Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
Sixty-percent sodium hydride (520 mg, 13 mmols) was washed with petroleum ether, and then suspended in 55 ml of dimethyl sulfoxide. To the suspension were added 2.0 g (10 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 40 minutes. To this reaction solution was added dropwise a solution of 3.1 g (12 mmols) of (S)-(+)-3-chloro-1-(4-methoxyphenethyl)piperidine[[α]D25=+10.1° (c=1.2, ethanol)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 14 hours and at 40° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 2.9 g of (R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 70%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A suspension of 17.75 g of sodium hydride (80% dispersion in oil) in 750 ml of THF is cooled in an ice bath, a solution of 100 g of 3,4-dichlorophenylacetonitrile in 250 ml of THF is added dropwise and the reaction mixture is stirred for two hours at RT. It is cooled to -20° C., a solution of 112.36 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 120 ml of THF is added dropwise and the reaction mixture is stirred for 2 hours at RT. It is concentrated under vacuum, the residue is taken up with water and extracted with ether, the organic phase is washed twice with a buffer solution of pH 4, with a buffer solution of pH 7 and twice with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (100/3; v/v) as the eluent to give 113.5 g of the expected product, which is used as such.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.N(CCO)(CCO)CCO.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>C(Cl)(Cl)Cl>[CH2:39]([O:38][C:36]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:37])[CH3:40]
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: OCCN(CCO)CCO
Product: CCOC(=O)Nc1ccccc1N1CC2(CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 10.36 g of 1-(2-aminophenyl)-1'-methylspiro[indoline-3,4'-piperidine] dihydrochloride of Example 1b in 60 ml of chloroform is treated portionwise with 12.3 ml of triethanolamine. The resulting mixture is cooled in an ice bath and treated dropwise over 40 minutes with a solution of 2.7 ml of ethyl chloroformate in 20 ml of chloroform. After stirring at room temperature for 1 hour, an additional 3.0 ml of ethyl chloroformate is added and the mixture is permitted to stand 16 hours. The product is washed thrice with water, brine, dried over anhydrous sodium sulfate, concentrated and pumped on under high vacuum to give a crude carbamate. Chromatography on silica gel (100 g) using ether-methylene chloride affords an oil. The material crystallizes on prolonged standing to yield 1-[2-(ethoxycarbonyl)aminophenyl]-1'-methylspiro[indoline-3,4'-piperidine], mp 99.5°-101.0° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][S:7][C:6](=[S:9])[N:5]1[C:10](=[O:12])[CH3:11])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:28][C@H:22]([CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27])[CH2:11][C:10]([N:5]1[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][S:7][C:6]1=[S:9])=[O:12]
Reactant: CC(=O)N1C(=S)SC[C@H]1C(C)C
Reactant: C=CCCCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC[C@@H](O)CC(=O)N1C(=S)SC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
A solution of (R)-1-(4-isopropyl-2-thioxothiazolidin-3-yl)ethanone (11.8 g, 58.1 mmol) in dichloromethane (380 mL) under an atmosphere of nitrogen was cooled to −78° C., titanium tetrachloride (6.37 mL, 58.1 mmol) was added, and the mixture was stirred for 10 min. Diisopropylethylamine (10.12 mL, 58.1 mmol) was added, and the mixture was stirred for 1 h at −78° C. A 1 M solution of hex-5-enal (58.1 mL, 58.1 mmol) in dichloromethane was added, and the mixture was stirred for 2 h at −78° C. The reaction was quenched by addition of half-saturated NH4Cl (30 mL) and warmed to room temperature. The mixture was extracted twice with dichloromethane, and the organic phase was dried and evaporated to provide a residue. Chromatography on silica gel afforded the title compound (12.92 g, 74%). This procedure has also been carried out using the (R)-1-(4-benzyl-2-thioxothiazolidin-3-yl)ethanone auxiliary, with a similar result.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][N:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ncc(OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a mixture of 1-chloroisoquinolin-4-ol (2.33 g, 13 mmol) and potassium carbonate (3 g) in anhydrous DMF (50 mL) is added benyl bromide (1.73 mL, 14.5 mmole) dropwise at room temperature. The resulting solution is stirred at room temperature for 48 hours, and then poured into ice water. The precipitate is collected by filtration and washed with water and hexanes, and dried to give the desired product as a white solid (3.25 g, yield: 93%). m.p. 97-98° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].[N:11]([Sn](C)(C)C)=[N+:12]=[N-:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]1[NH:13][N:12]=[N:11][N:5]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1c(F)cccc1I
Solvent: Cc1ccccc1
Product: Fc1cccc(I)c1-c1nnn[nH]1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-6-iodobenzonitrile (17.82 g, 72.15 mmol) and azidotrimethyltin (15.00 g, 72.88 mmol) in 150 mL toluene was heated to 125° C. for 72 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and 0.5 N HCl. The organic extract was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 5-(2-fluoro-6-iodophenyl)-1H-tetrazole that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 291.01 for M+H+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:15]3[C:11]([S:12][C:13]([C:19]([N:21]4[CH2:44][C@H:43]([F:45])[CH2:42][C@H:22]4[C:23]([N:25]4[CH2:32][C:29]5([CH2:31][CH2:30]5)[N:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:27][C@@H:26]4[CH2:40][OH:41])=[O:24])=[O:20])=[C:14]3[CH:16]([CH3:18])[CH3:17])=[N:10][C@:9]2([C:47]2[CH:48]=[N:49][C:50]([Cl:53])=[CH:51][CH:52]=2)[CH3:46])=[CH:4][C:3]=1[F:54].C(O)(=[O:57])C.C(O)(=O)C.IC1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[C:36]([O:35][C:33]([N:28]1[CH2:27][C@H:26]([C:40]([OH:57])=[O:41])[N:25]([C:23](=[O:24])[C@@H:22]2[CH2:42][C@@H:43]([F:45])[CH2:44][N:21]2[C:19]([C:13]2[S:12][C:11]3=[N:10][C@:9]([C:47]4[CH:48]=[N:49][C:50]([Cl:53])=[CH:51][CH:52]=4)([CH3:46])[C@@H:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:54])[CH:4]=4)[N:15]3[C:14]=2[CH:16]([CH3:17])[CH3:18])=[O:20])[CH2:32][C:29]21[CH2:31][CH2:30]2)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(=O)O
Reactant: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)OC(C)(C)C)C[C@@H]2CO)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: Ic1ccccc1
Solvent: CC#N
Product: CC(C)C1=C(C(=O)N2C[C@H](F)C[C@H]2C(=O)N2CC3(CC3)N(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)SC2=N[C@@](C)(c3ccc(Cl)nc3)[C@@H](c3ccc(Cl)c(F)c3)N21
Temperature: 25 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
The compound (100 mg, 0.12 mmol) obtained in Step 2 above was dissolved in a mixed solvent of acetonitrile (1.5 ml) and water (1.5 ml), iodobenzene diacetate (88 mg, 0.26 mmol) and 2,2,6,6-tetramethylpiperidine 1-oxyl (20 mg, 0.12 mmol) were added and the resulting mixture was stirred at room temperature for 4 hours. Aqueous sodium thiosulfate solution (4 ml) was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel chromatography [chloroform:methanol=40:1→10:1 (v/v)] to give the title compound (58 mg, 59%) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[N:7]=1.Cl[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[K]>C1COCC1.CN(C=O)C>[C:22]1([S:19]([CH2:18][C:9]2[C:8]([N+:14]([O-:16])=[O:15])=[N:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[C:11]([O:12][CH3:13])[CH:10]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=S(=O)(CCl)c1ccccc1
Reactant: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Agent: [K]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(CS(=O)(=O)c2ccccc2)c([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
A mixture of 0.6 g (2.6 mmol) 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine, 0.55 g (2.9 mmol) of chloromethylphenylsulfone and 2.9 ml (2.9 mmol) of potassium t-butoxode (1M solution in THF) in 5 ml of DMF were combined at 5° C. and stirred at ambient temperature for 18 hours. The reaction mixture was quenched with 25 ml of water and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4), and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.28 g of 3-benzenesulfonylmethyl-6-[1,3]dioxolan-2-yl-5-methoxy-2-nitro-pyridine as an oil. TLC: Rf=0.4 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 7.7 (m, 3H), 7.55 (m, 2H), 7.42 (s, 1H), 6.30 (s, 1H), 4.90 (s, 2H), 4.30 (m, 2H), 4.10 (m, 2H), 4.02 (s, 3H).). Mass Spectrum: m/e=381.0 (p+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]#[CH:15])[N:12]=2)=[CH:4][CH:3]=1.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[Cl:34])=[N+:25]=[N-:26]>C(#N)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:17][C@H:18]([OH:23])[C:19]([F:21])([F:22])[F:20])[C:10](=[O:16])[N:11]([CH2:13][C:14]3[N:26]=[N:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: C#CCn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: [N-]=[N+]=Nc1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cn(-c3cccc(Cl)c3Cl)nn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
124 mg (0.36 mmol) of the compound from Example 14A were dissolved in 2 ml of acetonitrile, and 0.6 mg (0.003 mmol) of copper(II) acetate monohydrate and 56 mg (0.30 mmol) of 1-azido-2,3-dichlorobenzene were added. The mixture was stirred at 50° C. for 2 h. For work-up, the crude mixture was allowed to cool to RT and filtered through a little silica gel. The product was eluted with ethyl acetate and the solution obtained was concentrated under reduced pressure. The crude product was then purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). This gave 61 mg (31% of theory) of the target compound.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Reactant: CCOC(=O)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CCCc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 108.4 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with ethyl 4-bromobutyrate (0.037 ml, 0.256 mmol) and stirred at 60° C. for 2 hours. Additional quantities of ethyl 4-bromobutyrate (37 ul) were added and the reaction heated at 60° C. for 3 hours. The reaction was left standing overnight. EtOAc (50 ml) was added and the mixture washed with water (2×60 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (90 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccnc(Sc2ccc(CO)cc2)c1
Product: CCc1c(OCc2ccc(Sc3cc(C#N)ccn3)cc2)ccc(C(C)=O)c1O
Yield: 100.2 %

Procedure:
Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.10 g, 4.54 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (818 mg, 4.54 mmol) affords the title compound (1.84 g, quant.). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1[C:25]([OH:27])=[O:26])=[O:14]>CO.O.C(O)C.O>[NH2:3][CH2:12][C:13]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][CH:16]1[C:25]([OH:27])=[O:26])=[O:14]
Reactant: O=C(O)C1CCc2ccccc2N1C(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CO
Solvent: O
Solvent: CCO
Product: NCC(=O)N1c2ccccc2CCC1C(=O)O
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
To a stirred mixture of the compound of Example I (75.2 g, 0.206 mole) and methanol (400 ml) was added 85% N2H4.H2O (12.7 ml, 0.220 mole) dissolved in methanol (30 ml) dropwise over 0.5 hours. After stirring under ambient conditions for 15 minutes, the solution was heated to reflux. Reflux was maintained for 6.0 hours, then allowed to cool overnight at 0°. The crystalline solid was collected, washed with methanol (50 ml) and air dried to give 68.0 g. This solid (68.0 g) was stirred in H2O (175 ml) for 2.0 hours, then filtered. The insoluble solid was washed with H2O (2×5 ml). The filtrate and washing were combined and concentrated under high vacuum to 1/3 its volume. This was diluted with abs. ethanol (150 ml) and concentrated under reduced pressure to a solid residue. This residue was triturated in abs. ethanol (100 ml), collected by filtration and air dried to give 25.2 g. This crude solid was stirred in ethanol/H2O (9:1, 300 ml) for 2.0 hours, filtered and air dried to give 18.6 g (0.079 mole, 38% yield) of title product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:8]=1
Reactant: Fc1ccccn1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1cn(-c2ccccn2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 25.9 %

Procedure:
A suspension of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (60 mg), 2-fluoropyridine (65 mg) and cesium carbonate (364 mg) in NMP (2 mL) was stirred at 100° C. for 3 days, 1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol) to give the title compound (20 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N+:12]([O-])([OH:14])=[O:13]>>[Br:1][C:2]1[C:3]([F:11])=[C:4]2[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1c(Br)cnc2[nH]ccc12
Product: O=[N+]([O-])c1c[nH]c2ncc(Br)c(F)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 47 mmol) was added to fuming nitric acid (50 mL) at 0° C., and the reaction was stirred at 0° C. for 30 minutes. Ice (300 mL) was added, and the reaction was allowed to warm to room temperature. The resulting suspension was filtered and dried under high vacuum to provide 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (9.2 g, 76% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 13.63 (br s, 1H), 8.85 (s, 1H), 8.56 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Li+]>C1COCC1.O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Reaction time: 70 h
Yield: 92.4 %

Procedure:
To a mixture of Methyl 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylate (1.1 g, 3.16 mmol) dissolved in THF (20 mL) was added a mixture of lithium hydroxide (227 mg, 9.5 mmol) in water (15 mL). The reaction was stirred 70 hours. The reaction mixture was concentrated to remove the THF and the aqueous solution was adjusted to pH=1 with 4N HCl (aq). The solid was collected by filtration, rinsed with water, and dried under vacuum to obtain 2-(3-(trifluoromethoxy)phenyl)quinoline-8-carboxylic acid as a tan solid (973 mg, 92% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:13][CH:12]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: O=C(NNc1ccc(F)cn1)c1ccc(CN2CCOCC2)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(-c3ccc(CN4CCOCC4)cc3)n2c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To an ice cold solution of Intermediate 18a (980 mg, 2.97 mmol) in THF (15 mL) was added triphenylphosphine (1.56 g, 5.94 mmol), triethylamine (1.65 mL, 11.9 mmol) and hexachloroethane (1.40 g, 5.94 mmol). The reaction was stirred for 90 min then partitioned between EtOAc (75 mL) and water (75 mL) and the aqueous layer extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo then purified by SCX-2, washing with MeOH and eluting with 2M NH3 in MeOH to give the title compound (640 mg, 2.05 mmol, 69%). LCMS (Method 2): Rt 0.28, 1.32, m/z 313 [MH+].
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](O)=[CH:10]2)=[CH:5][CH:4]=1.[CH3:14][O-:15].[Na+].O.[CH3:18][N:19]([CH3:22])C=O>CO>[N:19]1[C:22]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[CH:11][C:18]=1[CH2:14][O:15][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([NH2:2])=[CH:12]2)=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: C[O-]
Reactant: Nc1ccc2ccc(O)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc2ccc(OCc3ccc4ccccc4n3)cc2c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a suspension of 40.0 g 7-amino-2-naphthol hydrochloride (205 mmol) in 250 mL methanol under nitrogen is added 451 mL of 0.91N sodium methoxide (410 mmol) in methanol. After 1 hour of stirring, the solvent is removed and the residue is taken up in 500 mL dimethylformamide and cooled to 10° C. under nitrogen. A solution of 36.3 g (2-chloromethyl)quinoline (205 mmol) in 200 mL dimethylformamide is added. After stirring overnight at ambient temperature, the reaction is stripped of solvent, water is added and the precipitate is filtered off, dried and recrystallized from toluene to afford 31.1 g (62%) of white crystals, which is further purified by filtration through Florisil. Recrystallization from toluene affords white crystals, m.p. 164.5°-166.0° C.