Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>Cl.CCOCC>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(O)cc1OC
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(OC2CCCCO2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dimethoxyphenol (30.8 g) was added in small portions to a mixture of dihydropyran (29.2 ml) and conc. hydrochloric acid (3 drops) under nitrogen so that the temperature did not rise above 50° C. After the addition was complete the dark solution was stirred at room temperature for 3 hrs. and then diluted with ether. The resulting solution was washed with water, 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give 3,4-dimethoxyphenol tetrahydropyranyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15].C1N2CCN(CC2)C1>CN(C=O)C>[C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:8][C:14](=[S:15])[N:13]([CH3:17])[CH3:12])(=[O:11])[CH3:10]
Reactant: CC(=O)c1c(O)cccc1F
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1OC(=S)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
1-(2-Fluoro-6-hydroxy-phenyl)-ethanone (2.5 g, 16.22 mmol) (available from Apollo Scientific) was dissolved in anhydrous DMF (20 mL.) Dimethylthiocarbamoyl chloride (2.2 g, 17.84 mmol) and DABCO (2.0 g, 17.84 mmol) were added sequentially in one portion. The reaction was permitted to stir overnight at ambient temperature. The reaction was quenched by pouring it into a mixture of 1N HCl-ice. The oily residue was extracted with dichloromethane and dried over sodium sulfate. The crude residue was purified by SGC (20% ethyl acetate in hexanes) to provide the title compound (2.93 g.) 1H NMR (200 MHz, CDCl3): δ (ppm)=7.407 (dd, 1H), 7.026 (t, 1H), 6.876 (d, 1H), 3.404 (s, 3H), 3.341 (sd, 3H), 2.58 (d, 3H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:5]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([O:11][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[F:10])[C:3]([OH:19])=[O:2])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Reaction time: 5 h

Procedure:
3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester (2.81 g, 10.0 mmol) was dissolved in tetrahydrofuran (15 mL) and mixed with 2M lithium hydroxide (15 mL, 30 mmol). The suspension was stirred for 5 h. To the reaction was added water, then extracted with EtOAc. The aqueous layer was treated with 6M HCl (5 mL, 30 mmol) and then extracted with EtOAc (3×25 mL). The extract was dried (MgSO4), filtered and evaporated to 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid. Yield: 2.22 g, 83%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:16][NH:17][C:18]([NH2:20])=[O:19]>>[NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[N:16][NH:17][C:18]([NH2:20])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NNC(N)=O
Reactant: Nc1ccccc1C(=O)c1ccccc1
Product: NC(=O)NN=C(c1ccccc1)c1ccccc1N

Procedure:
A number of methods for preparing 1,3,4-benzotriazepine-2-ones have been described in the literature. In general, the compounds are prepared by either of two methods from a 2-aminobenzophenone. In the first method, the 2-aminobenzophenone is treated with semicarbazide to give an aminobenzophenone semicarbazone. This product is cyclized to give the benzotriazepine-2-one. See Bull. Chem. Soc. Jap., 43, 135-138 (1970); Japanese publications 70 11,148 (CA 73:25544a) and 70 11,147 (CA 73:25545b). Alternately, a 2-amino-benzophenone hydrazone is treated with phosgene to give the desired benzotriazepine-2-one. See U.S. Pat. No. 3,176,008; J. Pharm. Sci. 63 (b), 838-41 (1974) and J. Med. Chem. 7(3), 386 (1964).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][C:2]([OH:6])([C:4]#[C:5][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
2-Methyl-but-3-yn-2-ol (24 ml; 247 mmol), 2-(4-bromo-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.7 g; 30.85 mmol) (J.Organomet. Chem. 2006, 691(26), 5725), Pd(PPh3)2Cl2 (4.33 g; 6.17 mol) Cul (1.17 g; 6.17 mmol) in DMF (140 ml) and triethylamine (60 ml) are heated to 110° C. for 20 minutes. The reaction mixture is evaporated to dryness and the residue taken up in hexanes/acetone (85:15), filtered and the filtrate purified via chromatography ((SiO2; hexaneslacetone 85:15) to deliver the target compound as light-brown crystals. 1H-NMR (400 MHz; DMSO-d6): 7.65 (d, 2H); 7.40 (d, 2H); 5.51 (s, 1H); 1.48 (s, 6H); 1.31 (s, 12H). MS (m/z) ES+: 269 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:43](Cl)(=[O:45])[CH3:44]>C(#N)C>[C:43]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([F:25])[CH:23]=4)[NH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=1)(=[O:45])[CH3:44]
Reactant: Cc1ccc(N)cc1CCN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1ccc(C)c(CCN2CCC(c3c[nH]c4ccc(F)cc34)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Polymer bound 3-[1-(2-{5-amino-2-methylphenyl}ethyl)piperidin-4-yl]-5-fluoro-1H-indole (100 mg, 100 μmol), triethylamine (90 μL), and dimethylaminopyridine (0.50 mL of an 0.2 M solution in dry acetonitrile) were mixed in a reactor tube. The mixture was cooled to 0° C. and treated with acetyl chloride (0.50 mL of an 1M solution in dry acetonitrile). The reaction mixture was left at 0° C. for 2 h. The resin was filtered off and washed with dry acetonitrile (3×1 mL). The resin was treated for 1 h with 1 mL of a mixture of sodium methoxide (2 mL, 5 N sodium methoxide in methanol), methanol (50 mL) and tetrahydrofuran (50 mL). After filtration, the resin was washed with methanol (1 mL). The combined filtrates were loaded on a pre-conditioned ion exchange column (500 mg SCX column, commercially available from Analytical Instruments, part no. 1210-2040), washed with acetonitrile (1 mL) and methanol (1 mL). The product was eluted with 4 M ammonia in methanol. Evaporation of volatile solvents afforded the title compound as a yellow oil (6 mg, 15 μmol). LC/MS (m/z) 394 (MH+), RT=1.98, purity: 88%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:32])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:31][C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:32][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1sc2c(sc3ccccc32)c1O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(sc3ccccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
tert-Butyl bromoacetate (0.082 ml, 0.56 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (50 mg, 1.2 equiv) and 1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (113 mg, 0.43 mmol, 1 equiv) in DMF (10 ml). The resulting mixture was stirred at 60° C. for 16 hr. Addition of water followed by extraction with EtOAc and washing with water left crude product. Purification by column chromatography gave 140 mg (86%) of 1-tert-butoxycarbonylmethoxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:30]([OH:32])=O)[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])=[CH:18][C:17]3=[O:29])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:33][NH:34][CH3:35].CN1CCOCC1>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([C:30]([N:34]([CH3:35])[CH3:33])=[O:32])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])=[CH:18][C:17]3=[O:29])[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CNC
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOC[C@@H]3C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (55.6 mg, 0.17 mmol), was added in one portion to a stirred solution of 8-(1-(3,5-difluorophenylamino)ethyl)-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (70 mg, 0.16 mmol), dimethylamine (0.095 mL, 0.19 mmol) and 4-methylmorpholine (0.038 mL, 0.35 mmol) in DMF (1 mL). The resulting solution was stirred at RT for 1 hour. The reaction mixture was purified by preparative HPLC using a reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford a residue which was triturated with Et2O, filtered and dried to give 8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-((S)-3-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (45 mg, 61%) as a pale orange solid. Mass Spectrum: M+H+ 471. NMR Spectrum (CDCl3): 1.37 (d, 1.5H), 1.41 (d, 1.5H), 1.59 (d, 1.5H), 1.60 (d, 1.5H), 2.89 (s, 1.5H), 2.91 (s, 1.5H), 3.08 (s, 3H), 3.35-3.43 (m, 1H), 3.52-3.69 (m, 2H), 3.75-3.83 (m, 2H), 3.98-4.09 (m, 2H), 4.52 (d, 1H), 4.85-4.96 (m, 1H), 5.53 (s, 1H), 5.97 (d, 2H), 6.11 (t, 1H), 7.71 (d, 0.5H), 7.73 (d, 0.5H), 8.13 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CCOC(C)=O>[C:12]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(N)nc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)=O)nc1
Temperature: 100 °C

Procedure:
To a mixture of methyl 6-aminopyridine-3-carboxylate (3 g, 19.72 mmol, Aldrich) in 1,4-ioxane (50 mL) was added acetic anhydride (3.72 mL, 39.4 mmol, Aldrich). The resulting mixture was then heated at 85° C. for 3 h and at 100° C. for an additional 3 h. The mixture was then cooled to rt and diluted with EtOAc (400 mL). The mixture was then washed with saturated NaHCO3 solution (2×200 mL), brine (150 mL), dried over MgSO4, and concentrated in vacuo to afford the title compound as a white solid, which was used in the next step without purification. MS (ESI, positive ion) m/z: 195 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.Cl>CN(C)C=O.CCCCCC>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A slurry of hexane-washed sodium hydride (3 g, 75 mmol) in dimethyl formamide (80 mL) was stirred as a solution of N-(t-butoxycarbonyl)4-hydroxypiperidine (10 g, 50 mmol) in dimethyl formamide (10 mL) was added dropwise. Slight heating was used to initiate reaction, but the reaction needed to be cooled in an ice bath to control the reaction rate. Approximately 30 min after the addition was complete, solid 4-fluoro-1-nitrobenzene (7.4 g, 52 mmol) was added at once. The reaction was stirred for about 3 hours. The reaction was poured into ice water. The pH of the resulting liquid was adjusted to neutrality with 1 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 16 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.72 (m, 2), 1.98 (m, 2), 3.38 (m, 2), 3.68 (m, 2), 4.62 (m, 1), 6.98 (m, 2), 8.19 (m, 2).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[Br:11]Br>C1COCC1>[CH:5]1[C:4]([C:2]([CH2:1][Br:11])=[O:3])=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)cc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(O)cc1

Procedure:
4-Hydroxyacetophenone (25 g) was treated with bromine (9.5 mL) dropwise over 15 minutes in THF (60 mL) at room temperature and stirred until the color was consumed. The whole was carefully poured into saturated sodium bicarbonate solution until basic. The aqueous layer was extracted with ether (3×100 mL) and the ether layer was washed with saturated sodium bicarbonate solution (100 mL) followed by 5% aqueous sodium bisulfite (100 mL), H2O (100 mL) and finally saturated brine solution (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide an oil (30 g) of crude material used in the preparation of thiazoles.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:8][CH2:9][C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[Br-].[F:27][C:28]1[CH:33]=[CH:32][C:31]([Zn+])=[CH:30][CH:29]=1>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.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:8][CH2:9][C:10]=1[C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc([Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(=O)C1=C(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 6 h

Procedure:
To a mixture of 4-trifluoromethanesulfonyloxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (10.1 g, 25.9 mmol), 4-fluorophenylzinc bromide solution (0.5 M in THF, 86.3 ml, 43.1 mmol) and 290 ml THF was added tetrakis(triphenylphosphine)palladium(0) (0.83 g, 0.72 mmol) at RT. After stirring for 6 h the reaction was quenched with ice. The mixture was diluted with tert-butyl methyl ether and washed with 2 M aqueous sodium carbonate solution. The aqueous layer was extracted with two portions of tert-butyl methyl ether. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification of the residue by flash chromatography (heptane/ethyl) gave the title compound as a lightly yellow amorphous residue (6.8 g, 71%).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8](=[O:21])[CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[O:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])=[CH:26][C:25]=3[O:37][CH3:38])=[CH:12][CH:11]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Reactant: O=Cc1c[nH]c2cc(CC(=O)NCC3CCCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(CC(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 97.5 %

Procedure:
A mixture of N-cyclopentylmethyl-3-formylindole-6-acetamide (0.52 g), t-butyl 4-bromomethyl-3-methoxybenzoate (0.66 g), and potassium carbonate (0.37 g) in N,N-dimethylformamide (10 ml) was stirred for 48 hr under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and purified by flash chromatography, eluting with 1:49 methanol:chloroform, to give t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-formylindol-1-ylmethyl]-3-methoxybenzoate (0.90 g, 97%) as a white solid; partial NMR (80 MHz, CDCl3): 1.56 (s, 9H, C(CH3)3), 3.09(t, 2H, NHCH2), 3.65(s, 2H, COCH2), 3.93(s, 3H, OCH3), 9.98(s, 1H, CHO).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([N:36]1[CH2:41][CH2:40][CH:39]([O:42][C:43]2[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][C:44]=2[F:51])[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:47]=[CH:48][C:43]([O:42][CH:39]2[CH2:40][CH2:41][NH:36][CH2:37][CH2:38]2)=[C:44]([F:51])[CH:45]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2F)CC1
Product: CCN(Cc1ccc(OC2CCNCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 19.3 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 4-(2-fluoro-4-formylphenoxy)piperidine-1-carboxylic acid tert-butyl ester (75 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (5.1 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[N:5][O:6][CH:7]=1.C(OCC)(=O)[CH2:21][C:22]([O:24]CC)=[O:23].[H-].[Na+].Cl>O1CCCC1>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([CH2:2][CH2:21][C:22]([OH:24])=[O:23])=[CH:7][O:6][N:5]=3)=[CH:9][CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1conc1-c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1conc1-c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 4-chloromethyl-3-(4-phenylphenyl)isoxazole (3.20 g) in tetrahydrofuran (100 ml) was added to a mixture of diethyl malonate (5.70 g), sodium hydride (60%, oil, 1.40 g) and tetrahydrofuran (50 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and then at room temperature overnight. The reaction mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a colorless oil was obtained from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). A mixture of the obtained colorless oil, 6N hydrochloric acid (30 ml) and acetic acid (30 ml) was refluxed for 5 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give 3-[3-(4-phenylphenyl)-4-isoxazolyl]propionic acid (2.89 g, yield 83%). The crystals were recrystallized from acetone-hexane. melting point: 169–170° C.
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23]Br)[CH3:17]>CC(C)=O>[CH2:16]([O:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:17]
Reactant: CCOC(=O)CCCCBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCOc1ccccc1
Temperature: 60 °C

Procedure:
Dehydrated acetone of 240 ml was put in a 3-necked round-bottom flask, potassium iodide (0.06 mol), potassium carbonate (0.11 mol), and phenol (0.07 mol) were added to stir sufficiently. In this solution, 5-bromo valeric acid ethyl ester (0.06 mol) was dropped in a nitrogen atmosphere and refluxed at 60±5° C. to react for 24 hours. After completion of the reaction, a reaction solution was exsiccated to condensation using an evaporator, and dissolved again in methylene chloride, and water was added to the solution to separate and an organic layer was dehydrated by using magnesium sulfate anhydride followed by exsiccation for condensation using the evaporator. Hot methanol was added to a dried matter (reactant) yielded to dissolve and cooled slowly to precipitate again, resulting in a yield of 5-phenoxy valeric acid ethyl ester (PxVA). At this point, the yield ratio of this ester to 5-bromo valeric acid ethyl ester was 72 mol %.
Reaction SMILES: Cl[CH:2](Cl)[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:4]=1.ClC(Cl)C1N=C(N2CCCC2)N(CC2C=CC([O:42]C)=CC=2)N=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:7]2[C:3]([CH:2]=[O:42])=[N:4][C:5]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:6]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(Cn2nc(N3CCCC3)nc2C(Cl)Cl)cc1
Reactant: COc1ccc(Cn2nc(C(Cl)Cl)nc2N2CCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nc(N3CCCC3)nc2C=O)cc1
Temperature: 60 °C
Yield: 29 %

Procedure:
The mixture of 5-(dichloromethyl)-1-(4-methoxybenzyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazole and 3-(dichloromethyl)-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole from the previous step (299 mg, 0.876 mmol, Eq: 1) was suspended in ethanol (5 ml) and water (5 ml). Sodium acetate (180 mg, 2.2 mmol, Eq: 5) was added. The reaction mixture was heated for 16 h at 60° C. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. The product (74 mg, 29%) was obtained as a yellow solid by column chromatography (SiO2, ethyl acetate n-heptane). MS: m/z=287.3 (M+H+)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>C(Cl)Cl>[C:5]([O:17][C:12]1[CH:13]=[CH:14][C:15]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:16][C:11]=1[F:10])(=[O:8])[CH2:6][CH3:7]
Reactant: Oc1ccccc1F
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)Oc1ccc(C(=O)CC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To a mixture of aluminum chloride (45.8 g, 0.343 mol) in methylene chloride (140 mL) was added propionyl chloride (10.85 mL, 124.9 mmol) all at once followed by 2-fluorophenol (5.57 mL, 62.44 mmol in 25 mL of methylene chloride with a 10 mL rinse). The mixture was gently refluxed 5 h, cooled to ambient temperature and poured onto ice. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with aqueous bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to give 11.43 g (82%) of 4-propionyl-2-fluorophenyl propionate as a clear tan oil which was used without characterization.