Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:10]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24](O)=[O:25])=[CH:18]2)=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.C1COCC1>[C:10]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:11]=[CH:12][C:13]([CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]([NH:1][CH2:2][CH2:3][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[O:25])=[CH:18]2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(NCCN1CCCCC1)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
To a solution of 1-(2-aminoethyl)piperidine (260 mg) in acetonitrile (5 ml)/THF (10 ml) were added 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid (500 mg), WSC (380 mg), HOBt (260 mg), and triethylamine (0.7 ml) at room temperature. After stirring at room temperature for 12 hr, the reaction mixture was diluted with 5% aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was purified by alumina column chromatography (eluent; THF) and recrystallized from ethyl acetate/diisopropyl ether to obtain the titled compound (410 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH2:5][CH2:6][O:7][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32]
Reactant: COC(=O)C(CCO)Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CCOS(=O)(=O)c1ccc(C)cc1)Oc1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 48 h
Yield: 46 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-4-hydroxy-butyric acid methyl ester (Example 473b), 0.225 g) in dichloromethane (1.88 mL) at room temperature, was added triethylamine (116 mg) and 4-methylbenzene-1-sulfonyl chloride (177 mg). The mixture was stirred at 22° C. for 48 hr. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated. The aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and filtered. The crude mixture was concentrated to dryness and purified by chromatography on silica gel to yield the title compound as a colorless oil (169 mg; 46%). MS (ESI): m/z=419 [M+NH4]+.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([Cl:26])=[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[Cl:25])[CH:18]=1)=[O:12])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:9][CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([Cl:26])=[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[Cl:25])[CH:18]=1)=[O:12]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)sc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)C(CN)Cc2ccccc2)sc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl[3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate (740 mg, 1.453 mmol) in dichloromethane (7.263 ml) at 25° C. was added TFA (1.119 ml, 14.53 mmol) in one portion. After 30 min, the solution was dry loaded onto silica and neutralized through silica (0-20% MeOH in DCM (1% NH4OH) affording the free base of the title compound. The free base was then dissolved in MeOH (10 mL) and treated with excess 4M HCl in dioxane (2 mL) providing the HCl salt of 3-amino-N-[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]-2-(phenylmethyl)propanamide (426 mg, 0.908 mmol, 62.5% yield) as an orange solid: LCMS (ES) m/e 409, 411 (M, M+2)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (s, 1 H) 8.06 (br. s., 3 H) 7.68 (s, 1 H) 7.26-7.40 (m, 4 H) 7.24 (d, J=6.82 Hz, 1 H) 6.70 (s, 1 H) 3.94-3.96 (m, 1 H) 3.70 (s, 3 H) 3.14-3.17 (m, 1 H) 3.05 (dd, J=13.52, 6.44 Hz, 2 H) 2.85 (dd, J=14.02, 7.45 Hz, 2 H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCC(O)CC1
Reactant: BrCCCCCBr
Product: OC1CCC(N2CCCCC2)CC1

Procedure:
Prepared from 4-amino-cyclohexanol and 1,5-dibromopentane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccccc3)ccc21
Yield: 92.2 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (57.5 mg, 0.140 mmol) was dissolved in acetonitrile (3 mL), and the solution was treated with aniline (0.051 mL, 0.56 mmol), acetic acid (0.160 mL, 2.80 mmol) and sodium triacetoxyborohydride (89 mg, 0.42 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-(phenylaminomethyl)indol-2-yl)isoindolinone (63.0 mg, yield 92%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][C:13]3[C:20]4([CH3:23])[CH2:21][CH2:22][CH:17]([C:18]([CH3:25])([CH3:24])[O:19]4)[C:14]=3[N+:15]=2[O-])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)Cl.[OH-].[Na+]>ClCCCl>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[N:12][C:13]3[C:20]4([CH3:23])[CH2:21][CH2:22][CH:17]([C:18]([CH3:25])([CH3:24])[O:19]4)[C:14]=3[N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC12CCC(c3c1nnc(-c1cccc([N+](=O)[O-])c1)[n+]3[O-])C(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClP(Cl)Cl
Product: CC12CCC(c3nc(-c4cccc([N+](=O)[O-])c4)nnc31)C(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a flask equipped with stirrer, reflux condenser and gas inlet there is added under nitrogen a mixture of 6.9 g. (0.020 mole) of (+)-3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine-4-oxide, 20 ml. (0.23 mole) of phosphorous trichloride in 300 ml. of 1,2-dichloroethane. The resulting mixture is refluxed for 6.5 hours and then cooled to room temperature, and poured into a beaker containing 500 g. of ice. To this mixture there is added cautiously 60 ml. of 50% aqueous sodium hydroxide while maintaining stirring for 1 hour. The resulting mixture is then transferred to a separatory funnel and permitted to separate. The layers are partitioned and the aqueous phase extracted twice with 300 ml. of methylene chloride and the extracts combined with the organic phase. The resulting solution is washed once with brine, dried over anhydrous magnesium sulfate, and then concentrated to yield a residue which is then recrystallized from absolute ethanol to give (-)-3-(m-nitrophenyl)-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano[4,3-e]-as-triazine; m.p. 184° to 185° C.; ORD-1.8°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CCOC(=O)C1Cc2ccccc2C1
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium his(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) drop wise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 minutes. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl (50 mL) and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1.[CH3:13][C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.O>[CH3:13][C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[S:17][C:18]=1[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:12])[C:4]=2[N:3]=1
Reactant: Cc1csc(-c2cccnc2)n1
Reactant: O=C1CCCc2ccc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(-c2cccnc2)sc1-c1ccc2c(n1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.1 %

Procedure:
A mixture of 2-chloro-6,7-dihydro-8(5H)-quinolinone (0.100 g, 0.551 mmol, prepared as described in J. Org. Chem., 55, 4789-91, 1990) and 4-methyl-2-(3-pyridyl)thiazole (0.116 g, 0.661 mmol, WO 2010006713), potassium acetate (0.0648 g, 0.661 mmol) in DMA (2.8 mL) was stirred at ambient temperature under argon. To this solution was added [1,2-Bis(dppe)]Cl2Pd(II) (0.0159 g, 0.0275 mmol) and the solution irradiated in a microwave reactor at a temperature of 170° C. for 20 min. LCMS analysis showed the product and starting materials. Further irradiation at 190° C. led to no change and thus a further 0.0648 g of potassium acetate, and 0.0159 g mol of [1,2-Bis(dppe)]Cl2Pd(II) were added and irradiation continued at 180° C. for 20 min. LC-MS showed reaction completion. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was then washed with successively saturated aqueous NaHCO3 and brine, the organic phase dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with 0 to 100% ethyl acetate and then 10% MeOH in CH2Cl2 gave the title product (55 mg, 31%) as a beige solid.
Reaction SMILES: [O:1]=[C:2]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][N:5]=1)[CH3:3].[BH4-].[Na+]>CO>[OH:1][CH:2]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][N:5]=1)[CH3:3]
Reactant: CC(=O)c1nnc(-c2ccccn2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1nnc(-c2ccccn2)s1
Reaction time: 2 h

Procedure:
To a mixture of 2-[5-(1-oxo-ethyl)-1,3,4-thiadiazol-2-yl]-pyridine (1.5 gm), in methanol (25 ml) was added sodium borohydride (0.2 gm) in lots at 30° C. It was stirred over a period of 2 h. The reaction was monitored by TLC. Solvent was evaporated under vacuum and water (20 ml) was added. The mixture was extracted with ethyl acetate (100 ml×2). Combined organic layers was washed with water and concentrated under vacuum to provide title compound in 1.0 gm quantity (67%). It as used as without purification for the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][CH2:27][C:28]1[O:29][CH:30]=[CH:31][CH:32]=1>>[O:29]1[CH:30]=[CH:31][CH:32]=[C:28]1[CH2:27][O:26][CH2:25][CH:23]([OH:22])[CH2:24][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1coc(COCC2CO2)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COCc3ccco3)CC1)O2

Procedure:
Compound 165 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(oxiran-2-ylmethoxy)methyl]furan and conditions outlined in procedure X. M.p.=143-145° C.; LCMS: 456 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:31])[CH:37]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(C(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropylphenyl)indole-3-carboxylic acid ethyl ester (150 mg, 0.37 mmol, see step (b) Example 10) and 3-chlorophenylboronic acid (116 mg, 0.74 mmol). Yield 130 mg (68%).
Reaction SMILES: [Na].N.BrC(Br)C[CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1([C:22]1[CH:27]=CC=[CH:24][CH:23]=1)[CH:14]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.O1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[C:31]([C:32]1[CH:33]=[CH:27][C:22]([C:7]2([CH:14]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:6]2)=[CH:23][CH:24]=1)#[CH:30]
Reactant: C1CCOC1
Reactant: BrC(Br)CC1CCCCCCC1(c1ccccc1)C1CCCCCCC1
Agent: N
Agent: [Na]
Product: C#Cc1ccc(C2(C3CCCCCCC3)CCCCCCC2)cc1
Reaction time: 0.54 h

Procedure:
Small pieces of sodium were added to liquid ammonia until a blue color persisted. Ferric nitrate (100 mg) was added and the solution was stirred. When the solution turned colorless, sodium (6 g) was added in small pieces. After about 30 to 35 minutes following the addition the blue color disappeared and a solution of the above dibromoethylphenyl bicyclooctane in tetrahydrofuran was added to the solution. The ammonia was allowed to evaporate overnight and the residue was partitioned between ether and ice/water. The organic layer was separated, dried over K2CO3 and evaporated to leave crude 1-(4-ethynylphenyl)bicyclooctane. This was purified by chromatography on alumina (made basic with NH3) and elution with dichloromethanehexane (1:4) and recrystallization from hexanedichloromethane. The compound was characterized by NMR (300 MHz, CDCl3): δ 0.9 (9H, s, (CH3)3C), 3.05 (1H, s, C≡CH), 4.15 (6H, s, (CH2O)3), 7.45 (2H, d, aromatic), 7.55 (2H, d, aromatic). The compound was also characterized by mass spectrometry (M+ 272) and was found to have a melting point of 167°-168 C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
To a stirred solution of methyl 4-[({[5-fluoro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)methyl]benzoate (step 3, 407 mg, 1.02 mmol) in methanol (10 ml)_was added 2 N sodium hydroxide aqueous solution (2 mL). The reaction mixture was stirred at room temperature for 3 h and then evaporated. The residue was partitioned between ethyl acetate (100 mL) and 2 N hydrochloric acid (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with brine (50 mL), dried (sodium_sulfate), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 248 mg (64%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.40 (1H, dd, J=8.3, 3.1 Hz), 8.30 (1H, br.s), 8.09–8.04 (3H, m), 7.45 (2H, d, J=8.1 Hz), 7.17–7.06 (4H, m), 4.79 (2H, d, J=5.9 Hz); MS (EI) m/z 384 (M+), (ESI) m/z 385 (M+H)+, 383 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH3:10].C1COCC1.C([Li])CCC.C(O[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)(C)C>O>[CH2:9]([S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:25]1[O:33][C:30]([CH3:32])([CH3:31])[C:27]([CH3:29])([CH3:28])[O:26]1)[CH3:10]
Reactant: CCSc1ccccc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of 14.1 g of 1-bromo-2-ethylsulfanylbenzene and 65 mL of THF was cooled to −70° C., and 44.7 ml of n-butyl lithium (1.63M hexane solvent) was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was stirred at −50° C. for 30 minutes. A mixture of 14 g of isopropoxyboronic acid pinacol ester and 5 mL of THF was added at a rate such that the internal temperature of the mixture was kept at −60° C. or less, and the mixture was heated to the room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 7.9 g of 2-ethylsulfanylphenylboronic acid pinacol ester.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13]O)=[O:6])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=3)[C:11]=2[CH:12]=[CH2:13])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (124 mg, 0.361 mmol) obtained in Example 114 was dissolved in THF (2.5 ml), tributylphosphine (102 mg, 0.469 mmol, 1.3 eq.) and ADDP (120 mg, 0.469 mmol, 1.3 eq.) were added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate (30 ml), washed with 2% aqueous sodium carbonate solution, 10% aqueous sodium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to column chromatography (elution solvent, ethyl acetate-hexane=1:1-2:1) on silica gel (manufactured by E. Merck, Art.7734, 10 g). The fraction obtained by elution with ethyl acetate-hexane (3:2-2:1) was concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (101 mg, 0.310 mmol, 86.0%).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[CH2:32]([O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCc4ccccc4)cc3)n2C)n(CC)c1=O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
Compound 184 (100 mg, 0.29 mmol) obtained in Reference Example 181 was dissolved in 2 ml of dimethylformamide. To the solution were added 162 mg (1.17 mmol) of potassium carbonate and 0.28 ml (2.35 mmol) of benzyl bromide, and the mixture was stirred at 80° C. for 2.5 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give 67 mg (yield 53%) of Compound 185 as yellow needles.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[C:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][C:3]=1[F:35].[SH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]>>[C:39]([CH2:38][CH2:37][S:36][CH:22]1[C:21]2[CH:24]=[CH:25][C:26]([CH2:28][CH2:29][C:30](=[O:32])[CH3:31])=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([F:35])[CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:41])=[O:40]
Reactant: O=C(O)CCS
Reactant: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2O
Product: CC(=O)CCc1ccc2c(c1)COc1ccc(OCc3ccc4cc(F)c(Cl)cc4n3)cc1C2SCCC(=O)O

Procedure:
2-(7-Chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-8-(2-acetylethyl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:11][CH2:12][C@@H:13]([OH:30])[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17][CH2:16]1.CO>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[Cl:28])[O:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][C@H:13]([OH:30])[CH2:12][NH:11][C:8]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:10])=[O:9])[CH2:20][CH2:19]1
Reactant: Cc1ccccc1N=C=O
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1NC(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 40.9 %

Procedure:
A solution of o-tolylisocyanate (64 ml, 0.51 mmol) in dichloromethane (1 ml) was added to a suspension of (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.15 g, 0.47 mmol) in dichloromethane (3 ml) over a five minute period. After 1 h methanol (1 ml) was added and the solvents removed under vacuum. The residue was purified by reverse phase chromatography (C8 Symmetry column) to give the title compound (87 mg).