenser and heating mantle, is placed a solution of 0.54 g (0.01 moles) of sodium methoxide dissolved in 3 ml absolute methanol. The reaction mass is maintained at 25°-30° C and a solution of 0.64 g (0.005 moles) of 2,5-dimethyl-3-furan thiol in 3 ml absolute methanol is added to the reaction mass. While maintaining the reaction at 25° C, picolyl chloride hydrochloride (0.82 g; 0.005 moles) dissolved in 2 ml absolute methanol is added to the reaction mass. The reaction being exothermic, the reaction mass warms up to 42° C and a white solid precipitate forms. The reaction mass is allowed to cool to 25° C with stirring over a period of 30 minutes. The reaction mass is then heated to reflux (60° - 65° C) under nitrogen and reflux is continued for a period of 1 hour. The reaction mass is cooled to 30° C and flushed with nitrogen. After remaining at room temperature for a period of 20 hours, 10 ml. of water is added to the reaction mass with stirring, causing the reaction mass to now exist in two phases; an aqueous phase and an organic phase. The pH of the reaction mixture is 5. 7 ml of n-hexane is then added to the reaction mass with stirring and transferred into a separatory funnel. The aqueous layer is separated from the organic phase and extracted with 8 ml n-hexane after first diluting the aqueous phase with another 10 ml of water. The hexane extracts are combined, washed with 7 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, gravity filtered, and concentrated on a rotary evaporator using water-aspirator vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)[C:5]([Br:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:26])[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(C(=O)COc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)COc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Yield: 45.8 %

Procedure:
To a mixture of 1-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-2-phenoxyethanone (0.048 g, 0.11 mmol), and ethanol (4.0 ml) was added 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was triturated with water, the precipitate was collected by filtration, washed with water, ethanol, and diethyl ether to afford the title compound as a pale yellow solid (0.027 g, 46%); 1H-NMR (500 MHz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.58 (br s) and 3.70 (br s) (8H, 2× piperazine N(CH2)2), 4.92 (s, 2H, COCH2O), 6.95 (m, 3H) and 7.30 (m, 2H) (ArH), 6.82 (d, J=9.02 Hz, 2H) and 8.02 (d, J=8.92 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.19 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.23 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCBr
Reactant: Oc1ccccc1
Product: CCCCCCCCOc1ccccc1

Procedure:
effecting reaction between phenol and a-bromo octane in the presence of an aqueous basic solution and a phase transfer catalyst to form n-octylphenyl ether,
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CN(C)c1ccc(N)c(C(=O)O)c1
Yield: 61.1 %

Procedure:
The mixture of 2.1 g of 2-nitro-5-dimethylaminobenzoic acid, 7 mL of cyclohexene and 1.5 g of Pd/C (10%) is heated under reflux conditions in 60 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 1.1 g of the title compound. M.p.: 232° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH:46]([C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[CH:52]=[C:51]([CH:58]([CH3:60])[CH3:59])[C:50]=1[S:61]([Cl:64])(=[O:63])=[O:62])([CH3:48])[CH3:47]>CN(C)C=O>[ClH:64].[O:31]=[C:29]1[NH:28][C:27](=[O:32])[CH:26]([CH2:25][C:24]2[CH:33]=[CH:34][C:21]([O:20][CH2:19][C:17]3[N:16]([CH3:35])[C:15]4[CH:36]=[C:11]([O:10][C:9]5[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][NH:3][S:61]([C:50]6[C:51]([CH:58]([CH3:59])[CH3:60])=[CH:52][C:53]([CH:55]([CH3:57])[CH3:56])=[CH:54][C:49]=6[CH:46]([CH3:48])[CH3:47])(=[O:63])=[O:62])=[CH:38][CH:37]=5)[CH:12]=[CH:13][C:14]=4[N:18]=3)=[CH:22][CH:23]=2)[S:30]1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)NCCc2ccc(Oc3ccc4nc(COc5ccc(CC6SC(=O)NC6=O)cc5)n(C)c4c3)cc2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (0.17 g) and anhydrous N,N-dimethylformamide (10 ml) was added 2,4,6-triisopropylbenzenesulfonyl chloride (0.17 g) and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1 as the eluant. To a solution of the product in ethyl acetate (15 ml) was added 4N hydrogen chloride in 1,4-dioxane (2 ml) and the mixture was stirred at room temperature for 20 minutes. The precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.28 g, mp 134-136° C.).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:7]=2[N:6]=[CH:5][CH:4]=[C:3]3[C:2]([F:1])([F:14])[F:15])(=[O:25])=[O:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=1
Reactant: Nc1cccc2c(C(F)(F)F)ccnc12
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Nc1cccc2c(C(F)(F)F)ccnc12
Yield: 60.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 4-trifluoromethyl-quinolin-8-ylamine (Intermediate 469) (325 mg, 1.53 mmol), 4-chloro-2-nitrobenzenesulfonylchloride (Intermediate 454) (507 mg, 1.99 mmol), DMAP (cat.), pyridine (0.5 ml), and DCM (5 ml) gave the title compound (400 mg, 60%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([O:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:22])[CH3:21])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1>C(O)C1C=CC=CC=1.C1C=CC=CC=1>[OH:4][C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]([CH3:21])[CH3:22])[CH:13]=1)[C:6]([O:8][CH2:9][C:10]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)[C@@H](Cc1ccc(OC)c(N(C)C)c1)OC(C)=O
Solvent: OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc(C[C@@H](O)C(=O)OCc2ccccc2)cc1N(C)C
Yield: 59.3 %

Procedure:
To a solution of ethyl (R)-2-acetoxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(1.56 g) in benzyl alcohol (3.7 ml)and benzene (7.4 ml) was added p-toluenesulfonic acid (0.82 g)and heated under reflux for 6 hours. After cooling, the solvent wasevaporated in vacuo, and the gained crude product was purified bysilica gel column chromatography. The residue was eluted withmixed solvent of hexane, ethyl acetate, and ethanol (60:35:5, v/v).The fractions containing the desired product were combined andevaporated in vacuo to obtain benzyl (R)-2-hydroxy-3-(4-methoxy-3-dimethylaminophenyl)propionate(0.93 g).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13]OC(OC)N(C)C>CN(C)C=O>[CH3:13][N:7]1[C:8]2[C:3](=[C:2]([CH3:1])[N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:12]
Reactant: Cc1nccc2[nH]c(=O)ccc12
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1nccc2c1ccc(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
E-9. 1,5-Dimethyl-1,6-naphthyridin-2(1H)-one--A mixture containing 4.5 g of 5-methyl-1,6-naphthyridin-2(1H)-one, 15 ml of dimethylformamide and 4 ml of dimethylformamide dimethyl acetal was stirred at room temperature overnight, then heated on a steam bath for 7 hours and then evaporated to dryness on a rotary evaporator. The solid residue was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 3.5 g of 1,5-dimethyl-1,6-naphthyridin-2(1H)-one, m.p. 203°-205° C.