Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8](B(O)O)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].Cl[C:16]1[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=2)[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:16]3[C:25]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[N:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:31]([O:33][CH3:34])=[O:32])[CH:22]=4)[N:17]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CCn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc2cc(-c3nc4ccc(C(=O)OC)cc4nc3N(C)C(C)C)ccc21
Temperature: 90 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 1-ethyl-1H-indazol-5-ylboronic acid (196 mg, 1.03 mmol) in dioxane (6 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 120 mg, 0.41 mmol), K3PO4 (259 mg, 1.23 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (5 drops) with stirring for 4 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 1% to 5% ethyl acetate in petroleum ether to afford methyl 2-(1-ethyl-1H-indazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[CH3:11][C:12]([C:14]([CH3:16])=[CH2:15])=[CH2:13].[Cr](O)(O)(=O)=O.OS(O)(=O)=O>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[C:5]2[C:6]([C:7](=[O:9])[CH:8]=1)=[CH:15][C:14]([CH3:16])=[C:12]([CH3:13])[CH:11]=2
Reactant: C=C(C)C(=C)C
Reactant: COC1=CC(=O)C=CC1=O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COC1=CC(=O)c2cc(C)c(C)cc2C1=O
Temperature: 45 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Methoxy-p-benzoquinone (0.50 g) and 2,3-dimethyl-1,3-butadiene (0.63 ml) were added to 23.0 mL of glacial acetic acid. The mixture was heated at 45° C. for 18.5 hrs. A chromic acid solution consisting of 1.85 g of Na2Cr2O7.2H2O, 1.16 mL water, and 0.09 mL of concentrated H2SO4 was then added, and the temperature was kept at approximately 67° C. for 1 hour. The product was precipitated by the addition of ice water, washed several times with cold water, and then dried over P2O5. A 71% yield (0.557 g) of 2-methoxy-6,7-dimethyl-1,4-naphthoquinone was obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:16])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cccc2c1CCC(=O)N2CCCCl
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3c(C)cccc32)CC1
Yield: 73 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11,3) (0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083 g, 0.50 mmol), and K2CO3 (0.069 g, 0.50 mmol) in MeCN and shaken at 50°. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR (CD3OD) δ 7.15 (t, J=8.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.92 (d, J=7.4 Hz), 4.00 (t, J=7.2 Hz, CH2), 3.10 (d, J=12.1 Hz, 2H), 2.87-2.83 (m, 2H), 2.66-2.62 (m, 2H) 2.59-2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH3), 1.93-1.87 (m, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.31-1.24 (m, 9H), 0.90 (t, J=6.8 Hz, CH3); 13C NMR (CD3OD) δ 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0, 23.9, 22.4, 19.7, 14.4; HPLC-MS (ammonium acetate) [M+H+]=343.36.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH2:12][S:13][CH3:14]>O.CO>[OH:7][CH2:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:11][CH2:12][S:13]([CH3:14])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSCC[C@@H](CCO)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)CC[C@@H](CCO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 108 %

Procedure:
A suspension of sodium periodate (7.0 g) in water (32 ml) was added to a solution of (R)-tert-butyl (1-hydroxy-5-(methylthio)pentan-3-yl)carbamate (8.16 g) obtained in Step 1 in methanol (98 ml) at a temperature 10° C. or lower, and the mixture was stirred at room temperature for 2 hours. The generated insoluble matter was filtered off, and the filtrate was distilled off under reduced pressure. The resulting residue was dissolved in a saturated sodium chloride solution, followed by extraction with chloroform for 3 times. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a light-yellow solid (9.38 g).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[C:12]2[CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH2:16][N:11]2[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([OH:8])[CH:26]=[C:12]3[CH2:13]2)=[O:18])=[CH:20][CH:21]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(OCc3ccccc3)cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Yield: 98.9 %

Procedure:
A solution of 2-(benzyloxy)-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.53 g, 1.51 mmol) in a mixture of AcOEt/DMF (1.8/1.8 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm, Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.39 g, 90% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>O1CCOCC1>[CH3:24][O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid (1.5 g, 4.8 mmol) in MeOH (10 mL) was added 4N HCl in 1,4-dioxane (2 mL), and the reaction was stirred at 80° C. for 1 hour. The mixture was concentrated and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([CH:23](O)[C:24]([F:27])([F:26])[F:25])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([CH2:23][C:24]([F:26])([F:27])[F:25])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:15])=[O:16]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(C(O)C(F)(F)F)c(-c2ccccc2)n1CC(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(CC(F)(F)F)c(-c2ccccc2)n1CC(=O)O
Temperature: 0 °C
Yield: 29.4 %

Procedure:
2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-5-phenyl-4-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrrol-1-yl)acetic acid (0.063 g, 0.114 mmol) was dissolved in 2 mL DCM and cooled to 0° C. 2,2,2-trifluoroacetic acid (1 ml, 0.114 mmol) was then added followed by triethylsilane (0.2 ml, 1.252 mmol). LC/MS shows reduction was instantly complete. The reaction mixture was directly concentrated to yield ˜5 mg of crude material, which was purified by preparative HPLC chromatography to give 18 mg (29.4%) of the desired material.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) and glycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absolute ethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). The resulting solution was stirred overnight at room temperature under nitrogen. An additional portion of absolute ethanol (10 ml) was added and the suspension was filtered and the solid was washed with 3-10 ml portions of absolute ethanol. The combined filtrate and washings were evaporated under reduced pressure at room temperature to give a yellow solid which was triturated in water (30 ml) collected by filtraton, and rinsed with additional water. The solid was recrystallized from isopropyl ether/light petroleum ether, and the resulting solid was purified by column chromatography (10 g of silica gel) with 1:1 isopropyl ether/light petroleum ether as the eluting solvent. The appropriate fraction was recrystallized from isopropyl ether and dried under high vacuum to give the title compound, mp 77.5°-80° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12](Br)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[SH:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.[OH-].[Na+].O>CCO>[C:13]1([C:12]2[S:21][C:22]3=[N:26][CH:25]=[CH:24][N:23]3[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ncc[nH]1
Reactant: CS(=O)(=O)c1ccc(C(=O)C(Br)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)sc3nccn23)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 8 %

Procedure:
A mixture of the bromoketone of step 2 of example 8 (141.2 mg, 4 mmol), 2-mercaptoimidazole (400 mg, 4 mmol) and NaOH (400 μL, 10 N) in EtOH (4 mL) was stirred at r.t. for 6 h. H2O was added and the precipitate that formed was filtered. The solid was washed with water and dried under vaccum. The dried solid residue (234 mg) was heated with P2O5 (900 mg) in PPA (3.5 mL) at 170 ° C. for 20 h. The mixture was quenched with ice and NH4OAc and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated to a solid. The solid residue was chromatographed on silica gel (eluted with 40 % EtOAc/Hexane) to give 113 mg of the title compound. 1H NMR (CD3COCD3): δ3.10 (s, 3H), 7.40-7.20 (m, 7H), 7.65 (d, 2H), 8.00 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1>O1CCCC1>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([N:22]5[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Solvent: C1CCOC1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)CC1
Reaction time: 72 h
Yield: 18 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperazin-4-yl)piperidin-1-yl]carbonylamino}pyridine (86.9 mg) in tetrahydrofuran (2.5 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 2.12 ml) at room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:methanol=97:3) to provide the titled compound (22.5 mg, 18%) as white powder.
Reaction SMILES: CN[C@H](C(N[C@H:13]([C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=O)CC1N=CNC=1.C([N:30](CC)CC)C.C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[NH2:30][CH:14]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:13][C@@H:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: CCN(CC)CC
Reactant: CN[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCC(C)C
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)CC[C@H](O)CC(N)C1CCCCC1
Reaction time: 1 h
Yield: 270.1 %

Procedure:
To a solution of 2(S)-(Nα -methyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (900 mg) and triethylamine (494 mg) in methylene chloride (20 ml) was added trityl chloride (696 mg) at 0° C. The mixture was stirred at the same temperature for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. Evaporation of the solvent gave 2(S)-(Nα -methyl-Nim -trityl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (1.46 g) as an amorphous powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C[O-].[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([O:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH:9]=3)[NH:13][CH:12]=2)=[CH:20][CH2:19]1
Reactant: CN1CCC(=O)CC1
Reactant: c1ccc(Oc2ccc3[nH]ccc3c2)nc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Oc4ccccn4)cc23)CC1

Procedure:
5-(Pyrid-2-yloxy)indole (0.22 g, 1.04 mmol), 1-methylpiperid-4-one (0.235 g, 2.08 mmol) and sodium methoxide (0.337 g) were heated at reflux in MeOH (20 mL) for 48 hr, over activated molecular sieves. After cooling and work-up, the residue was chromatographed (silica gel; CH2Cl2 /MeOH; 0-25%) to give 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, a gum, 0.083 g (26%). This free base was treated with oxalic acid in MeOH/Et2O to give: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole oxalate, m.p. 240°-45° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22](O)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([CH:17]2[CH2:18][NH:19][CH2:20][CH2:21][N:16]2[CH2:15][C:2]2([CH3:1])[CH2:6][C:5]3[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=3[O:3]2)=[O:31])=[CH:24][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: COc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)C2CNCCN2CC2(C)Cc3c(C)c(N)c(C)c(C)c3O2)cc1
Yield: 67 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and p-anisic acid, the procedure of Example 10, presented hereinafter, was otherwise followed to provide the title compound. Yield 67%.
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([N:15]=[C:16]=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCOCC>[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([NH:15][C:16]([CH:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2
Reactant: C1CCNCC1
Reactant: S=C=NC1CCCc2sccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: S=C(NC1CCCc2sccc21)C1CCNCC1
Reaction time: 2.5 h

Procedure:
In 50 ml. of tetrahydrofuran, 5.85 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isothiocyanate is stirred and 2.81 grams of piperidine is added. An exotherm is observed and the temperature rises to about 40° C. to 50° C. After 2.5 hours, the mixture is heated at reflux temperature for 3.5 hours. After stirring overnight, the mixture is evaporated to dryness to afford a sticky yellow-brown solid. Ether is added to this material and the off-white, insoluble product is collected. The crude product, 5.25 grams, melts at 102° C. to 104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:22])[S:12][C:13]=2[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>>[CH3:37][O:36][C:32]1[CH:31]=[C:27]([CH:26]=[C:25]([O:24][CH3:23])[C:33]=1[O:34][CH3:35])[C:28]([NH:22][C:11]1[S:12][C:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:29]
Reactant: COc1ccc(-c2nc(N)sc2CCc2ccccc2)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2CCc2ccccc2)cc1
Yield: 67.2 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-phenylethyl-thiazol-2-ylamine prepared in Example 57 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product as a foam, which was recrystallized with petroleum ether and ethyl acetate at a ratio of 2:1 (V:V) to obtain a product as a white solid in a yield of 67.2%, mp: 78-79 └. 1H-NMR (CDCl3, 400 MHz) δ: 3.03 (2H, t, J=7.60 Hz, CH2), 3.19 (2H, t, J=7.60 Hz, CH2), 3.80 (6H, s, 2×OCH3), 3.81 (3H, s, OCH3), 3.91 (3H, s, OCH3), 6.78 (2H, d, J=8.40 Hz, ArH), 7.02 (2H, s, ArH), 7.15˜7.32 (7H, m, ArH), 11.54 (1H, br, CONH); EI-MS m/e (%): 504.2 (M+, 24), 413.2 (53), 195.1 (100); HREI-MS Calcd. for C28H28N2O5S: 504.1719. found: 504.1716.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:12]2[N:11]=[C:10]([SH:13])[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17].Cl.Cl[CH2:21][C:22]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>O.C(O)C>[F:18][CH:2]([F:1])[O:3][C:4]1[C:12]2[N:11]=[C:10]([S:13][CH2:21][C:22]3[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][N:23]=3)[NH:9][C:8]=2[CH:7]=[C:6]([O:14][CH3:15])[C:5]=1[O:16][CH3:17]
Reactant: COc1ccnc(CCl)c1C
Reactant: COc1cc2[nH]c(S)nc2c(OC(F)F)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccnc(CSc2nc3c(OC(F)F)c(OC)c(OC)cc3[nH]2)c1C
Yield: 87.7 %

Procedure:
1.0 g of 4-difluoromethoxy-5,6-dimethoxy-1H-benzimidazole-2-thiol, 0.75 g of 2-chloromethyl-4-methoxy-3-methylpyridine hydrochloride, 0.3 g of sodium hydroxide, 2 ml of water and 10 ml of ethanol are stirred for 2.5 h at 60° C. The mixture is poured onto 100 ml of water and cooled in an ice bath. This gives 1.3 g (87%) of the title compound (m.p. 177°-179° C., from diisopropyl ether).
Reaction SMILES: [CH2:1]([NH:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[CH2:1]([N:8]=[CH:9][O:10][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CNCc1ccccc1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC=NCc1ccccc1

Procedure:
A solution of 690 mg (5.1 mmoles) of N-benzylformamide in 5 ml of methylene chloride is cooled in an ice-water bath and put under an argon blanket. The solution is stirred while 4.9 ml (4.9 mmoles) of 1 M triethyloxonium fluoroborate in methylene chloride is added dropwise. After a 45 minute reaction time, the mixture is concentrated to dryness under reduced pressure at room temperature, and the residue is dried under reduced pressure over P2O5. The nuclear magnetic resonance spectrum of the product in deuterochloroform is fully in accord with the product being a fluoroborate etherate complex of ethyl N-benzylformimidate.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])=[O:19])=[CH:16][CH:15]=2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1ccccc1O
Product: O=C(Nc1ccccc1O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 2-aminophenol (27 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(2-hydroxyphenyl)benzamide as an off-white solid. Yield: 23 mg (23%). 1H-NMR: 9.72 (br s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.24-7.02 (m, 4H), 6.91 (dd, J=8.0, 1.0 Hz, 1H), 6.81 (dt, J=8.0, 8.0, 1.0 Hz, 1H), 3.85-3.79 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].C([N:34](CC)CC)C.N>CN1C(=O)CCC1.CCOC(C)=O>[NH2:34][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCN(CC)CC
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(F)ccc1-c1nc(N)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 43 %

Procedure:
To a solution of the product of Example 48 (1.0 g, 2.2 mmol) and triethylamine (1 mL) in 2 mL of NMP was bubbled NH3 gas at 23° for 30 min. The mixture was diluted with EtOAc and washed with H2O to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the title compound, (360 mg, 43%). LC-MS: 383.0 (MH+, m/z), 1.95 (Rt, min).