Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[CH:9]=1)[C:5]#[N:6].Cl>CCO.CO>[NH2:11][CH2:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Br:1])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: N#Cc1cc(Br)cc(CN)c1
Yield: 64.4 %

Procedure:
To a suspension of 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 10.3 mmol) in EtOH (60 mL) was added N2H4H2O (85%, 1.31 g). The mixture was refluxed for 3 h. At room temperature 2 N HCl (20 mL) was added (pH=3), and the mixture was filtered and rinsed with water (20 mL×2). The filtrate was concentrated to about 50 mL and filtered again. After addition of NaHCO3 (pH=9), the filtrate was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a mixture of colorless solid and colorless oil. 2N HCl in MeOH (50 mL) was added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O yielded the product 3-(aminomethyl)-5-bromobenzonitrile (1.40 g, 55%) as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.92 (m, 1 H), 7.84 (m, 1 H), 7.69 (m, 1 H), 4.11 (s, 2 H); 13C NMR (400 MHz, D2O): δ 137.1, 135.9, 135.8, 131.7, 123.0, 117.7, 113.8, 42.0; MS: m/z 209.0 (M+−HCl); HPLC: retention time: 9.313 min; purity: 98.4%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24][OH:25])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=[O:25])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
A mixture of [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-5-yl]methanol (9.50 g), active manganese dioxide (30.00 g) and tetrahydrofuran (300 ml) was stirred at room temperature for 15 hrs. Manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (7.27 g, yield 77%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 103–104° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@@H:13]([CH3:19])[CH2:14][C:15](OC)=[O:16])=[CH:10][CH:11]=2)[N:6]([CH3:20])[C:5]1=[O:21].CC(C[AlH]CC(C)C)C.C1COCC1.CCCCCCC>C1COCC1>[CH3:22][C:2]([CH3:1])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@H:13]([CH2:14][CH2:15][OH:16])[CH3:19])=[CH:10][CH:11]=2)[N:6]([CH3:20])[C:5]1=[O:21]
Reactant: COC(=O)C[C@H](C)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@@H](CCO)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 36-1 (0.46 g, 1.38 mmol) in THF (8 mL) chilled to −78° C. was added DIBAL 1.0M in THF heptane (4.22 mL, 4.22 mmol) dropwise. The resulting mixture was stirred at −78° C. for 3 hr, then quench with slow addition of Rochelle's salt solution (5 mL). The resulting mixture was allowed to warm to room temperature, diluted with water and extracted with ethyl acetate. The organic phase was concentrated and flash column separation using a 50-100% ethyl acetate/hexane gradient gave 36-2. (0.26 g, 64%). LRMS (ES) (M+H)+: observed=292.1, calculated=292.4.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[N+:9]([CH3:12])([O-])=[O:10].[O-]CC.[Na+].[Na]>C(O)C.CCOCC>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]([CH:12]=[N:9][OH:10])=[O:8])[O:4][N:3]=1
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C=O)on1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(C(=O)C=NO)on1
Temperature: 25 °C
Yield: 70.8 %

Procedure:
In 50 ml of ethanol were dissolved 5.5 g of 3-methylisoxazole-5-carbaldehyde and 3.3 g of nitromethane. To the solution was added dropwise a solution of sodium ethoxide in ethanol, which had been prepared from 1.5 g of sodium and 30 ml of ethanol, while stirring at room temperature. After dropping the resultant was stirred for a further 3 hrs. at room temperature and then ether was added thereto to separate the sodium salt. This was dissolved in water, which was followed by acidification with hydrochloric acid. The resulting precipitate was filtered off and recrystallized from chloroform to obtain 5.4 g of (3-methylisoxazole-5-yl)glyoxal-2-oxim having m.p. of 179° C.-180° C. Yield, 70%; Elemental Analysis (C6H6N2O3):
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]2[O:29][C@@H:13]32)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2].[ClH:30].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>>[C:1]([O:4][C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[O:18][CH:19]2[OH:27])[C@H:14]([Cl:30])[C@H:13]3[OH:29])[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 20 mg of 17α-acetoxy-6α,7α-epoxy-1ξ-hydroxy-2-oxa-4pregnene-3,20-dione and 3 ml of 16% hydrochloric acid-ethyl acetate solution was stirred at room temperature for 10 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated to give 21 mg of 17α-acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20dione.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:25][C:26]1([NH:30]C(=O)C(F)(F)F)[CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:28]4[CH2:29][C:26]([NH2:30])([CH3:25])[CH2:27]4)[CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC1(NC(=O)C(F)(F)F)CNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1(N)CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Yield: 51.9 %

Procedure:
A mixture of 0.8 g (2.5 mmoles) of 1-(4-fluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.3 g (6 mmoles) of 3-methyl-3-trifluoroacetamidoazetidine hydrochloride and 1 g of triethylamine is heated under reflux in 20 ml of pyridine for 3 hours. The mixture is evaporated, and extracted with methylene chloride. Filtration and evaporation yield 1.1 g of 1-(4-fluorophenyl)-6-fluoro-7-(3-trifluoroacetamido-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 146°-151° C., which is subsequently hydrolysed in a manner similar to that in example 41, to obtain 0.5 g (56%) of 1-(4-fluorophenyl)-6-fluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 270°-6° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.[Br:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[CH:19]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([C:2]1[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=1)[CH:22]=[CH:21]2
Reactant: OB(O)c1ccc2oc3ccccc3c2c1
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccc2cc(-c3ccc4oc5ccccc5c4c3)ccc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 40.5 %

Procedure:
In argon atmosphere, a mixture of 18.53 g (87.4 mmol) of 2-dibenzofuranboronic acid, 25.00 g (87.4 mmol) of 2,6-dibromonaphthalene, 5.05 g (4.40 mmol) of tetrakis(triphenylphosphine)palladium (0), 300 ml of dimethoxyethane, and 132 g of a 2 M sodium carbonate aqueous solution was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 13.20 g (yield: 38%) of 2-(6-bromonaphthalene-2-yl)dibenzofuran.
Reaction SMILES: O.NN.[CH3:4]/[C:5](/[CH2:19][CH2:20]/[CH:21]=[C:22](\[CH3:34])/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:33])/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:6]\[CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O>CCO>[CH3:4]/[C:5](/[CH2:19][CH2:20]/[CH:21]=[C:22](\[CH3:34])/[CH2:23][CH2:24]/[CH:25]=[C:26](\[CH3:33])/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:6]\[CH2:7][NH2:8]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CN
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Hydrazine monohydrate (0.138 ml, 2.86 mmol) was added to a solution of intermediate 34 (0.80 g, 1.9 mmol) in EtOH (90 mL), and the resulting mixture was stirred at room temperature for 24 h. After filtration of a white solid, the solution was evaporated and the residue was extracted with Et2O (2×20 mL). The organic layers were filtered and evaporated to give intermediate 35 (0.520 g, 95%) as an oil, which was used for the following reaction without any further purification; 1H-NMR (CD3OI), 80 Mhz) δ 1.59 (s, 9H, 3×CH3), 1.65 (s, 6H, 2×CH3), 2.02 (m, 12H, 6×CH2), 3.27 (d, 2H, J=7.2 Hz, CH2), 5.12 (br, 3H, 3×CH), 5.25 (t, 1H, J=7.2 Hz, CH); MS (FAB+) m/e 290 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1.[O-:27][CH2:28][CH3:29].[Na+].O>C(O)C>[CH2:28]([O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[N:3]=1)[CH3:29]
Reactant: CC[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 65 °C

Procedure:
2-Chloro-6-(4-fluorophenyl-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile (Example 7) (200 mg, 0.52 mMol) was added to freshly prepared sodium ethoxide (0.57 mMol) (from addition of sodium metal to ethyl alcohol) in ethyl alcohol (50 ml) and heated to 65° C. for 3.5 hours. The reaction mixture was cooled to room temperature. Water (3 ml) was added and the mixture was concentrated. The product was partitioned between water (50 ml) and ethyl acetate (50 ml). The ethyl acetate portion was dried over sodium sulfate, filtered and concentrated to a solid. The product was purified by a silica gel chromatography to give a white solid: m.p. (DSC): 207.22° C. Anal. Calc'd. for C21H17N2O3SF (396.44): C, 63.62; H, 4.32; N, 7.07. Found: C, 63.56; H, 4.32; N, 6.88.
Reaction SMILES: Br[C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[C:3]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=4)=[CH:13][CH:12]=3)=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc(Oc2ccc(Nc3ccc(C)cn3)cc2)c(-c2ccnc(F)c2)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
N-(4-(3-bromo-5-methoxypyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.076 g, 0.20 mmol), 2-fluoropyridine-4-boronic acid (0.056 g, 0.39 mmol), and tetrakis(triphenylphosphine)palladium (0.023 g, 0.020 mmol) were mixed in dioxane (0.8 mL) under an argon atmosphere. Sodium carbonate (0.30 mL, 0.59 mmol, 2.0 M in water) was added via syringe, and the reaction mixture was stirred at 80° C. for 20 h before being warmed to 90° C. and stirred for 24 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layer was separated, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give N-(4-(2′-fluoro-5-methoxy-3,4′-bipyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine. MS (ESI, pos. ion) m/z: 403.2 (M+1). IC50 (uM) 0.004.
Reaction SMILES: [C:1]12(CS(O)(=O)=O)[C:8]([CH3:10])(C)[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1>C1(C)C=CC=CC=1>[CH:16]1[CH:10]=[CH:8][C:1]2[C:7](=[CH:6][CH:5]=[CH:4][C:2]=2[OH:3])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Oc1cccc2ccccc12
Temperature: 25 °C

Procedure:
The compound of the above formula (30) and 221.1 mg (0.9 mmol) of (±)-10-camphorsulfonic acid were dissolved in 150 ml of toluene and refluxed for 30 minutes. The resulting solution was left to be cooled to room temperature, added to 100 ml of a toluene solution of 4.5 g (27.3 mmol) of p-toluenesulfonic acid heated at 90° C. and refluxed for 4 hours. After the reaction, the reaction solution was washed in water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a naphthol compound represented by the following formula (31) as 3.7 g (8.2 mmol, yield rate of 45%) of a yellow solid.
Reaction SMILES: [O:1]1CCCC(=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:1]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C1CCCOc2ccccc21
Product: CCOC(=O)CCCOc1ccccc1

Procedure:
Scheme 1 shows a general method for preparation of 3,4-dihydrobenzo[b]oxepin-5(2H)-one intermediates 66 by O-alkylation of a phenolic compound with ethyl 4-bromobutanoate to give a ethyl 4-phenoxybutanoate intermediate 67, followed by saponification to the carboxylic acid 68 and intramolecular cyclization under acidic conditions.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[C:33]([O:32][CH2:31][C@@H:29]1[CH2:28][O:27][C:26](=[O:25])[N:30]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.18 g) described in Preparation Example 177 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.53 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(C=O)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1OCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
4-Hydroxy-3-methylbenzaldehyde (365 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a white solid (542 mg, yield: 69%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: Cc1nnc(S)s1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSc2nnc(C)s2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol were reacted to form {4-methoxy-3-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-4-nitro-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to {3-[4-amino-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid provided Compound 19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11]O)[CH:5]=[CH:6][C:7]=1[Cl:8].CS(Cl)(=O)=O.Cl.[C-:19]#[N:20].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][C:19]#[N:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [C-]#N
Reactant: OCCCc1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: N#CCCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 253.1 %

Procedure:
Intermediate 17A (2.0 g, 9.8 mmol) was dissolved in pyridine (20 mL) and treated with methane sulfonyl chloride (0.84 mL, 10 mmol) drop wise while maintaining the temperature below 20° C. The reaction mixture was stirred at rt for 3 h and added to concentrated HCl (10 mL) in crushed ice. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated NaHCO3 twice and brine and the organic portion dried over Na2SO4, filtered and concentrated. The resulting light yellow sulfonate ester was immediately dissolved in DMF (20 mL) and water (4 mL) and cooled to 0° C. Solid potassium cyanide (0.95 g, 15 mmol) was added to the reaction mixture and the mixture was stirred at rt for 72 h. The reaction mixture was then diluted with water and the aqueous phase extracted with ethyl acetate twice. The combined organic layers were washed with H2O twice, brine twice, dried over Na2SO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-80%, column 80 g) to give Intermediate 17B (1.06 g, 24.8 mmol, 51.0%) as a white solid. HPLC/MS (Method L) RT=1.952 min, [M+1]+=214.0.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH2:17][CH2:18][CH:19]=[CH2:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:21]1O[CH2:22]1>C1C=CC=CC=1.CCO>[CH2:17]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:22][CH2:21]1)[CH2:18][CH:19]=[CH2:20]
Reactant: C1CO1
Reactant: C=CCCC(C(=O)OCC)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: C=CCCC1(C(=O)OCC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a stirred suspension of NaH (60% dispersion in mineral oil, 3.02 g, 75.5 mmol) in dry benzene (100 mL), at 22° C. and under nitrogen, was added dropwise ethyl 2-(diethoxyphosphoryl)hex-5-enoate with anhydrous EtOH (0.044 mL, 0.76 mmol) over 30 minutes. Stirred for 30 minutes, this reaction, cooled at 0° C. and attached with a dry ice/acetone condenser, was added via cannula ethylene oxide (12.7 g, 289.3 mmol), then refluxed at 50° C. for 5 hours. Quenched at 22° C. with 1N aqueous NH4Cl (100 mL), the reaction solution was extracted with Et2O (3×200 mL). The combined Et2O layers were washed with aqueous saturated NaHCO3 (100 mL), water (70 mL), brine (70 mL), dried over Na2SO4, filtered and concentrated. The residue was flash chromatographed on 120 g silica gel 60, eluting with 20-100% EtOAc/Hexane, to give the title product (5.07 g, 48%). LRMS (ESI) m/z 169.2 [(M+H)+; calcd for C10H17O2: 169.1].
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:29]([CH3:38])[CH:28]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:29]([CH3:38])[CH:28]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COCCOc1ccc(I)cc1C
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCCOc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 192 mg (0.66 mmol) of 4-iodo-1-(2-methoxy-ethoxy)-2-methyl-benzene in 2 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 39 mg of a white powder. LC-MSD, m/z for C26H23BrN2O4 [M+H]+=507.0, 509.0; HPLC retention time: 2.5 min.