Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][CH:46]=[C:47]([O:49][CH3:50])[CH:48]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[N:44]=[N:45][CH:46]=[C:47]([O:49][CH3:50])[CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: COc1cnnc(-c2cc(C)c(Cl)c(C)c2)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(OC)cnn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-chloro-3,5-dimethyl-phenyl)-5-methoxy-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 11): tR=1.10 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: C(Cl)CCl.[N:5]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([OH:9])=O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.FC(F)(F)C([O-])=O.[NH2:44][C@@H:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[N:5]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([NH:44][C@@H:45]([C:53]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:9]
Reactant: N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: O=C([O-])C(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
EDC (1.68 g, 8.78 mmol) was added to a solution of N-Boc-D-Pro (372 mg, 1.73 mmol) and hydroxybenzotriazole (281 mg, 2.08 mmol) in dry dichloromethane (17.3 ml) and the resulting mixture was stirred at room temperature for 2.5 hours. Distilled triethylamine (482 μl, 3.46 mmol) was then added, followed by the crude trifluoroacetate salt of D-Phe-OBn, prepared as described above. The solution was stirred for an additional 3 hours, diluted with dichloromethane and washed sequentially with a dilute solution of HCl (<5%, pH 3.0), a solution of saturated sodium bicarbonate, and brine. The combined organic layers were dried over MgSO4 and concentrated to obtain a yellow oil. This substance was subjected to silica gel chromatography, eluted with a solution that was 2:1 hexanes:ethyl acetate, and resulted in a yield of 658 mg of N-Boc-D-Pro-D-Phe-OBn as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][SH:5].Br[C:11]1[N:12]=[C:13]([O:37][CH3:38])[C:14]([N:17](COCC[Si](C)(C)C)[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:15][CH:16]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[C:13]([O:37][CH3:38])=[N:12][C:11]([S:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:16][N:15]=1)(=[O:20])=[O:19]
Reactant: SCc1ccccc1Cl
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Product: COc1nc(SCc2ccccc2Cl)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 82 using 2-chlorobenzylmercaptan (0.15 g) and N-(5-bromo -3-methoxy-2-pyrazinyl)-2,3-dichloro-N-[{2-(trimethylsilanyl)ethoxy}methyl]benzenesulphonamide (0.4 g). Yield 0.18 g.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.[NH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O>>[NH2:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH2:4][CH2:3][O:2][CH3:1])=[O:10]
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: COCCO
Agent: O=S(=O)(O)O
Product: COCCOC(=O)CC(N)c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 6.00 mL (76.3 mmol) of 2-methoxyethanol were added 2.00 g (12.1 mmol) of 3-amino-3-phenylpropionic acid (racemic mixture) synthesized in Reference example 1 and 1.78 g (18.2 mmol) of conc. sulfuric acid, and the mixture was reacted under stirring at 60° C. for 4 hours. After completion of the reaction, the resulting reaction mixture was concentrated under reduced pressure, and then, 6 mol/L aqueous sodium hydroxide solution was added to the reaction mixture to adjust a pH thereof to 8.5. Then, 10 mL of ethyl acetate and 4 mL of water were added to the mixture to carry out extraction, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2.22 g (Isolation yield based on 3-amino-3-phenylpropionic acid (racemic mixture): 82.2%) of 2-methoxyethyl 3-amino-3-phenylpropionate (racemic mixture) as colorless liquid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([C@@H:9]1[C@H:5]2[O:4][CH2:3][C@@H:2]([OH:1])[C@H:6]2[O:7][CH2:8]1)=[N+:22]=[N-:23]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CO[C@H]2[C@@H]1OC[C@H]2O

Procedure:
A solution of 2.5 g of toluene-4-sulfonic acid (3R,3aS,6R,6aR)-6-hydroxy-hexahydro-furo[3,2-b]furan-3-yl ester in 30 ml of DMF is heated with 0.8 g of sodium azide under reflux for 2 hours, solvent is distilled off and the distillation residue obtained is dissolved in EtAc and extracted with H2O. The organic phase obtained is dried and solvent is evaporated. (3R,3aR, 6S,6aR)-6-azido-hexahydro-furo[3,2-b]furan-3-ol is obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19](C)[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24](O)(=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:24](=[O:31])[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:12][CH2:11]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: O=C(O)CCCC(=O)O
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: O=C(O)CCCC(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and glutaric acid
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[CH3:18][CH:19]1[NH:20][CH2:21][CH2:22][N:23]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24]1
Reactant: CC1CNCCN1
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: CC1CN(c2nccnc2OCCOc2ccccc2)CCN1

Procedure:
The title compound was prepared according to the procedure described In Example 4, Step 2, starting from 2-chloro-3-(2-phenoxyethoxy)pyrazine (150 mg, 0.54 mmol; from Example 1, Step 1) and 2-methylpiperazine (250 mg, 2.5 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out This gave 138 mg (73%) of the title product. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:12]1[C:17]2[CH:18]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:29])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)C(O)=O>>[C:8]([C:12]1[C:17]2[CH2:18][CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:20][C:16]=2[CH:15]=[CH:14][C:13]=1[OH:29])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCCCCCCCc1cc2c(C(C)(C)C)c(O)ccc2o1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC1Cc2c(ccc(O)c2C(C)(C)C)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Triethylsilane (2.8 ml) was added to 4-tert-butyl-5-hydroxy-2-octylbenzofuran (300 mg, 1.0 mmol) and, then, trifluoroacetic acid (1.4 ml) was added dropwise under ice cooling. The mixture was stirred first at 0° C. for 15 min, then at room temperature for 1 h. Thereafter, the mixture was poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (chloroform) to afford 4-tert-butyl-5-hydroxy-2-octyl-2,3-dihydrobenzofuran [252 mg (yield, 83%)] as a colorless oil. Mass 304(M+), 289, 137, 57
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:4].[CH2:15]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH3:19].[I-].[K+].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([N:20]([CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:37]=[N:36][N:35]=2)=[CH:26][CH:27]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1cc(C)c(NC(=O)CCl)c(C)c1
Reactant: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCN(CC(=O)Nc1c(C)cc(C)cc1C)Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
N-(Chloroacetyl)-2,4,6-trimethylaniline (443.2 mg), N-pentyl-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (780.0 mg), potassium iodide (129.1 mg) and triethylamine (1.15 g) were suspended in dimethylformamide (6 mL). The resulting mixture was heated to about 80° C., and then stirred at that temperature. Three hours later, the reaction mixture was cooled, ethyl acetate (50 mL) was added, and the mixture was washed four times with brine (100 mL, each). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane/ethyl acetate) to afford N-pentyl-N-[[[(2,4,6-trimethylphenyl)amino]carbonyl]methyl]-N-[[2′-[N-(triphenylmethyl)tetrazol-5-yl]-1,1′-biphenyl-4-yl]methyl]amine (395.4 mg). Yield: 39%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C(=O)C.O.[Cl:13][C:14]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:15]=1[C:16]([C:18]1[CH:34]=[CH:33][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](O)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)=[O:17]>C(#N)C.S1(CCCC1)(=O)=O>[Cl:13][C:14]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:15]=1[C:16]([C:18]1[CH:34]=[CH:33][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([Cl:3])(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1ccc(Oc2ccc(S(=O)(=O)O)cc2)cc1)c1cc(Cl)ccc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CC(=O)N(C)C
Product: O=C(c1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1)c1cc(Cl)ccc1Cl
Temperature: 72 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To 215 g (about 400 mmol) of the crude crystal of A-SO3Na, 300 mL of acetonitrile and 200 mL of sulfolane as a solvent were added, and further phosphoryl trichloride (245.3 g, 1.6 mole) was added and then reacted at 70° C. to obtain a reaction mixture. Further, 5 mL of N,N-dimethyl acetoamide was added thereto and the resulting yellow suspension was stirred at 71 to 73° C. for 40 min and then cooled to 3° C. To the suspension, 1 L of cool water was added at a rate such that the temperature of the reaction system was not over 10° C. The resulting precipitate was collected, washed with cool water and re-crystallized with 350 mL of toluene to obtain 153 g of the aimed white crystalline A-SO2Cl having a melting point of from 130.5 to 131.5° C. (yield: 87% on the basis of A). The IR spectrum is shown in FIG. 4 and the NMR spectrum is shown in FIGS. 5 and 6.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CN(C(O[N:31]1[N:39]=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(Cl)Cl.CN(C=O)C.NN>C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:31][NH2:39])=[O:15])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: NN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Yield: 105.5 %

Procedure:
4-(Octyloxy)-3-(trifluoromethyl)benzoic acid (D5) (600 mg, 1 equiv) was stirred with HATU (859 mg, 1.2 equiv) and DIEA (1.63 mL, 5 equiv) in CH2Cl2-DMF (10 mL, 4:1, 3 equivalents) followed by addition of hydrazine (282 μL, 3 equiv). The reaction mixture was then diluted with ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the title compound (661 mg). MS (ESI): 333.08 (MH+)
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11]>C(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:7])([Cl:6])[C@@H:3]1[N:8]2[CH2:15][CH2:14][CH2:13][C@H:9]2[C:10](=[O:11])[O:4]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: OC(O)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1O[C@H](C(Cl)(Cl)Cl)N2CCC[C@@H]12
Yield: 72 %

Procedure:
Chloral hydrate (1.5 eq) was added to a solution of L-proline in CHCl3 (1 M), the suspension was refluxed (inverse Dean-Stark trap) for 6 h; the mixture was washed with water and the aq. phase re-extracted with CHCl3, the combined organic layers were dried and concentrated. Recrystallization (EtOH) of the residue afforded (3R,7aS)-3-(trichloromethyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one in 72% yield. This material was dissolved in dry THF (0.12M), 2M LDA (1.5 eq) was added at −78° C. and the mixture was stirred for 40 min; 60% benzyl chloromethyl ether (3 eq) was added and stirring was continued from −78 to 0° C. for 3 h; after quenching with water the mixture was extracted with CHCl3 (3×), dried over Na2SO4 and concentrated. Flash chromatography (PE:EtOAc 5:1) afforded the title compound which was used without further characterisation in the next reaction (48%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([OH:59])=[O:58])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:61][CH2:62][O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].Cl>CN(C)C=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([O:59][CH2:61][CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)=[O:58])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCOCc1ccccc1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(C(=O)O)cc3)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(C(=O)OCCOCc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A suspension of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-carboxybenzyl)-7-methyl-1H-indole (90 mg), benzyl 2-bromoethyl ether (37 mg), cesium carbonate (74 mg) and sodium iodide (3 mg) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 1 day. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-3/2) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-{4-[2-(benzyloxy)ethoxycarbonyl]benzyl}-7-methyl-1H-indole (0.10 g). This material was dissolved in a mixed solvent of methanol (2 mL) and tetra hydrofuran (2 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1-5/1) to give the title compound (42 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[SH:18].[C:19](O)(=[O:22])[CH:20]=[CH2:21]>>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:22])[CH2:20][CH2:21][S:18][C:3]=2[CH:4]=1)([OH:17])[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1S
Reactant: C=CC(=O)O
Product: O=C1CCSc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1

Procedure:
To 4-amino-3-mercapto[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzene is added acrylic acid. The reaction mixture can be heated in a nitrogen atmosphere until analysis by thin layer chromatography indicates the reaction to complete. The residual material can be chromatographed and recrystallized to give 2,3-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]1,5-benzothiazepin-4(5H)-one
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCc1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A mixture of ethyl 3-(4-cyanophenyl)propionate (6.00 g, 29.5 mmol), 2N-sodium hydroxide (30 ml, 60.0 mmol) and ethanol (60 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give 3-(4-cyanophenyl)propionic acid as colorless crystals (4.40 g, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 65 °C

Procedure:
To a solution of 3-benzyloxy-5-bromo-nitrobenzene (27.0 g, 87.60 mmol) in THF (800.0 mL) was added SnCl2.2H2O (99.0 g, 438.30 mmol) and the resulting reaction mixture was heated to reflux at 65° C. for 2 h. The reaction mass was then cooled to 0-5° C. and basified with a saturated solution of NaHCO3 till pH 8 and then extracted with EtOAc (3×1.0 L). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained (23.60 g, 95%) was carried forward to the next step without further purification.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][NH:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:31][CH:30]=1
Reactant: CN(C)CCNc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Product: CN(C)CCNc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-dimethylamino-ethylamino)-aniline.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:26])[C:10]([CH3:25])=[C:11]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:16]3)[O:12]2)=[CH:7][CH:6]=1)C=C.Cl.CN(C)[C:30]1[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:14]1[C:5]([OH:4])=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:24])[CH2:22][CH3:23])[CH2:17][CH2:16]1)=[C:10]([CH3:25])[C:9]2=[O:26])[CH:30]=[CH2:31]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc2c1
Agent: Cl
Product: C=CCc1c(O)ccc2c(=O)c(C)c(C3CCN(C(=O)CC)CC3)oc12
Temperature: 200 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 7-(allyloxy)-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (920 mg, 2.59 mmol) obtained in Example 31-3 in dimethylaniline (4 mL) was heated with stirring at 200° C. for 6 hours. A 1 N aqueous hydrochloric acid solution (100 mL) was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/0→95/5) to obtain 798 mg of the title compound (yield: 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]([F:39])([F:38])[CH2:36]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:36][C:35]([F:39])([F:38])[F:34]
Reactant: FC(F)(F)CI
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCC(F)(F)F)c2)n1
Temperature: 50 °C

Procedure:
A 0.3 g quantity of the N-[2-(3-hydroxy-4-methoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide obtained in Example 2 and 0.22 g of potassium carbonate were dissolved in 10 ml of dimethylformamide, and 0.34 g of 1,1,1-trifluoro-2-iodoethane was added thereto. The mixture was stirred with heating at 50° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.14 g of white powdery N-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-ylmethyl}-2-ethoxybenzamide.