Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][OH:6])=[NH:4].[CH3:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=O.C(N(CC)CC)C>CN(C)C=O>[Cl:1][CH2:2][C:3]1[N:4]=[C:7]([C:8]([CH3:13])([CH3:12])[CH3:9])[O:6][N:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: N=C(CCl)NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(CCl)no1
Temperature: 130 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
5.0 g of 2-chloro-N-hydroxyacetoamidine and 6.11 g of trimethylacetyl chloride were dissolved in 100 ml of N,N-dimethylformamide, and 5.6 g of triethylamine was then added dropwise under ice-cooling. After completion of the addition, the reaction mixture was stirred at 130° C. for 6 hours and then cooled to room temperature. After aqueous saturated sodium chloride, the reaction mixture was extracted with methyl-t-butyl ether. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.0 g of 3-(chloromethyl)-5-t-butyl-1,2,4-oxadiazole.
Reaction SMILES: CO.[C:3](O)(=O)[CH3:4].[N+:7]([C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])([O-])=O.[C:28](=[O:31])([O-])O.[Na+]>[Fe].C(OCC)(=O)C>[C:28]([NH:7][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:31])[C:4]1[CH:3]=[CH:12][CH:11]=[CH:10][CH:19]=1
Reactant: O=C([O-])O
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(COc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.31 g of iron powder was added to a mixed solution of 5.3 mL of methanol and 1.6 mL of acetic acid containing 0.53 g of methyl 2-nitro-4-(phenoxymethyl)benzoate, and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 5.3 mL of methylene chloride and 0.51 mL of triethylamine and 0.26 mL of benzoyl chloride were added while ice-cooled sequentially and stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and washed with saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.31 g of methyl 2-(benzamido)-4-(phenoxymethyl)benzoate as white solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH2:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:2][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:8]([NH2:10])=[O:9])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C[C@@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
To a solution of (D)-leucinamide hydrochloride (0.25 g, 1.5 mmol), and Et3N (0.43 mL, 3.0 mmol) in CH2Cl2 (150 mL) was added 4-chlorobenzene-sulfonyl chloride (380 mg, 1.8 mmol). The resulting solution was stirred at rt for 18 h. The reaction was then diluted with CH2Cl2 (200 mL) and washed with H2O, 0.5 N HCl, brine, and dried over MgSO4, to afford the titled compound (410 mg) as a white solid in 90% yield. MS (ESI), (M+H)+305.2; 1H NMR (DMSO-d6) δ7.77 (d, 2H, J=8.7), 7.62 (d, 2H, J=8.7), 6.90 (br s, 1H), 3.67 (m, 1H), 1.54 (m, 1H), 1.31 (m, 2H), 0.81 (d, 3H, J=7.0), 0.71 (d, 3H, J=7.0).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C@H:17]2[CH2:19][C@H:18]2[CH2:20][CH2:21][O:22][C:23]2[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31](O)=[O:32])=[C:25]([F:34])[CH:24]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][NH:36][CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:35][N:36]([CH3:37])[C:31](=[O:32])[CH2:30][C:26]1[C:25]([F:34])=[CH:24][C:23]([O:22][CH2:21][CH2:20][C@@H:18]2[CH2:19][C@@H:17]2[CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)=[C:28]([F:29])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[2-((1S,2R)-2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}cyclopropyl)ethoxy]-2,5-difluorophenyl}acetic acid (313 mg, 0.661 mmol) in 2.5 ml anhydrous DMF at RT was added dimethylamine (2.0 M solution in THF, 0.661 ml, 1.32 mmol) and N, N-diisopropylethylamine (0.562 ml, 3.31 mmol). 0-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (503 mg, 1.32 mmol) was then added to the solution and the mixture stirred at RT overnight. The reaction was quenched by addition of water (12 ml) and the mixture extracted with ethyl acetate (12 ml). The layers were separated and the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage column, 25 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (800 ml) to afford the title compound. LC/MS (m/z): 501.4 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:18]=2)=[CH:9][CH:8]=1.[N+:25]([O-])([OH:27])=[O:26]>>[F:6][C:7]1[C:8]([N+:25]([O-:27])=[O:26])=[CH:9][C:10]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:18]=2)=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)cc2)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To 2.5 ml of concentrated sulfuric acid was added 0.34 g of 3-(4-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-4) at 5° C. Furthermore, 0.13 ml of 61% nitric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was added to ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.337 g (yield, 85%) of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13; m.p., 134.4° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cn1cc(N)cn1
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)c2c(Cl)cc(Br)cc2Cl)cn1
Yield: 83.8 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (500 mg, 1.54 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (496 mg, 1.29 mmol, 84%). δH (D-6 DMSO, 300K) 7.64 (2H, s), 7.45 (1H, s), 7.18 (1H, s), 7.01 (1H, s), 3.85 (3H, s). m/z (ES+, 70V) 385.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-:13].[Na+].Cl.[NH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)=O>O.C(O)C.O1CCCC1>[NH2:16][C:17]1[C:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(I)cc1
Reactant: [OH-]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccc(I)cc2)nc2ccc(Cl)cc2c1C(=O)O
Temperature: 85 °C
Yield: 66.7 %

Procedure:
To a stirred suspension of 4.17 g of 5-chloroisatin in 40 ml of water was added a solution of 5.15 g of sodium hydroxide in 18 ml of water. The solution was heated to 85° C. and a solution of 9.8 g of 2-amino-1-(4-iodophenyl)ethanone hydrochloride in a mixture of 70 ml of ethanol and 30 ml of tetrahydrofuran and 130 ml of water was added dropwise over 2 hours. After the addition was complete, the solution was refluxed for an additional 30 minutes and then the ethanol and tetrahydrofuran were removed by distillation. The mixture was cooled to 20° C. and filtered through celite. The filtrate was acidified to pH 4 with acetic acid. The solid was filtered off, washed with water and dried, giving 6.5 g of the desired compound as a yellow solid, mp 243°-245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12]OS(C)(=O)=O)=[CH:5][CH:4]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][N:18]=[N+:19]=[N-:20])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(COS(C)(=O)=O)CC2
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C(CN=[N+]=[N-])CC2
Reaction time: 1 h

Procedure:
12.8 g (50 mmol) of methanesulphonic acid (6-methoxyindan-1-ylmethyl) ester and 5.2 g (80 mmol) of sodium azide are dissolved in 130 ml of dimethyl sulphoxide and stirred at 80° for 1 hour. The reaction mixture is poured onto ice-water and extracted by shaking with diethyl ether. The organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation under reduced pressure. 9.7 g of crude, oily 6-methoxyindan-1-ylmethylazide are obtained as residue.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[CH:5][N:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:6][CH:5]=2)[CH2:10][CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:2]1=[O:1])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NC1Cc2cc(-c3ccccc3)ncc2NC1=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1Cc2cc(-c3ccccc3)ncc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
To a solution of 3F (400 mg, 1.07 mmol) in DMF (8 mL) was added cesium carbonate (873 mg, 2.68 mmol), followed by benzyl bromide (0.38 mL, 3.21 mmol). The reaction mixture was stirred at 50° C. for 1 h. After cooling to RT, water (100 mL) was added. The reaction mixture was extracted with EtOAc (3×30 mL). During the extraction, some precipitates formed. The solid was collected by filtration and washed with EtOAc to give the title compound (250 mg). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resultant residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give additional 160 mg of the title compound (total 410 mg, 83%) as a white solid. LC/MS (method A): retention time=3.55 min, (M+H)+=464.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH2:20][NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=[N:18][CH:19]=1.[CH3:27]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH2:20][N:21]([CH3:27])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=[N:18][CH:19]=1
Reactant: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)Cc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of ethanesulfonic acid [5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 16, 0.15 g, 0.39 mmol) in DMF (5 mL) was added potassium tert-butoxide (67.2 mg, 0.60 mmol) at 0° C. The resulting mixture was stirred for 30 minutes at 0° C. before methyl iodide (84.6 mg, 0.6 mmol) was added dropwise. After stirring for 2 hours, the mixture was treated with water, and extracted with EtOAc. The combined organic layers were then washed with water and brine in sequence, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 5% methanol in dichloromethane) to afford the title compound (93 mg, 60%) as a white solid. MS: 392.1 (M+H+)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[OH:45][C:44]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[O:10][C:41](=[O:42])[C:40]=1[S:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1cccc(O)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(O)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3'-hydroxyacetophenone (2.06 g, 15.1 mmol), trimethylsilyl triflate (7.0 mL, 36.2 mmol), triethylamine (8.52 mL, 61.1 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (3.11 g, 10.0 mmol) m.p. 201°-204° C.; 1H NMR (250 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.41 (m, 1H), 6.82 (s, 1H), 6.93 (m, 2H), 7.09 (m, 2H), 7.30 (m, 4H), 9.91 (br, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[C:45]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH3:45])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: CO
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OC(C)(C)C)c3cc4c(cc32)COC4)n1
Reaction time: 12 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.17 mmol) in dichloromethane (20 mL), add methanol (5.85 mmol) and triphenylphosphine (3.51 mmol). To this solution, add diethyl azodicarboxylate (3.51 mmol) dropwise at room temperature. After stirring for 12 h, remove the solvent under vacuum and chromatograph the intermediate over silica gel eluting with ethyl acetate/hexane (2-35%) to afford (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester as a colorless oil. To this intermediate in dichloromethane (5 mL), add TFA (2 mL). After stirring for 2 h, quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (10 mL). Separate the organic portion, dry over sodium sulfate, filter, and remove the solvent under vacuum. This provides the title compound as a crude oil that is further used without purification.
Reaction SMILES: CC([N:4](C)C)=O.[CH3:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH3:14])[N:9]1[CH2:15][CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1)=[O:19].Cl[C:27]1[N:31](C(OC(C)(C)C)=O)[C:30]2[CH:39]=[C:40]([F:44])[C:41]([F:43])=[CH:42][C:29]=2[N:28]=1>C1(C)C(C)=CC=CC=1>[NH3:4].[CH3:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([CH3:7])[N:9]1[CH2:15][CH2:16][NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:27]1[NH:28][C:29]2[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:30]=2[N:31]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)n1c(Cl)nc2cc(F)c(F)cc21
Reactant: CC(=O)N(C)C
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2cc(F)c(F)cc2[nH]1
Product: N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Dimethylacetamide (1 ml) was added to a mixture of (2S)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-2-piperidinecarboxamide (267 mg) [see Preparation 15] and tert-butyl 2-chloro-5,6-difluoro-1H-1,3-benzimidazole-1-carboxylate (350 mg) [see Preparation 43]. The reaction mixture was heated to 60° C. for 4 hours, after which time the mixture was reduced to low volume, xylene (50 ml) was added, and all solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and treated with trifluoroacetic acid (5 ml). After 2 hours stirring at room temperature, the mixture was reduced to low volume. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated to dryness. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0, changing 95:4.5:0.5 dichlomethane:methanol:0.880 aqueous ammonia solution to afford (2S)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-1-[5,6-difluoro-1H-1,3-benzimidazol-2-yl]-2-piperidinecarboxamide (50 mg) as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([S:7][C:8]1[N:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1)[CH3:6])C.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:14][C:12]1[CH:11]=[C:10]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:9]=[C:8]([S:7][CH:5]([CH3:6])[C:4]([OH:3])=[O:16])[N:13]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Sc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(Sc1nc(Cl)cc(NCc2ccc(Cl)cc2)n1)C(=O)O

Procedure:
A stirred mixture of 5.6 g of 2-(4,6-dichloro-2-pyrimidinylthio) propionic acid ethyl ester, 2.9 g of p-chlorobenzylamine and 2.1 g of anhydrous sodium carbonate in 50 ml. of ethanol were heated under reflux for 6 hr. The reaction mixture was filtered and taken to dryness on a rotary evaporator. The residue was dissolved in ether and filtered free of insoluble material. The ether was removed on a rotary evaporator and the residue was treated with approximately 10 ml. of 30% sodium hydroxide solution to which was added enough ethanol until a clear solution was obtained. The reaction mixture was heated on a steam bath for a few minutes then acidified with concentrated hydrochloric acid solution. The precipitate which was formed was recrystallized from 95% ethanol affording 5.0 g of product, mp. 133°-136°C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:24]([C:36]([F:39])([F:38])[F:37])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:40])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[C:24]([C:36]([F:37])([F:38])[F:39])[CH:23]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2.[CH3:22][NH2:23]>C(#N)C>[ClH:1].[Cl:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:23][CH3:22])=[CH:13][CH:12]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CN
Reactant: ClCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Solvent: CC#N
Product: CNCCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Product: Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from product from step 1 (0.6 g, 1.9 mmol) and methyl amine (40% in water, 16.2 mL, 0.47 mol) in acetonitrile (6 mL) was heated to 60° C. for 7 h, and then room temperature for 16 h. The mixture was extracted with ethyl acetate. The combined organic portions were acidified with 10% HCl to pH to 1, and stirred at 0° C. for 1 h. The product was collected on a filter, washed with 1N HCl, water and hexane. After drying under vacuum, the title compound (0.5 g, 79%)as a hydrochloride salt. 1H NMR (400 MHz, CD3OD) δ 7.66-7.60 (m, d, J=9.2 Hz, 4H), 7.43-7.39 (m, 1H), 7.23-7.18 (m, d, J=9.2 Hz, 3H), 4.24 (t, J=6 Hz, 2H), 3.27 (t, J=6 Hz, 2H), 2.77 (s, 3H), 2.24 (m, 2H); MS (APCI) m/z 316 (M+1, 100); LC/MS (APCI) m/z: 99%.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([OH:18])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+](=[CH2:27])=[N-]>ClCCl.CO.CCOCC>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:27])=[C:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(C(=O)OCC)c(O)c2cc(C)ccc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2cc(C)ccc21

Procedure:
Then a solution of the 1-hexyl-3-ethoxycarbonyl-4-hydroxy-6-methyl-2(1H)-quinolinone (12.4 g) in dichloromethane (50 ml ) and methanol (10 ml) was treated with excess diazomethane in ether for 10 mins. This solution was then evaporated. The crude methylation product upon chromatography on silica gel yielded 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (11.5 g). The 1-hexyl-3-ethoxycarbonyl-4-methoxy-6-methyl-2(1H)-quinolinone (7.13 g) in dry toluene (80 ml) was cooled to -78° C. and then a 1M solution of di-isobutyl aluminum hydride (30 ml) was added dropwise in 10 min. After 2.5 hours of stirring at -78° C. the reaction mixture was worked up by stirring with aqueous ammonium chloride/1N hydrochloric acid which was then followed by extraction with methylene chloride. The crude reduction product was chromatographed on silica gel and then crystallized from ethyl acetate/hexane to give 1-hexyl-3-formyl-4-methoxy-6-methyl-2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS(CI): m/e 302 (M+.1); NMR (CDCl3): δ2.42 (s, 3H, Ar--CH3), 4.10 (s, 3H, OCH3), 10.50 (s, 1H, CHO).