Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([OH:23])[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2].N1C=CN=C1.[Si:29](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>ClCCl>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([O:23][Si:29]([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O)C4)[C@H]3CC[C@]12C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.9 %

Procedure:
To a solution of the alcohols 10 (1.08 g, 3.42 mmol) in dichloromethane (20 mL) was added imidazole (1.6 eq, 0.37 g, 5.43 mmol) followed by tert-butyldiphenylsilylchloride (1.6 eq, 1.42 mL, 3.64 mmol). The mixture was stirred 16 h at room temperature under nitrogen then poured into 1N HCl (100 mL). The layers were separated and the aqueous layer was extracted with ether (3×50 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give an oil (2.2 g), Rf 0.55 (10% EtOAc/hexane), which was used without further purification.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([O:4][N:5]=[C:6]([C:12]2[N:13]=[C:14]([NH:17][CH:18]=[O:19])[S:15][CH:16]=2)[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=NOC1CC1)c1csc(NC=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Temperature: 0 °C
Yield: 78 %

Procedure:
To a suspension of ethyl 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetate (syn isomer)(9.92 g) in methanol (99.2 ml) was dropwise added 2N aqueous solution of sodium hydroxide (122 ml) below 10° C. The mixture was stirred under ice-cooling for 4 hours. The mixture was poured into ice-water, washed with ethyl acetate, adjusted to pH 2 with 6N hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with petroleum ether to give 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer)(6.97 g).
Reaction SMILES: C[OH:2].N12CCCN=C1CCCCC2.[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C[CH:21]([OH:23])[CH3:22]>>[C:16]1([C@H:21]([OH:23])[CH2:22][OH:2])[CH:15]=[CH:14][CH:19]=[CH:18][CH:17]=1
Reactant: CCCCCC
Reactant: CO
Reactant: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: OC[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 5 h

Procedure:
To a 100 mL autoclave with a stirrer, 2-hydroxyacetophenone (340 mg, 2.5 mmol) and RuCl[(S)-xylbinap][(S)-daipen] obtained from the Example 1 above (1.5 mg, 0.00125 mol, 1/2,000 molar fold of 2-hydroxyacetophenone) were added. After purging with nitrogen, methanol (1.25 mL) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (1.9 mg, 0.0125 mmol) were added. Subsequently, purging with hydrogen, the mixture was stirred at 30° C. for 5 hours under hydrogen pressure of 1 MPa. As a result of analysis of the reaction solution by using gas chromatography (HP-1), the conversion rate was found to be 99% or more. The optical purity was measured by high performance liquid chromatography (CHIRALPAK AS-H, eluent; hexane:2-propanol=92:8), and it was found to be 94% ee.
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[NH:16][C:17]([NH:19][O:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:23])=[O:18])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:29]([C@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22](=[O:23])[CH2:21][O:20][NH:19][C:17](=[O:18])[NH:16][N:12]1[CH2:13][CH2:14][CH2:15][CH:11]1[C:9]([OH:10])=[O:8])([OH:31])=[O:30]
Reactant: O=C(NOCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)NN1CCCC1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NOCC(=O)N1CCC[C@@H]1C(=O)O)NN1CCCC1C(=O)O

Procedure:
0.14 g (0.36 mmol) (R)-1-[[3-[2-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-ureido]-pyrrolidine-2-carboxylic acid benzyl ester in 60 ml ethanol were hydrogenated in the presence of 40 mg 5% Pd on carbon. Filtration, evaporation of the solvent and crystallization from methanol/ethylacetate yielded 0.07 g (52%) as white crystals with melting point 157-160° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O.CC(O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[O-:13].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: [O-]c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a flask were added 1.0 g 3,5-bis(trifluoromethyl)phenol, 1.8 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 10 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 10 ml of 2-propanol were added and removed by distillation under reduced pressure. An oil was obtained which crystallized on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[NH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:13]=2)=[C:4]([F:19])[CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:18])[N:10]([CH3:20])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:13]=2)=[C:4]([F:19])[CH:3]=1
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.5 %

Procedure:
First, 2.93 g of 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1005) was dissolved in 15 ml of N,N-dimethylformamide, to which 2.07 g of potassium carbonate and 1.25 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=6:1), which afforded 1.98 g (yield, 65%) of 3-(4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-11; m.p., 83.2° C.).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:5](OCC)=[O:6].[CH3:17][C:18]([CH3:30])([CH3:29])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][NH2:28])=[N:25][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:17][C:18]([CH3:30])([CH3:29])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:5](=[O:6])[C:4]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][NH:28]2)=[N:25][CH:26]=1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
220 mg (1.0 mmol) of the compound from Example 2A are initially charged in 5 ml of ethanol. 260 mg (purity 75%, 1.0 mmol) of the compound from Example 19A and 38 mg (0.2 mmol) of p-toluenesulfonic acid are added, and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, and the solid formed is filtered off, washed with tert-butyl methyl ether and dried under high vacuum. This gives 37 mg of the title compound. The mother liquor is put aside and used for preparing the hydrochloride (see Example 89).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=O.O.C1(C)C=CC=CC=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CCC(C=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC1CCC(C(=O)OC)CC1
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a mixture of 25.2 g (70.5 mmol) of methyltriphenylphosphonium bromide with 125 ml of tetrahydrofuran (THF) was added 7.9 g (70.5 mmol) of potassium-tert-butoxide (t-BuOK) while being kept at a temperature lower than −20° C. and stirred at the same temperature for 1 hour. Then, 50 ml of solution of 10.0 g (58.8 mmol) of methyl 4-formylcyclohexanecarboxylate in THF was added dropwise to the reaction solution while being kept at a temperature lower than −20° C. and stirred at the same temperature for 2 hours. After finishing of the reaction, 50 ml of water was added to the reaction mixture and then the product was extracted with 200 ml of toluene. The organic layer thus obtained was washed with water thrice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (eluent: toluene) to obtain 6.8 g of a crude methyl 4-vinylcyclohexanecarboxylate.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1C=CC=CC=1.[Li].CC(C)([O-])C.[K+].C1(C2C=CC=CC=2)C=CC=CC=1.[C:33](=[O:35])=[O:34]>C1COCC1>[C:33]([OH:35])(=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: ClC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(O)c1ccccc1
Yield: 79 %

Procedure:
A mixture of 0.2 mol of chlorocyclohexane and 0.2 mol of benzene is added dropwise to a suspension of 0.4 mol of lithium granules, 0.21 mol of potassium tert-butoxide and 35 mg of biphenyl in 300 g of THF at −72° C. After a conversion of the chlorocyclohexane of >97% determined by means of GC (total of 24 h), carbon dioxide is passed in until saturation is achieved. The work-up is carried out by a method analogous to that in example 3; benzoic acid is obtained in a yield of 79%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][C:30]([NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:31])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCNC(=O)Cn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 11.1 %

Procedure:
[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetic acid (149.3 mg) was dissolved in N,N-dimethylformamide (1.6 mL), 2-(methylsulfonyl)ethanamine (60.3 mg), 1H-1,2,3-benzotriazol-1-ol (67.8 mg), triethylamine (0.15 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (93.0 mg) were added, and the mixture was stirred at room temperature for 17 hrs. Moreover, 2-(methylsulfonyl)ethanamine (120.6 mg), 1H-1,2,3-benzotriazol-1-ol (134.6 mg), triethylamine (0.3 mL) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (181.4 mg) were added, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→90:10), and basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67→0:100→ethyl acetate:methanol=90:10) to give the title compound (20.3 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16](O)=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.COC(Cl)=O.Cl>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][OH:17])[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CO)CC1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of trans-4-(tert-butoxycarbonylamino-methyl)-cyclohexanecarboxylic acid (obtained according to: EP 0614 911 A1) (34.5 g) and triethylamine (28 ml) in dichloromethane (700 ml) is cooled to −70° C. and treated with methylchloroformate (12.9 ml). The reaction mixture is stirred 0.5 h at −70° C. The temperature is allowed to increase to 0° C. and the solution is stirred another 0.5 h until completion of the reaction. The reaction mixture is taken up in ice-cold dichloromethane, washed with an ice-cold 0.5 N HCl solution, a saturated aqueous sodium carbonate solution and water. The organics are dried over sodium sulfate and concentrated to 41.3 g of mixt-anhydride as an oil. This material is taken up in THF and treated at −70° C. with sodium borohydride (5.90 g), followed by absolute methanol (10 ml). The reaction mixture is stirred 15 h at 0° C. and 1 h at ambient temperature to drive the reaction to completion. A 0.5N HCl solution is then carefully added at 0° C., followed by ethyl acetate. The organics are washed with a saturated aqueous sodium carbonate solution, water, dried over sodium sulfate and concentrated. Chromatography on silica gel (A1) yields trans-(4-hydroxymethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white powder, melting at 88-89° C. Rf (A1) 0.24.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[Si:5]([O:12][C@@H:13]1[CH2:17][C:16](=[O:18])[CH:15]=[CH:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]>CO>[Si:5]([O:12][CH:13]1[CH:17]2[C@@H:16]([O:18]2)[C:15](=[O:1])[CH2:14]1)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)[C@@H]2OC12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Hydrogen peroxide (4.5 mL, 46.3 mmol, 30% by wt.) and 1N NaOH (46 μL, 0.046 mmol) were added to a solution of enone 2 (2.5 g, 11.5 mmol) in MeOH (30 mL) at 0° C. After stirring 1.5 h at 0° C. the mixture was concentrated in vacuo, washed with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the above titled compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][C:8]=3[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[CH2:11][C:5]2=[N:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nnc2n1-c1ccc(N)cc1N(c1ccccc1)C(=O)C2
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N(c1ccccc1)C(=O)Cc1nnc(C)n1-2

Procedure:
3.47 g of 1-methyl-8-amino-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one and 1.02 g of acetic anhydride in 50 ml pyridine is stirred for 12 hours then refluxed for 30 minutes. The reaction is evaporated; the residue is taken up in chloroform, washed with dilute aqueous sodium bicarbonate, with water and dried. The solvent is evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@@H:9]([C@H:10]([O:26][C@@H:27]2[O:31][C@H:30]([CH2:32][NH2:33])[C@@H:29]([OH:34])[C@H:28]2[OH:35])[C@H:11]2[O:15][C@@H:14]([N:16]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[CH:18]=[CH:17]3)[C@H:13]([OH:24])[C@@H:12]2[OH:25])[C:7](=[O:8])[N:6]([CH3:36])[C@H:5]([C:37]([OH:39])=[O:38])[C@@H:4](O)[CH2:3]1>Cl>[CH3:1][N:2]1[C@@H:9]([CH:10]([O:26][C@@H:27]2[O:31][C@H:30]([CH2:32][NH2:33])[C@@H:29]([OH:34])[C@H:28]2[OH:35])[C@H:11]2[O:15][C@@H:14]([N:16]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[CH:18]=[CH:17]3)[C@H:13]([OH:24])[C@@H:12]2[OH:25])[C:7](=[O:8])[N:6]([CH3:36])[C:5]([C:37]([OH:39])=[O:38])=[CH:4][CH2:3]1
Reactant: CN1C[C@H](O)[C@@H](C(=O)O)N(C)C(=O)[C@@H]1[C@H](O[C@@H]1O[C@H](CN)[C@@H](O)[C@H]1O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Agent: Cl
Product: CN1C(=O)[C@H](C(O[C@@H]2O[C@H](CN)[C@@H](O)[C@H]2O)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)N(C)CC=C1C(=O)O
Yield: 20 %

Procedure:
An amount of caprazol was dissolved in an amount of 1N aqueous hydrochloric acid and the resultant solution was heated at 100° C. for 3 hours, thereby to produce caprazene in the yield of 20%. About 20% of caprazol was left unreacted. Respective chemical structure of each compound was confirmed by NMR analysis. The resulting reaction solution was concentrated under a reduced pressure and the resulting residue was subjected to a silica-gel column chromatography. Thus, there can be separated caprazene and caprazol, from each other.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C@@H:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][C@H:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: Cc1c(CCN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-((1R)-1-hydroxy-2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(O[CH2:18][CH2:19][C:20]#[C:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1)(C1C=CC(C)=CC=1)(=O)=O>N1CCCCC1.C(#N)C>[N:30]1([CH2:18][CH2:19][C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH:36][CH:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(OCCCN3CCCCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: CC#N
Product: C(#Cc1ccc(OCCCN2CCCCC2)cc1)CCN1CCCCC1
Yield: 97.2 %

Procedure:
A suspension of potassium carbonate (760 mg) in a solution of 1-{3-[4-(4-tosyloxybut-1-yn-1-yl)phenoxy]propyl}piperidine (487 mg) in a mixture of piperidine (1.09 mL) and acetonitrile (8 mL) is heated at a temperature close to 60° C. for 24 h. The suspension is filtrated. The filtrate concentrated under reduced pressure and purified by chromatography over silica gel using a gradient dichloromethane/methanol from 100/0 to 95/5. Fraction containing the expected product are pooled, concentrated under reduced pressure and salted with oxalic acid to give 190 mg of 1-{3-[4-(4-piperidinobut-1-yn-1-yl)phenoxy]propyl}piperidine as an off white solid melting at 167° C.
Reaction SMILES: O[C@@H:2]([CH3:18])[C@@H:3]([NH:7][C:8]([O:10][C:11]1([CH3:17])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:9])[C:4]([OH:6])=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH3:17][C:11]1([O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1(C)CCOCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1(C)CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 19.2 %

Procedure:
In a round bottomed flask equipped with a magnetic stirrer and a dropping funnel (2R,3S)-3-hydroxy-2-[(4-methyltetrahydropyran-4-yl)oxycarbonylamino]-butanoic acid (0.2 g, 0.77 mmol) was dissolved in anhydrous CH2Cl2 (7 mL). The clear yellow solution was cooled to 0° C., PyBOP (0.48 g, 0.92 mmol) was added, followed by dropwise addition, over a period of 10 min, of Et3N (0.32 mL, 3.85 mmol) solution in anhydrous CH2Cl2 (5 mL). The crude mixture was stirred at 0° C. for 1 h then overnight at rt. The reaction was quenched by addition of 5% NaHCO3 solution (10 mL) and the corresponding mixture was vigorously stirred for 10 min. The two phases were separated and the organic one collected, dried over Na2SO4 and concentrated to dryness to leave an oil, which was purified by typical chromatography eluting with petroleum ether/AcOEt (from 20:80 to 0:100) to give title compound (0.036 g, 19%) as a light yellow oil. MS (ESI) m/z: 244.1 [M−H]+; (ESI) m/z: 242.2 [M−H]−. 1H NMR (DMSO-d6) δ 1.20 (d, J=6.3 Hz, 3H), 1.48 (s, 3H), 1.67 (m, 2H), 1.99 (m, 2H), 3.60 (m, 4H), 4.83 (m, 1H), 5.37 (dd, J=9.3, 6.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CC=CC=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1O
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1Oc1ccccc1
Temperature: 145 °C
Yield: 12 %

Procedure:
6.0 g of 4-hydroxy-3-methoxybenzaldehyde, 75 ml of pyridine, 12.0 g of iodobenzene, 10.9 g of potassium carbonate and 6.24 g of cupric oxide were mixed and heated at 145° C. for 18 hours in a sealed tube. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and subjected to celite filtration. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 1.11 g (yield: 12%) of the above identified compound as a colorless oily substance.