Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[C:15](OC)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.[H-].[Na+].C(O)(=O)C>O1CCOCC1.O>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:1]([CH2:2][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)=[O:3]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: COC(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(O)c(C(=O)CC(=O)c2cccnc2)c1
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A solution consisting of methyl 3-acetyl-4-hydroxy-benzoate (16 g) and methyl nicotinate (23 g) in dioxane (100 ml) was slowly added at room temperature under stirring to a suspension of sodium hydride 50% (12 g) in dioxane (60 ml). The solution was kept for 6 hours at 80° C., then cooled, diluted with petroleum ether (200 ml), and filtered. The product obtained was dissolved in water and treated with acetic acid; the precipitate obtained was washed with water and crystallised with methylene chloride/methanol to give (2-hydroxy-5-carbomethoxy-benzoyl)-nicotinoylmethane (17.2 g; m.p. 200°-202° C.) which was then treated with ethanol (300 ml) containing concentrated hydrochloric acid 1% at reflux temperature for 2 hours. After concentration under vacuum, dilution with water, neutralisation with sodium acetate, the precipitate was filtered. The raw 6-carbomethoxy-2-(3'-pyridyl)-chromone (15.1 g) was hydrolysed with the stoichiometric quantity of potassium hydroxide 1% in ethanol 95% at reflux temperature for an hour. After cooling, dilution with water (600 ml), neutralisation with acetic acid, the precipitate was collected, to obtain, after crystallisation from dimethylformamide, 6-carboxy-2-(3'-pyridyl)-chromone (9.8 g; m.p.> 350° C.); I.R. (KBr): νC=O (carboxy) 1680 cm-1, νC=O (chromone) 1630 cm-1, 1610 cm-1, γC-H (meta-substituted pyridine) 770 cm-1, 696 cm-1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[C:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.C1COCC1>[C:28]1([NH:38][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:3])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: Nc1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 18.7 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]-pyrimidine (0.0376 mmol) and 1-naphthylamine (0.169 mmol) were mixed in CH2Cl2 (2 mL) and then triethylamine (0.187 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.172 mmol), and 4-dimethylaminopyridine (˜1 mg) were added in that order. Poor overall solubility was observed so THF (1 mL) was then added to the mixture, which became more homogeneous. The mixture was stirred at room temperature for 22 h then concentrated under reduced pressure. Purified by silica gel chromatography (1-2% MeOH in CH2Cl2) to yield 3.4 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.49 (br s, 1H); 8.41 (d, J=5.5 Hz, 1H); 8.17 (br s, 1H); 8.12 (br s, 1H); 8.02 (br s, 1H); 7.85-7.92 (m, 3H); 7.81 (m, 1H); 7.77 (d, J=8.2 Hz, 1H); 7.69 (d, J=7.5 Hz, 1H); 7.51-7.58 (m, 4H); 7.33 (br s, 2H); 6.82 (d, J=5.5 Hz, 1H); 5.78 (br s, 1H); 5.32 (br s, 1H); 1.71 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 485.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH:32]1(O)[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([O:18][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A solution of N-benzyloxycarbonyl-L-isoleucine (10.0 g, 37.7 mmol) in DCM (150 mL) was treated with N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (7.94 g, 41.5 mmol), cyclopentanol (3.90 g, 45.2 mmol) and N,N-dimethylaminopyridine (20 mg). The reaction was allowed to stand at room temperature for 18 hours. The reaction mixture was washed with 1M hydrochloric acid, saturated sodium bicarbonate, and brine before drying over magnesium sulphate, filtration and removal of solvent under reduced pressure to leave N-benzyloxycarbonyl-L-isoleucine cyclopentyl ester as a colorless oil (10.99 g, 87%). 1H-NMR; δ (CDCl3) 7.44-7.30 (5H, m), 5.37-5.34 (1H, m), 5.22-5.18 (1H, m), 5.11 (2H, s), 4.33-4.27 (1H, m), 1.90-1.55 (10H, m), 1.51-135 (1H, m), 1.28-1.20 (2H, m), 0.93 (3H, d, J 6.9 Hz) and 0.91 (3H, d, J=7.0 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[CH:8]=2)[CH2:3]1.[CH:17](OCC)=[O:18]>C(Cl)(Cl)Cl>[CH:17]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[CH:8]=2)[CH2:3]1)=[O:18]
Reactant: CN(C)C(=O)Sc1ccc2c(c1)CC(N)C2
Reactant: CCOC=O
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Sc1ccc2c(c1)CC(NC=O)C2
Temperature: 55 °C
Yield: 35 %

Procedure:
To dimethylthiocarbamic acid-S-[2-aminoindan-5-yl) ester (2.0 g; 8.46 mmol) in CHCl3 (10 mL) is added ethyl formate (50 mL) and the reaction heated at 55° C. for 24 h. The reaction is cooled, the solvent removed under reduced pressure, and the crude oil purified by flash chromatography (SiO2) eluting with an ethyl acetate-methanol gradient to afford 0.77 g (35%) of dimethylthiocarbamic acid-S-(2-formylaminoindan-5-yl)ester as a white solid.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:45])[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9][C:8]=1[CH2:17][C@H:18]([OH:44])[C@H:19]([N:29](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])([CH3:4])([CH3:3])[CH3:2].[NH4+].C([O-])=O>CO.O.[Pd]>[NH2:29][C@H:19]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[F:28])[C@@H:18]([OH:44])[CH2:17][C:8]1[N:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=[CH:12][C:7]=1[C:6]([NH:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:45]
Reactant: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)nc1C[C@H](O)[C@@H](Cc1cc(F)ccc1F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)(C)NC(=O)c1ccc(C(F)(F)F)nc1C[C@H](O)[C@H](N)Cc1cc(F)ccc1F
Temperature: 40 °C

Procedure:
To 10% Pd/C (0.94 g, 0.44 mmoles) in MeOH (40 mL) is added N-tert-Butyl-2-[(2S,3R)-3-dibenzylamino-4-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-6-trifluoromethyl-nicotinamide (5.89 g, 9.42 mmoles) rinsed in with 19 mL of MeOH. To the reaction is added a solution of Formic Acid, Ammonium Salt (2.35 g, 37.4 mmol) in water 6.0 mL and heated to 40° C. for 20 minutes. The reaction is allowed to cool, the catalyst filtered, washed with MeOH and the organics concentrated under reduced pressure. The concentrate is taken up in MTBE and water to which is added NH4OH (pH˜10) and the aqueous layer extracted with MTBE. The organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH3:13][N:14]=[C:15]=S.C(Cl)CCl>N1C=CC=CC=1>[CH3:13][NH:14][C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: CN=C=S
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CNc1nc2cc([N+](=O)[O-])ccc2n1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
A solution of diamine 248 (1.88 g, 11.2 mmol) in pyridine (20 mL) was treated with methyl isothiocyanate (970 mg, 12.9 mmol) and the mixture was stirred at 80° C. for 30 minutes, cooled down to 15° C., treated with solid EDC (3.03 g, 15.8 mmol, 1.40 eq) and the heating continued at 80° C. for 16 h. After removal of pyridine in vacuo, the residue was purified by flash chromatography (eluent 5% MeOH in CH2Cl2) to afford the title compound 268 (1.44 g, 62% yield). 1H NMR: (CD3OD) δ (ppm): 8.12 (d, J=2.2 Hz, 1H), 7.94 (dd, J=2.2, 8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.44 (bs, 2H), 3.51 (s, 3H), 3.04 (s, 3H). LRMS: (calc.) 206.2; (obt.) 207.1 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Yield: 57.3 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (0.11 g, 0.39 mmol) was dissolved in 10 mL of DMF. Glycine (0.58 g, 7.75 mmol) and sodium ethoxide (0.40 g, 5.81 mmol) were added and the mixture was refluxed for 14 h. The mixture was cooled to room temperature and diluted with 60 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 70 mg of the title compound. MS: (+) m/z 314.00 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:10]([O:23][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCO
Reactant: C(OCC1CO1)C1CO1
Product: CCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of tridecanol.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8](Cl)[N:7]=[CH:6][N:5]=2.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1>C(O)C>[Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]3[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[NH:15][C:14]3=[O:13])[CH2:24][CH2:23]1)[N:7]=[CH:6][N:5]=2
Reactant: Cn1c(Br)nc2c(Cl)ncnc21
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCO
Product: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 74 %

Procedure:
8-bromo-6-chloro-9-methyl-9H-purine (175 mg, 0.71 mmol) was combined with 4-(2-keto-1-benzimidazolinyl)piperidine (185 mg, 0.85 mmol) and dissolved in ethanol (2 mL). The resulting solution was warmed to 100° C. in a sealed tube for 15 minutes. A precipitate formed which was collected and washed with ethanol. An amount of 225 mg of a tan solid was isolated, which was 80% pure an indicated by LCMS analysis. A portion of this material was purified by prep HPLC to provide 6 mg of a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.21 (s, 1H), 7.14-7.00 (m, 1H), 6.88 (m, 3H), 5.38 (s, 2H), 4.48 (m, 1H), 3.62 (s, 3H), 3.13 (s, 2H), 2.25 (m, 2H), 1.78 (m, 2H). EI (MS) for C18H18BrN7O, found 428.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:17]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]([CH2:9][OH:17])=[N:6][CH:7]=1
Reactant: Cc1c(OC(C)C)cc(Br)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Br)cnc1CO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-3-isopropoxy-2-methyl-pyridine 1-oxide (Stage 190.1.3, 2.054 mmol) in THF (13 ml) was added trifluoroacetic anhydride (10.27 mmol). The RM was stirred for 4 h at rt. The RM was evaporated to dryness. The residue was treated with saturated aqueous NaHCO3 (20 ml), stirred for 15 h at it and then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in DMA and purified by preparative HPLC. The fractions containing the product are basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give a yellowish slowly crystallizing solid. (HPLC: tR 2.21 min (Method A); M+H=246, 248 MS-ES).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C([Li])CCC.[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30](=[O:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:12]([O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH:24]([CH:27]3[CH2:32][O:31][C:30]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([OH:33])[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[C:17]([F:36])[C:16]=1[F:37])[CH3:13]
Reactant: CCOc1ccc(OCC2CCC(C3CCC(=O)OC3)CC2)c(F)c1F
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(OCC2CCC(C3CCC(O)(C#C[Si](C)(C)C)OC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
2.55 g of trimethylsilylacetylene was dissolved in 20 mL THF, and then 15.7 mL of a 1.66 M hexane solution of n-butyllithium was added dropwise thereto at −70° C., followed by stirring at that temperature for 1 hour. To the resulting solution, a solution containing 9.12 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one obtained in the twelfth step of Example 1 dissolved in 30 mL of THF was added dropwise at −70° C., followed by stirring at that temperature for 1 hour, and then the temperature of the solution was gradually increased to room temperature. The reaction product was poured into 50 mL of a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and concentrated under reduced pressure. The resulting brown residue was purified by silica gel column chromatography to provide 10.7 g of 5-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]-2-trimethylsilanylethynyltetrahydropyran-2-ol as a brown solid.
Reaction SMILES: C1(C[O:8][C:9]([CH2:11][CH2:12][C:13]2[CH:31]=[CH:30][C:16]([O:17][CH2:18][C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:15][CH:14]=2)=[O:10])C=CC=CC=1.C(O)(=O)C.[H][H]>CC(C)=O.[Pd]>[C:9]([CH2:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][CH2:18][C:19](=[O:29])[CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([OH:10])=[O:8]
Reactant: O=C(COc1ccc(Cl)cc1)COc1ccc(CCC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: O=C(O)CCc1ccc(OCC(=O)COc2ccc(Cl)cc2)cc1

Procedure:
A solution of 44.0 g (0.1 mol) 3-[4'-(2-phenylmethoxycarbonylethyl)-phenoxy]-1-(4'-chlorophenoxy)-propane-2-on in 1000 ml acetone is mixed with 1 ml acetic acid and, after the addition of 8 g (10%) palladium/carbon, hydrogenated until the calculated amount of hydrogen is absorbed. After the catalyst is separated, the filtrate is concentrated in vacuo, the residue is absorbed in chloroform and the acid is precipitated through addition of petrol ether. Colorless crystals, melting point 114°-5° C. (trichloroethylene): yield 24.20 g (69.4%).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1>>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=3)[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: COC(=O)CCc1ccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)cc1

Procedure:
Reaction of 2-bromomethyl-4,5-diphenyloxazole and methyl 3-(4-hydroxyphenyl)propanoate according to the procedure of Example 17 provided the title compound, m.p. 92°-95° C.
Reaction SMILES: C1(C([O:9]C(C2C=CC=CC=2)=[Se])=[Se])C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([OH:29])=[CH:24][CH:23]=[CH:22]2>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24](=[O:9])[CH:23]=[CH:22]2
Reactant: [Se]=C(OC(=[Se])c1ccccc1)c1ccccc1
Reactant: Oc1cccc2cc(Cl)ccc12
Solvent: C1CCOC1
Product: O=C1C=Cc2cc(Cl)ccc2C1=O
Temperature: 70 °C
Yield: 82.2 %

Procedure:
To a solution of benzeneselenic anhydride (3.18 g, 8.8 mmol) in tetrahydrofuran (30 ml), which had been heated to 70° C. was added a solution of 6-chloro-1-naphthol (1.5 g, 8.4 mmol) in tetrahydrofuran (5 ml). The reaction was maintained at 70° C. for 15 minutes. The mixture was then concentrated under reduced pressure. The residue was suspended in hexanes (100 ml) and filtered. This was repeated 5 times. The residue was dissolved in dichloromethane (100 ml), filtered and concentrated under reduced pressure to afford the product as an orange solid (1.33 g, 82%); 400 MHz 1H NMR (CDCl3) δ: 8.06 (d, J=8.4 Hz, 1H), 7.49 (dd, J=2 and 8.4 Hz, 1H), 7.41-7.38 (m, 2H), 6.50 (d, J=10 Hz, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36]C(=O)C)[C@@H:28]([O:29]C(=O)C)[C@H:23]([O:24]C(=O)C)[C@H:18]3[O:19]C(=O)C)=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:46](I)[CH:47]=[CH2:48].[OH-].[Na+]>C(#N)C.O.CO>[CH2:48]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:11]([O:16][C@@H:17]2[O:34][C@H:33]([CH2:35][OH:36])[C@@H:28]([OH:29])[C@H:23]([OH:24])[C@H:18]2[OH:19])=[N:12]1)[CH:47]=[CH2:46]
Reactant: CCc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: C=CCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(CC)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-[(4-ethylphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.030 g) and cesium carbonate (0.036 g) in acetonitrile (0.4 mL) was added allyl iodide (0.010 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added methanol (0.4 mL) and 1 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 1-allyl-4-[(4-ethylphenyl)methyl]-3-(β-D-glucopyranosyloxy)-5-methyl-1H-pyrazole (0.018 g).
Reaction SMILES: O.C1(C)C=CC(C([C@](C(O)=O)(O)[C@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH2:30]([N:33]1[C:37]([CH2:38][S@@:39]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]>C(OCC)(=O)C>[CH2:30]([N:33]1[C:37]([CH2:38][S:39]([C:41]2[CH:42]=[CH:43][C:44]([NH2:45])=[CH:46][CH:47]=2)=[O:40])=[CH:36][N:35]=[CH:34]1)[CH2:31][CH3:32]
Reactant: CCCn1cncc1C[S@](=O)c1ccc(N)cc1
Agent: Cc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCn1cncc1CS(=O)c1ccc(N)cc1

Procedure:
(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartrate monohydrate (479 mg) was dissolved in ethyl acetate (5 ml) and 1 N hydrochloric acid (2.44 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (2.44 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) twice. The organic layers were combined, washed with saturated brine and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the resulting residue was added tetrahydrofuran, and then the solvent was again distilled off under reduced pressure-to give (S)-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylic acid (250 mg) in dichloromethane (10 ml) were added a drop of DMF, and then oxalyl chloride (0.063 ml) at 0° C. The mixture was returned to room temperature and stirred for 30 minutes under a nitrogen atmosphere, and then the resulting solution was added dropwise to a solution of (S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (1.16 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. The mixture was returned to room temperature and stirred overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water twice and saturated brine once, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the residue was separated and purified by basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=3:100) to give (S)-3-[4-(2-butoxyethoxy)phenyl]-10-isobutyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxamide (294 mg) (Compound 1) as a yellow amorphous material.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][CH2:35][S:36][CH3:37])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:38]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][CH2:35][S:36][CH3:37])=[O:39])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-L-methionine (75 mg, 0.3 mmol). The final product was triturated with ether to yield 170 mg (96%) of the desired material.