Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(OC(=O)C[N:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:22][C:21]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=2)=[N:20]1)C>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:20]1[C:21]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=2)=[N:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:19]1)[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)Cn1nc(-c2cc(Cl)cc(Cl)c2)nc1-c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cn1nc(-c2ccncc2)nc1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iso-nicotinic hydrazide (1.0 g, 7.3 mmol), 3,5-dichlorobenzonitrile (1.5 g, 8.8 mmol), and sodium ethoxide (1.5 g, 22 mmol) were transferred to a pressure tube. Ethanol (4 mL) was added and the reaction was stirred at 120° C. overnight. The reaction was monitored by LCMS. Upon completion, the ethanol was removed in vacuo to afford the triazole as a solid and carried on to the next step without purification. This material was dissolved in DMF (10 mL), and potassium carbonate (1.5 g, 11 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was monitored by LCMS. Upon completion, the reaction mixture was diluted with water. The precipitate was collected via vacuum filtration and the filtrate was discarded. The crude product was purified by silica gel chromatography (3:2 hexanes/ethyl acetate) to afford two regioisomers as solids. 1H NMR (400 MHz, d6-DMSO): δ 8.7 (d, 21, 7.95 (s, 2H), 7.9 (d, 1H), 7.8 (d, 2H), 5.5 (s, 2H), 4.1 (q, 2H), 1.1 (t, 3H). MS (EI) for C17H14N4O2Cl2: 377 (MH+). Ethyl[3-(3,5-dichlorophenyl)-5-pyridin-4-yl-1H-1,2,4-triazol-1-yl]acetate: 1H NMR (400 MHz, d6-DMSO): δ 8.8 (d, 2H), 8.0 (s, 2H), 7.8 (m, 3H), 5.5 (s, 2H), 4.1 (q, 2H), 1.2 (t, 3H). MS (EI) for C17H14N4O2Cl2: 377 (MH+).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:18](O)[CH3:19]>>[ClH:1].[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)[CH2:4][C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: CCO
Reactant: NC(CC(=O)O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCOC(=O)CC(N)c1cccc([N+](=O)[O-])c1

Procedure:
60 g of (1a) were suspended in 660 ml of ethanol, and gaseous HCl was passed in for 1 h. The reaction mixture was then heated under reflux for 4 h and then cooled and concentrated. 62 g of a white solid were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15](O)=[O:16])[CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O>>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([Cl:21])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)Cl)ccc21

Procedure:
6.6 g (26.8 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid and 20 ml of thionyl chloride are heated to reflux until gaseous evolution has ceased. The mixture is evaporated to dryness and 7.1 g (100%) of the crude acid chloride are obtained, which product is used for the next step of the synthesis without further treatment.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](=[O:7])[CH3:6].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].[Na].Cl>C(O)C.O>[O:7]=[C:5]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][O:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1
Reactant: CC(=O)C(=CN(C)C)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c(-c2ccccc2)co1
Temperature: 5 °C

Procedure:
A solution of 4-dimethylamino-3-phenyl-3-buten-2-one (30.3 g) and diethyl oxalate (43.5 ml) in ethanol (75 ml) was added to a stirred solution of sodium ethoxide prepared by dissolving sodium (5.5 g) in ethanol (150 ml). The stirred mixture was heated under reflux for 1 hour, cooled to 20°-25° C. and acidified by addition of 5 N hydrochloric acid (150 ml). The mixture was stirred for a further hour, then cooled to 5° C., and diluted with water (300 ml). The solid title product was recrystallised from ethanol-water (mp 110°-112° C.).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH2:14][C:15](=[O:20])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])[CH3:2].CO.Cl>O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@:4]2([C:22]#[CH:23])[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=C(CCC(=O)C4)[C@H]3CC[C@@]21CC
Agent: Cl
Solvent: O
Solvent: CO
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Stir 13β-ethyl-17α-ethynyl-17β-hydroxy-gon-5(10)-en-3-one (0.1 g.) with a mixture of methanol (36 cc.), water (1.6 cc.) and concentrated hydrochloric acid (2.4 cc.) for 1 hour. Add water and extract the mixture with ether. Wash, dry and evaporate the ethereal solution and recrystallize the residue from ether-hexane to obtain the title compound, m.p. 203°-6° undepressed on admixture with authentic material. Infrared spectrum 3.05, 3.5, 6.05, 9.4 μ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:11][C:12]1[C:13]([F:21])=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[C:13]=1[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1cccc(Cl)c1F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 47.2 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 500 mg, 3.4 mmol), 3-chloro-2-fluorophenylboronic acid (Aldrich; 584 mg, 3.35 mmol), copper(II) acetate (621 mg, 3.4 mmol) and triethylamine (480 μL, 3.4 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 20-40% ethyl acetate/hexanes, to give N′-(3-chloro-2-fluoro-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (434 mg, 46%) as a colorless oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:23][CH2:22][N:21]([C@@:24]4([CH3:42])[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C:30]([NH:33]C(=O)OC(C)(C)C)([CH3:32])[CH3:31])[CH2:25]4)[C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[N:13]=2)=[CH:4][N:3]=1.Cl.O1CCOCC1.C1(C)C=CC=CC=1>CO>[NH2:33][C:30]([CH3:31])([CH3:32])[C:29]([N:26]1[CH2:27][CH2:28][C@@:24]([N:21]2[C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[N:13]=[C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)[C:9]=3[CH2:23][CH2:22]2)([CH3:42])[CH2:25]1)=[O:41]
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C1)CC2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)C(C)(C)N)C1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 971.8 %

Procedure:
To a solution of tert-butyl {1-[(3S)-3-{4-(2-aminopyrimidin-5-yl)-2[(3S)-3-methylmorpholin-4-yl]-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-methylpyrrolidin-1-yl]-2-methyl-1-oxopropan-2-yl}carbamate (778 mg, 0.1 mmol) in MeOH (6.5 mL) was added 4 N HCl in dioxane (6.7 mL, 26.8 mmol) dropwise at 0° C. and the reaction was stirred at room temperature for 2 h. Toluene was added and the mixture was concentrated to give a residue that was purified by SFC/ZymorSpher HAP column (150×21.2 mm) eluting with 15-35% CO2 in MeOH over 6 min at 120 bar and with a flow of 100 mL/min to give 468 mg of the title compound as a white solid. The solid was treated with hydroxide resin in MeOH for 15 min or until pH˜8 was reached. The resin was removed by filtration washing with MeOH and 7 N ammonia in MeOH several times. The filtrate was concentrated under reduced pressure, dried under high vacuum and lyophilized to give the title compound (387.8 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 8.73 (s, 2 H), 6.60 (br s, 2 H), 4.63 (d, J=6.6 Hz, 1 H), 4.36-4.16 (m, 2 H), 4.00 (d, J=11.6 Hz, 1 H), 3.94-3.85 (m, 1 H), 3.75-3.37 (m, 7 H), 3.22-3.05 (m, 3 H), 2.44-2.29 (m, 1 H), 2.08-1.95 (m, 1 H), 1.69 (br s, 2 H), 1.32 (s, 3 H), 1.28 (s, 6 H), 1.22 (d, J=6.72 Hz, 3 H). m/z (APCI+) for C24H35N9O2 482.6 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI.C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:12][O:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1c(C)ccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Hydroxy-4-methyl-2-nitropyridine (5 g) was dissolved in dimethylformamide (50 ml), added with cesium carbonate (11.6 g) and methyl iodide (13.7 g), and then the mixture was stirred overnight at room temperature. The reaction mixture was added with ethyl acetate and hexane, washed with water and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain the title compound (quantitative).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K20) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (275 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10](=O)[NH2:11])[CH3:9])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.N[C:27]1[C:28]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:29]([C:32]([F:35])=[CH:33][CH:34]=1)[C:30]#[N:31]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:10]1[N:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:28]2[C:29]([C:30]#[N:31])=[C:32]([F:35])[CH:33]=[CH:34][C:27]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a suspension of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.12 g, 6.0 mmol) in DCM (7 mL) was added triethyloxonium tetrafluoroborate (969 mg, 5.1 mmol) and the reaction mixture stirred at RT for 3 h, during which time the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (7 mL). 3-Amino-6-fluoro-2-phenylaminobenzonitrile (400 mg, 1.8 mmol) was added and the reaction was heated at 75° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white solid (411 mg, 61%). LCMS (Method C): RT=3.55 min, [M+H]+=381.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]#N)=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].CC(C[AlH]CC(C)C)C.[O:30]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:30])=[N:13][CH:14]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Reactant: C1CCOC1
Agent: CC(C)C[AlH]CC(C)C
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-2-pyridinecarbonitrile (0.876 g, 2.93 mmol) in anhydrous tetrahydrofuran (30 mL), was added DIBAL-H (5.87 mL, 5.87 mmol) dropwise at −78° C. The reaction mixture was stirred for 1 h at −78° C., then quenched with 1N HCl solution, concentrated. Purification via ISCO afforded the title product (350 mg) as an off white solid. LC-MS (ESI): m/z 302 [M+H]+; 3.47 min (ret time).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([O:30]C)=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:32]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[CH2:25][O:26][CH3:27])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:28]([OH:30])=[O:29])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:32]=1
Reactant: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2nc1-c1cc2cc(F)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of methyl 2-(5-fluoro-1-benzofuran-2-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylate (135 mg, 0.31 mmol) in methanol (35.0 mL) and water (1.0 mL) was added sodium hydroxide (55 mg, 1.38 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30.0 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(5-fluoro-1-benzofuran-2-yl)-3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]quinoxaline-6-carboxylic acid (100 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23]([OH:25])=O)=[CH:18][CH:17]=[CH:16]2.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:33][C:23]([C:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][C:7]3[C:6]4[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:22][CH:21]=2)[CH:16]=[CH:17][CH:18]=1)=[O:25]
Reactant: Nc1ccccc1N
Reactant: Cc1cccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc12
Product: Cc1cccc2c(Oc3ccc4c(C(=O)Nc5ccccc5N)cccc4c3)ccnc12
Yield: 89.9 %

Procedure:
The title compound (37.7 mg, 90% yield) was prepared as a brown solid from 6-(8-methylquinolin-4-yloxy)-1-naphthoic acid (32.9 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 2.76 (s, 3H, Ar—CH3), 4.97 (s, 2H, benzene-NH2), 6.64 (t, J=7.1 Hz, 1H, Ar—H), 6.78 (d, J=5.0 Hz, 1H, Ar—H), 6.82 (d, J=7.8 Hz, 1H, Ar—H), 6.99 (t, J=7.3 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.55-7.58 (m, 2H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.71 (d, J=7.0 Hz, 1H, Ar—H), 7.87-7.89 (m, 2H, Ar—H), 8.07 (d, J=8.2 Hz, 1H, Ar—H), 8.20 (d, J=7.9 Hz, 1H, Ar—H), 8.44 (d, J=9.2 Hz, 1H, Ar—H), 8.76 (d, J=5.0 Hz, 1H, Ar—H), 9.84 (s, 1H, benzene-NH). LC-MS (m/z) 420 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21].C(OCC)C.O>O1CCOCC1.N1C=CC=CC=1>[Cl:18][CH2:19][C:20]([C:13]1[C:12]2[C:16](=[CH:17][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: O=C(CCl)c1c[nH]c2cc(OCc3ccccc3)ccc12
Yield: 47 %

Procedure:
6-(Benzyloxy)indole dissolved in a mixture of dioxane and pyridine was stirred at 60 C. under nitrogen while chloroacetyl chloride in dioxane was added dropwise during 1 hr. The reaction mixture was then stirred for another 0.5 hr. and poured into diethyl ether-water. The precipitate was collected by filtration and washed thoroughly with cold diethyl ether to yield 47% of 11 as an orange solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].Cl.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N1C=CC=CC=1C1OC2C=C(O)C=CC=2N=1>C(N(CC)CC)C>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:14]=1
Reactant: ClCc1cccnc1
Reactant: Nc1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: Oc1ccc2nc(-c3ccccn3)oc2c1
Solvent: CCN(CC)CC
Product: Oc1ccc2nc(-c3cccnc3)oc2c1

Procedure:
2-Pyridin-3-yl-benzoxazol-6-ol was prepared using 4-aminoresorcinol hydrochloride (1.5 g, 9.3 mM), nicotinyl chloride hydrochloride (1.8 g, 10.2 mM), triethylamine (3.0 g, 30.0 mM) and pyridinium-p-toluenesulfonate (PPTS, 800 mg, 3.2 mM) were refluxed in xylenes (50 mL) for about 24 hours as described for 2-pyridin-2-yl-benzoxazol-6-ol; m.p., 176-178° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([N:38]1[C:43](=[O:44])[C:42]([CH2:45]OS(C)(=O)=O)=[CH:41][C:40]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)=[N:39]1)[CH:35]([CH3:37])[CH3:36].C(N1CCNCC1)C1C=CC=CC=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:45][C:42]2[C:43](=[O:44])[N:38]([CH2:34][CH:35]([CH3:37])[CH3:36])[N:39]=[C:40]([C:51]3[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=3)[CH:41]=2)[CH2:13][CH2:12]1)[C:19]1[CH:18]=[CH:21][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1ccc(-c2cc(CN3CCN(Cc4ccccc4)CC3)c(=O)n(CC(C)C)n2)cc1
Yield: 97.7 %

Procedure:
Following the procedure of Example 1 (10), 2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one and 1-benzylpiperazine were reacted to yield the title compound as a pale yellow oil (yield: 97.7%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:36]([NH2:38])=[O:37])[C:16]2[CH:35]=[CH:34][C:19]([C:20](NNS(C3C=CC(C)=CC=3)(=O)=O)=[O:21])=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CO>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:36]([NH2:38])=[O:37])[C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[CH:34][CH:35]=2)[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)NNC(=O)c2ccc(C(C(N)=O)C(C)c3ccccc3N3CCCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Product: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C=O)cc1

Procedure:
The above compound was prepared by the heating of crude N1 -[4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoyl]-N2 -tosyl-hydrazine with anhydrous sodium carbonate at 160°-170° C. in ethylene glycol [prepared from 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid and tosyl-hydrazine with carbonyl diimidazole in tetrahydrofuran].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])([O-:16])=[O:15]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:19]2[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCCCCc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
4-Phenyl-1-butanol (1 mL, 6.49 mmol) in THF (3 mL) was combined under dry nitrogen with sodium hydride (0.26 g, 6.5 mmol) in a 60% mineral oil dispersion. The mixture was stirred vigorously for 5 minutes, combined with 3,4-dinitrochlorobenzene (1.3 g, 6.42 mmol) and then stirred 10 hours at room temperature. The mixture was partitioned between diethyl ether and 3N hydrochloric acid. The aqeuous layer was separated and extracted several times with diethyl ether. The combined organic layers were dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purfied by flash chromatography (9:1 hexanes/diethyl ether) to provide 4-(4-phenylbutoxy)-1,2-dinitrobenzene (1.16 g, 72% yield); 1H-NMR (300 Mhz, CDCL3): 7.84 (d, 1H, J=10.0 Hz), 7.19-7.36 (m, 5H), 7.00-7.06 (m, 2H), 4.10 (t, 2H, J=5.7 Hz), 2.73 (t, 2H, J=6.5 Hz), 1.89 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1F>>[Cl:16][C:17]1[CH:22]=[C:21]([S:23]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 34 step (i).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:21]([N:3]1[CH2:2][CH2:1][C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)OC(=O)C1=CNCCc2c1[nH]c1ccccc21
Product: CC(C)OC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using iso-propyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Example 3) and benzoyl chloride; 1H-NMR (CDCl3): δ 10.48 (1H, br s), 7.98 (1H, s), 7.47 (2H, m), 7.41 (2H, m), 7.40 (2H, m), 7.30 (1H, m), 7.15 (1H, m), 6.99 (1H, m), 5.04 (1H, m), 4.15 (2H, t), 3.2 (2H, d), 1.10 (6H, d); MS (ES): 375 (MH+).