Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[O-]Cl.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])CBr)=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].S([O-])([O-])(=[O:25])=S.[Na+].[Na+].Cl>O>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:16])=[O:25])=[CH:9][C:8]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCOc1cc(C(=O)CBr)ccc1O
Reactant: O=S([O-])([O-])=S
Agent: Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Product: CCCCCOc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.9 %

Procedure:
A solution of sodium hydroxide (680 mg), water (21ml) and antiformin (34 ml) was heated to 55° C. 1-(4-Hydroxy-3-pentyloxyphenyl)-2-bromoethanone (3.01 g, 0.01 mol, 1.0 eq) was added, and the mixture was stirred at 60° C.-70° C. for 40 minutes. An aqueous solution (10 ml) of sodium thiosulfate (1.2 g) was added, and the mixture was cooled to room temperature. Conc. hydrochloric acid (5 ml) was added to adjust the mixture to pH 5-6. Water (50 ml) was added to this reaction mixture, and the mixture was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with saturated brine (200 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate/acetic acid=2/1/0.01) to give 4-hydroxy-3-pentyloxybenzoic acid (1.24 g, 55.3%).
Reaction SMILES: CN(C)[C:3]1(OC)[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1.C(O)(C)C>C1C=CC=CC=1>[C:18]([C:17](=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8])[C:16]1[CH:20]=[CH:21][C:13]([Cl:12])=[CH:14][CH:15]=1)#[N:19]
Reactant: COC1(N(C)C)CCCN1C
Reactant: N#CCc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CN1CCCC1=C(C#N)c1ccc(Cl)cc1
Yield: 23.1 %

Procedure:
Stir 7.9 g of the title compound of Example 85 and 7.05 g of 4-chlorobenzylcyanide in 30 ml of benzene for 3 hours at 45°. Free the resulting reaction mixture from solvent by distillation to produce a dark-brown crystalline residue. Take up this residue with 10 ml of isopropanol and filter it to obtain 2.5 g of the title compound as yellowish crystals of m.p. 68° to 71°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][CH:28]=[O:29])[CH:4]=[N:3]1.[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].S([O-])(O)(=O)=O.[K+]>CN(C)C=O.[I-].[Na+]>[CH:28]([N:27]([CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Cn1ncc(NC=O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1ncc(N(C=O)CCCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a solution of N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]formamide (3.825 g) in N,N-dimethylformamide (66 ml) was added sodium hydride (264 mg, 60% oil suspension) under a nitrogen atmosphere at 0° C. under stirring. The mixture was stirred at 0° C. for 15 minutes. To the mixture were added tert-butyl N-(3-bromopropyl)carbamate (2.62 g) in N,N-dimethylformamide (10 ml) and sodium iodide (1.65 g). The mixture was warmed to room temperature and stirred for 2 hours. 10% Aqueous potassium hydrogen sulfate solution (5 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel eluting with methylene chloride/ethyl acetate (4:1) to give tert-butyl 3-{N-formyl-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}propylcarbamate (2.714 g). The NMR spectrum of this compound indicates the existence of its rotamer.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:13]O>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:13])=[O:9]
Reactant: CO
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(N)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
To a solution of saturated HCl in CH3OH (20 mL) at RT was slowly added 5-amino-2-hydroxybenzoic acid (2 g, 13.06 mmol). The resulting mixture was stirred at (RT, 16 h) and then heated (reflux, 24 h). The mixture was cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3. The organic solution was dried over MgSO4, filtered, concentrated under reduced pressure to afford methyl 5-amino-2-hydroxybenzoate as a pale yellow solid (1.72 g, 78.5%). Mass calculated for C8H9NO3=167.16; found: [M+H]+=168.2.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH:17]=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cc2ccccc2n1Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cc2ccccc2n1Cc1ccccc1
Yield: 42 %

Procedure:
This compound was produced by modifications of the methods used by Murakami, et. al. (Tetrahedron, 1997, 53, 1593-1606) starting with (1-benzyl-1H-indol-2-yl)-methanol (1.13 g, 4.76 mmol) and manganese dioxide (5.6 g). The crude material was purified by flash chromatography through silica gel using diethyl ether/hexanes (0/100 gradient to 10/90) to give 1-benzyl-1H-indole-2-carbaldehyde (0.47 g, 42%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 79.90 (s, 1H), 7.76 (d, 1H), 7.37 (s, 2H), 7.33 (s, 1H), 7.25-7.16 (m, 4H), 7.08 (d, 2H), 5.83 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][C:19]=3[O:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=3[O:28][CH3:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 80 °C

Procedure:
An amount of 830 mg (2.01 mmol) of the compound from Example 20A was dissolved in 10 ml of tetrahydrofuran/methanol (1:1) and admixed with 2 ml of a 2 N sodium hydroxide solution (4.01 mmol). The mixture was stirred at 80° C. for an hour. The reaction solution was diluted with 10 ml of water and extracted with twice 15 ml of ethyl acetate. The combined organic phases did not contain a product and were discarded. The aqueous product phase was acidified with 1 N hydrochloric acid and the resulting precipitate was isolated by filtration. The solid was dried in a high vacuum. Since the mother liquor still contained a large amount of product, it was concentrated completely on a rotary evaporator. This gave, all in all, 747 mg (93% of theory) of the target compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2.Cl.Cl.[CH3:35][O:36]C(=O)C(N)CC1C=C2C(=CC=1)C(N)=NC=C2.COC1C=C2C(C=CC(S(Cl)(=O)=O)=C2)=CC=1>>[CH3:2][O:3][C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([O:36][CH3:35])=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2
Reactant: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Agent: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Agent: Cl
Product: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccc(OC)cc2c1

Procedure:
Using the procedure described for 11a, the reaction of methyl ester 1j and sulfonyl chloride 12a gave 3-(1-amino-6-isoquinolinyl)-2-[[(7-methoxy-2-naphthalenyl)sulfonyl)amino]propionic acid methyl ester. This ester was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for the previous example to give the title compound 12b. 1H-NMR 200 MHz (CD3OD) δ: 0.18-0.85 (5H, m), 1.22-1.58 (3H, m), 1.78-3.18 (4H, m), 3.80-4.26 (2H, m), 3.88 (3H, s), 4.57-4.72 (1H, m), 6.97-7.04 (1H, m), 7.20-7.79 (8H, m) 8.01-8.14 (2H, m).
Reaction SMILES: C(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].N1CCOCC1.C(O)C.[CH3:16][O:17][C:18]([C:20]1[C:24](=O)O[C:22]2=[CH:26][CH:27]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:29]=[CH:30][C:21]=12)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)=[C:2]([CH:3]([CH3:5])[CH3:4])[CH:24]=1)=[O:19]
Reactant: CC(C)CC=O
Reactant: COC(=O)c1c2ccc(C(C)C)ccc-2oc1=O
Solvent: C1COCCN1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(C)C)c2ccc(C(C)C)ccc1-2

Procedure:
Isovaleraldehyde (5.16 g) and morpholine (4.36 g) are added to ethanol (14 ml) and then 3-methoxycarbonyl-6-isopropyl-2H-cyclohepta[b]furan-2-one (5) (2.46 g) is added thereto. The obtained mixture is heated under reflux for 16 hours, and then the solvent is distilled off under reduced pressure to give an oily material. The obtained oily material is dissolved in toluene (20 ml), washed twice with water (20 ml) and 4 times with 1N HCl (20 ml), and further, twice with water (40 ml). The obtained toluene layer is passed through silica gel column (1.05 kg), the column is eluted with toluene. From the eluted parts including the product (24), the solvent is distilled off under reduced pressure to give the compound (24) as a purple oily material in a yield of 2.08 g, 76.%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])#[C-:11]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C@@H:6]2[O:7][CH:11]=[N:10][C@H:12]2[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[O:14])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: [C-]#[N+]CC(=O)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
SLA 09052A was prepared in accordance with method D using thiophene-3-carbaldehyde (0.768 mL, 5.35 mmol), KOH (0.273 mg, 4.86 mmol) in methanol (5 mL) and 2-isocyano-1-morpholinoethanone SLA 07118 (0.75 g, 4.86 mmol). The solution was stirred for 2 h at 0° C. After work-up the residue was purified by column chromatography (florisil, EtOAc). After evaporation and drying, trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(morpholino)methanone SLA 09052A (0.327 g, 25% yield) was obtained as a yellow oil.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH2:10][C:11]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])(O)[N:12]=2)[C:8]=1[CH3:9]>C(O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:10]=[C:11]([C:14]([F:19])([F:20])[C:15]([F:18])([F:17])[F:16])[N:12]=2)[C:8]=1[CH3:9]
Reactant: CC1=C(Br)C=CC2=NC(O)(C(F)(F)C(F)(F)F)CN21
Agent: Br
Solvent: CCO
Product: Cc1c(Br)ccc2nc(C(F)(F)C(F)(F)F)cn12
Yield: 96.1 %

Procedure:
A mixture of 3.95 g of 6-bromo-5-methyl-2-pentafluoroethyl-2,3-dihydroimidazo[1,2-a]pyridin-2-ol hydrobromide and 20 ml of ethanol was stirred under heat-reflux for 1 day. The cooled reaction mixture was concentrated under reduced pressure, then water and a saturated aqueous sodium bicarbonate solution were added, and the precipitated solid was taken by filtration. The resulting solid was dried to obtain 2.92 g of 6-bromo-5-methyl-2-pentafluoroethylimidazo[1,2-a]pyridine.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:52])[CH2:10][CH2:11][S:12][CH2:13][CH:14]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH2:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:35]([O:34][CH:14]([CH2:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:13][S:12][CH2:11][CH2:10][C:9]([OH:52])=[O:8])(=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)OCc1ccc(OC)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid p-methoxybenzyl ester as obtained in Reference Example 3 (1.17 g), a solution of anisole (0.33 ml) in trifiuoroacetic acid (3.3 ml) was added at room temperature, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was washed with hexane to yield the title compound (643 mg, yield 65%) as a powder.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1>[O-2].[O-2].[Mn+4].O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([C:10]([CH3:11])=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(C)=O)n1Cc1ccccc1Cl
Reaction time: 17 h
Yield: 59.2 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole (1.07 g, 3.65 mmol), activated manganese dioxide (6 g) and toluene (75 mL) was heated at 90° to 100° C. under a slight vacuum with a Dean Stark water separator for 17 hours. The inorganics were filtered, the concentrated filtrate was applied to a flash silica gel column and the product was eluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.
Reaction SMILES: [Li+].[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([CH2:16][C:17]([O-:19])=O)([OH:15])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]([O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)[CH2:21][CH2:22][CH3:23].P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([O:24][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:17](=[O:19])[CH2:16][C:12]2([OH:15])[CH2:11][CH2:10][N:9]([CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:14][CH2:13]2)=[CH:30][CH:31]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=C([O-])CC1(O)CCN(Cc2ccccc2)CC1
Reactant: CCCCOc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCOc1ccc(NC(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of (1-benzyl-4-hydroxypiperidin-4-yl) acetic acid lithium salt (3.09 g) in methylene chloride (60 mL) were added 4-n-butoxyaniline (2.0 g) and pyridine (2.14 mL). Phosphorous oxychloride (1.19 mL) was added dropwise to the solution under cooling with an ice-sodium chloride, followed by stirring at 5 to 10° C. for 1 hour. The mixture was made alkaline with saturated aqueous sodium bicarbonate under cooling with an ice-water, and the solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography (elution solvent; methylene chloride:methanol=19:1 to 9:1) to obtain the titled compound (1.15 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][C:19](=O)[CH2:18][C@H:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([SH:25])[CH2:23][SH:24]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][C:19]2([S:25][CH2:22][CH2:23][S:24]2)[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Reactant: SCCS
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2

Procedure:
As described in Example 23, react 1-benzyloxycarbonyl-4-keto-(S)-proline, ethyl ester (prepared from the acid by esterification in ethanol) with 1,2-ethanedithiol to obtain 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro [4.4]nonane-8(S)carboxylic acid, ethyl ester, a yellow oil [α]D26 -21.0° (ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19]([NH:21]CC3C=CC(OC)=CC=3)=[O:20])[CH2:17][CH2:16]2)[C:12](=[O:31])[NH:11][C:10](=[O:32])[C:9]=1[CH:33]([CH3:35])[CH3:34])=[O:7])#[N:2].O>C(#N)C.C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19]([NH2:21])=[O:20])[CH2:16][CH2:17]2)[C:12](=[O:31])[NH:11][C:10](=[O:32])[C:9]=1[CH:33]([CH3:35])[CH3:34])=[O:7])#[N:2]
Reactant: COc1ccc(CNC(=O)CC2(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)CC2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2(CC(N)=O)CC2)c1
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
To a stirred solution of 2-{1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-N-(4-methoxy-benzyl)-acetamide (97 mg, 0.18 mmol) in acetonitrile (4 mL) and glacial acetic acid (1 mL) at room temperature, were added ceric ammonium nitrate (201 mg, 0.36 mmol) and water (2 mL) in this order. After stirring for 20 min., the mixture was diluted with ethyl acetate, washed with water twice, dried with MgSO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, from ethyl acetate to 10% methanol in ethyl acetate) to give 59 mg (78%) of 2-{1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetamide (85) as a white solid. m.p. 283-285° C.; 1H-NMR (500 MHz, DMSO-d6) δ 0.20-0.27 (2H, m), 0.31-0.36 (1H, m), 0.43-0.47 (1H, m), 0.99 (3H, d, J=6.8 Hz), 1.08 (3H, d, J=6.8 Hz), 2.02-2.13 (2H, m), 2.17 (1H, d, J=16.5 Hz), 2.44 (3H, s), 3.32 (1H, d, J=15.1 Hz), 3.39-3.41 (1H, m), 3.46-3.51 (1H, m), 3.79 (1H, d, J=15.1 Hz), 8.08 (1H, s), 8.19 (1H, s), 8.42 (1H, s), 11.45 (1H, s); m/z (EI) 408 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:28])[CH3:27])[C@H:21]1[CH3:29].[N:30]1(C(N2C=CN=C2)=O)C=CN=C1.N.O>CN(C)C=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([NH2:30])=[O:16])=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:27])[CH3:28])[C@H:21]1[CH3:29]
Reactant: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(N)=O
Yield: 29.2 %

Procedure:
2-({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyric acid (48 mg, 0.113 mmol) in N,N-dimethylformamide (2 mL) was stirred with di-1H-imidazolylmethanone (55 mg, 0.340 mmol) at room temperature for 2 days and then with 30% aqueous ammonia (0.2 mL) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (14 mg, 29% yield).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C@@H:11]2[O:12][CH2:13][CH2:14][C@H:10]2[C:9](=[O:15])[CH2:8]1.O.[OH-].[Na+]>C1COCC1>[O:7]1[C@@H:11]2[O:12][CH2:13][CH2:14][C@@H:10]2[C@H:9]([OH:15])[CH2:8]1
Reactant: O=C1CO[C@@H]2OCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O[C@@H]1CO[C@@H]2OCC[C@@H]21
Reaction time: 1 h
Yield: 87.7 %

Procedure:
To a suspension of lithium aluminum hydride (15 mg) dispersed in THF (0.2 mL) was added dropwise a solution of (3aR,6aS)-hekahydrofuro[2,3-b]furan-3-on (64 mg) obtained in Example 28 in THF (0.5 mL) at 0° C. and the mixture was stirred for 1 hr. Water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were successively added to the reaction mixture every 30 min and the mixture was filtered and washed well with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated to give the title compound (57 mg, 88% ee) as an oil, which was an almost pure anti-form. The spectrum data were the same as those in Example 27.
Reaction SMILES: [CH:1]12[NH:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19]([N:7]1[CH:6]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:20]
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: C1CCC2NC2C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1c(F)cc(C(=O)N2C3CCCCC32)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
A mixture of 1.45 g of 7-azabicyclo[4.1.0]heptane, 2 ml of triethylamine and 3 ml of ethyl acetate was added dropwise to a mixture of 10 ml of ethyl acetate and 2.3 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid chloride under ice-cooling. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.8 g of 7-[3,5-difluoro-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane represented by the formula:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1>>[C:23]1([C:20]2[CH:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[O:22][N:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCc1cc(-c2ccccc2)no1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2cc(-c3ccccc3)no2)c1C(F)(F)F

Procedure:
Synthesized in a manner similar to Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: MS (ES) m/z 368 (M+1).