Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:24]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:44]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:24]([O:31][C@H:32]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:34]([CH2:44][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:33]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2C[C@@H](OCc3ccccc3)CN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC1COc1ccccc1CCCCc1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
441 mg of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) and 241 mg of potassium t-butoxide were dissolved, with ice-cooling and stirring, in 20 ml of dimethylacetamide. 900 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)pyrrolidine were then added to the solution thus obtained, and the resulting mixture was stirred at 40° C. for 5 hours. At the end of this time, the reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 242 mg (yield 24%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([NH:14][CH2:15][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)#[N:20].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([N:14]([C:30]3[CH:29]=[CH:28][C:27]([C:24]4[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][CH:25]=4)=[CH:32][CH:31]=3)[CH2:15][CH2:16]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H]2CCN[C@H]2C1
Reactant: N#Cc1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccc(N3CC[C@@H]4CN(C(=O)OCc5ccccc5)C[C@@H]43)cc2)cc1
Temperature: 80 °C

Procedure:
The product of Example 1B (trifluoro-methanesulfonic acid 4′-cyano-biphenyl-4-yl ester) (135 mg, 0.55 mmole), the product of Example 1C (198 mg, 0.61 mmole), palladium acetate (2.7 mg, 0.012 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 20 mg, 0.033 mmole) and sodium tert-butoxide (80 mg, 0.83 mmole) were mixed in 1.5 ml of toluene and heated at 80° C. under N2 for 16 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (3×). The combined organics were dried over sodium sulfate and concentrated to provide the crude product, which was purified by chromatography (5% methanol in dichloromethane) to provide the title compound. MS: (M+H)+=424.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12][C:13]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[C:14]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: Cn1cc(Br)cn1
Reactant: CCOC(=O)c1ccc(C)c(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1ccc(C)c(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-4-methyl-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[S:4][CH:5]=[C:6]([C:8](=[O:11])[CH2:9]Br)[N:7]=1.[OH:14][CH2:15][CH2:16][NH:17][CH:18]([CH3:32])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1.[BH4-].[Na+]>>[C:28]([CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:18]([N:17]([CH2:16][CH2:15][OH:14])[CH2:9][CH:8]([OH:11])[C:6]2[N:7]=[C:3]([C:2]([F:13])([F:12])[F:1])[S:4][CH:5]=2)[CH3:32])=[CH:21][CH:22]=1)([O:30][CH3:31])=[O:29]
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)COc1ccc(CC(C)N(CCO)CC(O)c2csc(C(F)(F)F)n2)cc1
Reaction time: 3 h

Procedure:
Prepared analogously to Example 3 by reaction of 2-trifluoromethyl-4-bromoacetyl-thiazole and N-(2-hydroxyethyl)- 2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine. Before the reduction with sodium borohydride, the mixture is heated to boiling for 3 hours to complete the reaction. The base is then purified on a silica gel column using ethyl acetate as mobile phase.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:12][CH:11]([OH:13])[CH:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:17]2[CH2:18][CH2:19][N:14]([CH:10]3[CH:11]([OH:13])[CH2:12][N:8]([C:6](=[O:7])[C:5]4[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9]3)[C:15](=[O:20])[CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2=O)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)C(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 1-[1-(4-Chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-piperazin-2-one (50 mg, 0.15 mmol) in CH2Cl2 (1 mL) at 0° C., was added DIPEA (27 uL, 0.154 mmol) and 4-Chloro-benzoyl chloride (20 uL, 0.154 mmol). The mixture was stirred at RT for 4 h. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Methanol:Et3N:10.1:0.1) to give the desired product (36 mg, 50% yield) as a white solid. MS: (ESI), M/Z, 462 (M+1). Retention time: 2.25 min (FA-polar).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:28][CH2:29][CH2:30]I>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:30][CH2:29][F:28])[CH:16]=1)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FCCI
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)CC(NC(=O)OC(C)(C)C)c1cccc(OCCF)c1
Reaction time: 9 h
Yield: 73.2 %

Procedure:
To methyl 3-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (4.46 g, 20 mmol) in THF was added cesium carbonate (9.84 g, 30 mmol) and 1-fluoro-2-iodoethane (5 g, 30 mmol) and the mixture was stirred for 9 hours. After filtration the filtrate was concentrated in vacuum to yield 5.0 g of methyl 3-[(tert-butoxycarbonyl)amino]-3-[3-(2-fluoroethoxy)phenyl)propanoate.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:11]=1Cl)(=O)[CH3:8].C([O-])([O-])=O.[K+].[K+].O>CO>[CH3:24][O:23][CH2:22][CH2:21][O:20][CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:7]([CH3:8])=[C:2]([C:3]([O:5][CH3:6])=[O:4])[S:1][C:11]1=2
Reactant: COCCOCn1c(Cl)c(C(C)=O)c2ccccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COCCOCn1c2ccccc2c2c(C)c(C(=O)OC)sc21
Reaction time: 48 h

Procedure:
400 μl of methyl 2-mercaptoacetate was added to a slurry of 1050 mg of (80) and 1.1 g of K2CO3 in 10 ml of MeOH, and left with stirring for 48 hours. 20 ml of water was added, and the precipitate filtered off and dried. This material was thoroughly washed with pentane, filtered, dried, and recrystallized from EtOH giving 230 mg of (81) as a white powder. M.p. 85.4°-86° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][OH:21])[C:9](=O)[CH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:19][CH2:20][OH:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cccnc1Cl)N(CCO)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: OCCN(CCc1cccnc1Cl)Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of the compound (2.00 g) obtained in step 5 in THF (30 mL) was added 1M BH3.THF complex/THF solution (32.0 mL) at 0° C., and the mixture was stirred at 90° C. for 1 hr. After the reaction mixture was cooled to 10° C., MeOH (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was suspended in 6N hydrochloric acid (32 mL), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was cooled to 10° C., and made basic with aqueous sodium hydroxide solution, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 33→50% ethyl acetate/hexane) to give 2-(benzyl(2-(2-chloropyridin-3-yl)ethyl)amino)ethanol (0.88 g, 46%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]([CH2:12][OH:13])[O:7][C:6]=2[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:13][CH2:12][C@@H:8]2[O:7][C:6]3[CH:5]=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=[C:2]([Cl:1])[C:11]=3[O:10][CH2:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CS(=O)(=O)c1cc(Cl)c2c(c1)O[C@@H](CO)CO2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1

Procedure:
Preparation according to Preparation 22 using [(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methanol (0.33 g, 1.2 mmol), DCM (10 ml), p-toluenesulfonyl chloride (0.34 g, 1.8 mmol), TEA (0.18 ml, 1.8 mmol) and 4-DMAP (0.15 g, 1.2 mmol). Yield: 0.47 g. MS m/z (rel. intensity, 70 eV) 344 (28), 342 (bp), 340 (74), 263 (18), 233 (31). Molecular ion not found, however fragmentation consistent with the title compound. Used directly in the next step (Example 38) without further analysis.
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]CC.Cl.[CH3:13][CH:14]([CH3:18])[C:15](=[NH:17])[NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:13][CH:14]([C:15]1[NH:17][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:16]=1)[CH3:18]
Reactant: CCOC1=C(Br)C(=O)CCC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To 2-bromo-3-(ethyloxy)-2-cyclohexen-1-one (38.8 g) in a 1 L round-bottom flask in N,N-Dimethylformamide (DMF) (500 mL) was added 2-methylpropanimidamide hydrochloride (26.1 g) and potassium carbonate (61.2 g). The suspension was then stirred at 80° C. under nitrogen for 2 h. The mixture was filtered and as much DMF as possible was evaporated off under high vacuum. The sample was loaded in dichloromethane and purified by column chromatography over silica using a 0-30% methanol-dichloromethane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product 14.2 g as a brown solid. LC/MS MH+ 179, Rt 1.4 min (5 min run).
Reaction SMILES: [N+:1](C1C=CC(N)=CC=1)([O-])=O.N([O-])=O.[Na+].[CH3:15][C:16]1([CH3:35])[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[C:19]2[C:28]([CH3:34])=[CH:29][C:30]([CH3:33])=[C:31]([CH3:32])[C:18]=2[O:17]1>Cl>[CH3:15][C:16]1([CH3:35])[CH:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[C:19]2[C:28]([CH3:34])=[C:29]([NH2:1])[C:30]([CH3:33])=[C:31]([CH3:32])[C:18]=2[O:17]1
Reactant: Cc1ccc(C2c3c(C)cc(C)c(C)c3OC2(C)C)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
4-Nitroaniline (0.16 g) was dissolved in 2N hydrochloric acid (3 mL) at 60° C., and then cooled to 0 to 5° C. To the resultant solution was added sodium nitrite (79 mg), and stirred for 15 minutes. To the mixture were added 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran (0.27 g) and a solvent (3 mL), and stirred under a nitrogen atmosphere. After completion of the reaction, a sample was taken from the mixture and its composition was measured with HPLC (*1). Solvents, reaction conditions and results of measurement are shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.S([O-])([O-])(=O)=O.[NH4+].[NH4+].C[Si](C)(C)OC1N=C(O[Si](C)(C)C)C=C(C)N=1.C(O[CH:50]1[O:72][C@@H:71]([CH2:73][O:74][C:75](=[O:82])[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C@H:61]([O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@@H:51]1[O:52][C:53](=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C1(C)C=CC=CC=1>[C:53]([O:52][C@H:51]1[C@@H:61]([O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@H:71]([CH2:73][O:74][C:75](=[O:82])[C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[O:72][C@@H:50]1[N:7]1[C:2]([CH3:1])=[CH:3][C:4](=[O:9])[NH:5][C:6]1=[O:8])(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cc1cc(O[Si](C)(C)C)nc(O[Si](C)(C)C)n1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1cc(=O)[nH]c(=O)n1[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 6-methyluracil (2.52 g, 20.0 mmol), hexamethyldisilazine (50 mL) and ammonium sulfate (100 mg ) were refluxed at 135° C. for 6 h. The solvent was removed in vacuo and the residue that obtained was co-evaporated twice with dry toluene (2×50 mL) to remove last traces of hexamethyldisilazine. The solid thus obtained was dried under vacuum for 6 h. A solution of the 2,4-bis(trimethylsilyloxy)-6-methylpyrimidine (20.0 mmol) in dry acetonitrile (100 mL) was added 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose (10.12 g, 20 mmol) and trimethylsilyltriflate (5.78 g, 26.0 mmol). The reaction mixture was stirred under argon at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (200 mL). The organic layer was washed with sat. sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and concentrated to yield a white foam. Further separation of the crude product by silica gel flash column chromatography using the CH2Cl2 →EtOAc as the eluent gave two products. Yield of the 2nd fraction 4.50 g (42%). 1H NMR (CDCl3) δ 2.28 (s, 3H, CH3), 4.65-4.81 (m, 3H, C4'H and C5'H), 5.60 (m, 1H, C3'H), 5.72 (s, 1H), 6.11 (m, 1H), 7.24-8.06 (m, 16H, PhH) and 9.40 (br s, 1H, NH). The first fraction (4.20 g) did not correspond to the desired compound according to 1H NMR.
Reaction SMILES: C1(CCC(Cl)=O)CCCC1.[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[N:31]=[CH:30][CH:29]=[C:28]2[O:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([F:45])[CH:39]=1.C1(C)C=CC=CC=1>C(O)C>[CH:11]1([CH2:16][CH2:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1.[CH:11]1([CH2:16][CH2:17][C:18]([NH:20][C:21]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([O:37][C:28]3[C:27]4[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=4)[N:31]=[CH:30][CH:29]=3)=[CH:39][C:40]=2[F:45])=[S:22])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(CCC1CCCC1)N=C=S
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCC4CCCC4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
3-Cyclopentylpropanoyl isothiocyanate was prepared using commercially available 3-cyclopentylpropanoyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Cyclopentylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (63 mg, yield 80%).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(=[O:8])=[O:7])[CH3:3].C1C(=O)N([Br:32])C(=O)C1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:32][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([N:5]=[CH:4][N:2]([CH3:1])[CH3:3])(=[O:7])=[O:8])(=[O:16])=[O:17])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CN(C)C=NS(=O)(=O)c1ccccc1S(=O)(=O)c1ccc(CBr)cc1
Yield: 87.8 %

Procedure:
1.5 g of N-dimethylaminomethylene-2-(toluene-4-sulfonyl)benzenesulfonamide, 0.74 g of NBS and 20 mg of benzoyl peroxide are refluxed for 2 h in 15 ml of chlorobenzene. The reaction mixture is allowed to cool and is diluted with 100 ml of toluene, and washed once each with 20 ml of a saturated aqueous Na2SO3 solution and twice with 50 ml of a saturated aqueous Na2CO3 solution. It is dried over MgSO4 and the solvent is removed in vacuo. 1.6 g of an amorphous solid are obtained, which is further reacted without further purification.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)C1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].[OH-].[Na+]>C1C=CC=CC=1>[CH2:34]([O:33][C:31]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:15]2[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)[CH2:9]1)=[O:32])[CH3:35]
Reactant: c1ccc(CN2CCOC(CN3c4ccccc4CCc4ccccc43)C2)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCOC(CN2c3ccccc3CCc3ccccc32)C1

Procedure:
A mixture of 5-(4-benzyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine (1.62 g) and ethyl chloroformate (1.44 g) in benzene was stirred under reflux for 8 hours. The reaction mixture was cooled, admixed with 10% aqueous sodium hydroxide and extracted with benzene. The benzene extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(4-ethoxycarbonyl-2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. To a solution of the oil in ethanol was added 30% aqueous sodium hydroxide, and the resulting mixture was stirred at 65° C for 5 hours. The reaction mixture was cooled and extracted with benzene. The benzene extract was dried over anhydrous sodium sulfate and evaporated to afford 5-(2-morpholinylmethyl)-10,11-dihydro-5H-dibenz[b,f]azepine as an oily substance. M.P. 194.5°-195.5° C (oxalate).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C@@H:18]1[NH:22][C@@H:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[C@H:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[C:9]([OH:11])=O)[CH2:2][CH2:3][CH3:4].CC[N:48]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:9](=[O:11])[NH2:48])[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([CH:18]1[NH:22][CH:21]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:20]2([C:35]3[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=3)[NH:29][C:28]2=[O:37])[CH:19]1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=1[F:45])=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCOc1cc(C(N)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 80 °C
Yield: 89.5 %

Procedure:
To a solution of rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid (0.1 g, 0.15 mmol) prepared in Example 151 in anhydrous DMF (2 mL) were added EDCI (59 mg, 0.31 mmol), HOBt (41 mg, 0.31 mmol), NH4Cl (81 mg, 1.5 mmol), and triethylamine (31 mg, 0.31 mmol) sequentially. The reaction mixture was heated at 80° C. for 1 h. The mixture was cooled to room temperature, then partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate twice. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25-100% EtOAc in hexanes) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-butoxy-4-carbamoyl-phenyl)-amide as a white solid (88 mg, 89%).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([OH:8])=[CH:3][C:4]([OH:7])=[CH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:20][C:21](Cl)=[O:22].O>[N+](C1C=CC=CC=1)([O-])=O>[OH:8][C:2]1[C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:5]2[C:21](=[O:22])[CH2:20][O:7][C:4]=2[CH:3]=1
Reactant: Oc1ccc(-c2ccccc2)c(O)c1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1COc2cc(O)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A solution of biphenyl-2,4-diol (0.24 g, 1.3 mmol) in nitrobenzene (1.0 mL) was added with aluminum chloride (0.60 g, 4.5 mmol) at room temperature. Then, the reaction mixture was added with chloroacetyl chloride (0.60 g, 1.7 mmol) under ice cooling. The mixture was stirred at 40° C. for 3 hours, and then added with water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (100:0→90:10)) to obtain 6-hydroxy-5-phenylbenzofuran-3(2H)-one (0.12 g, 42%).