Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.S(=O)(=O)(O)O.[N+:25]([O-])([O-:27])=[O:26].[K+].[OH-].[NH4+]>>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[C:14]([N+:25]([O-:27])=[O:26])[CH:15]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCCC(c1ccc(NC(C)=O)cc1)n1ccnc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CCCC(c1ccc(NC(C)=O)c([N+](=O)[O-])c1)n1ccnc1
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a stirred and cooled (0° C.) mixture of 2.57 parts of intermediate 8, namely N-[4-[1-(1H-imidazol-1-yl)butyl]phenyl]acetamide and 23.0 parts of concentrated sulfuric acid were added portionwise 1.01 parts of potassium nitrate. Upon complete addition, stirring was continued for 30 minutes at 0° C. The reaction mixture was poured into crushed ice and treated with ammonium hydroxide to pH 10. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated, yielding 3 parts (99.4%) of N-[4-[1-(1H-imidazol-1-yl)butyl]-2-nitrophenyl]acetamide as a residue (interm. 9).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:13])[CH2:9][CH2:10][CH2:11][CH3:12]>C1(C)C=CC=CC=1>[CH2:8]([NH:13][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COCC(Cl)C=O
Reactant: CCCCCN
Solvent: Cc1ccccc1
Product: CCCCCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-pentylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: C[O-].[Na+].[Na].C(O[CH:8]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=1)[CH:10]=O)C.Cl.[C:26]([C@H:29]1[CH2:34][CH2:33][C@H:32]([C:35]([NH2:37])=[NH:36])[CH2:31][CH2:30]1)(=[O:28])[NH2:27].Cl>CO>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:8]=[N:36][C:35]([C@H:32]3[CH2:31][CH2:30][C@H:29]([C:26]([NH2:27])=[O:28])[CH2:34][CH2:33]3)=[N:37][CH:10]=2)=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N=C(N)[C@H]1CC[C@H](C(N)=O)CC1
Reactant: CCCCCCCc1ccc(C(C=O)=COCC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCc1ccc(-c2cnc([C@H]3CC[C@H](C(N)=O)CC3)nc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a sodium methylate solution prepared by the addition of 3.2 g. of sodium to 125 ml. of methanol are added 12.6 g. of 3-ethoxy-2-(p-n-heptylphenyl)acrolein and then 9.9 g. of trans-4-carbamoylcyclohexane-carboxamidine hydrochloride. The mixture is stirred at 50° C. overnight. The mixture is then acidified with dilute hydrochloric acid and the suspension is filtered. The residue is washed neutral and dried in vacuo. For purification, the residue is boiled with ether. There is obtained trans-4-[5-(p-n-heptylphenyl)-2-pyrimidinyl]cyclohexane carboxamide which is difficultly soluble.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13](OCC)=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH3:19]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:13]([NH2:19])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1cn(C)c2cc(Cl)ccc2c1=O
Product: Cn1cc(C(N)=O)c(=O)c2ccc(Cl)cc21
Reaction time: 21 h

Procedure:
A mixture of ethyl 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (5.0 g) and aqueous ammonia (specific gravity 0.88, 100 ml) can be stirred and heated on a steam bath for 3.5 hours. More aqueous ammonia (100 ml) can be added and heating continued for a further 21 hours. The mixture can be cooled in ice. The solid product can be collected by filtration and dried to give the compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, m.p. >240° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[NH:19][C:20](=[O:27])[CH:21](C(=O)CC)[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[NH:19][C:20](=[O:27])[CH2:21][CH3:22]
Reactant: CCC(=O)C(C)C(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCC(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 112.2 %

Procedure:
A solution of 22 g (48.5 mmol) N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-propionyl-propionamide, 4.9 g (30 mmol) iron(III) chloride and 7.2 g activated charcoal in 180 ml methanol was heated to 70° C. 23.8 ml (490 mmol) Hydrazine hydrate were added dropwise and the reaction mixture was refluxed for 90 min. After cooling to room temperature, the reaction was filtered through celite, the filter cake washed with dichloromethane, the filtrate reduced in volume and poured into water. The precipitate was filtered and washed with diethyl ether to afford 19 g (89%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]=1[N+:19]([O-])=O>[Pd].CO.CCOC(C)=O>[NH2:19][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:8]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(N2CCCCC2C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCCCC2C)c(N)c1

Procedure:
Ethyl 4-(2-methylpiperidin-1-yl)-3-nitrobenzoate (5 g; 17.10 mmol; 1 eq.) in a solution of MeOH/EtOAc 1:1 (340 mL, 0.05 M) was injected on a flow hydrogenation reactor (H-Cube), adapted with a Pd/C cartridge (44 mm), a flow of 1 mL/min, no heating and the full H2 option enabled, affording after evaporation of the solvents the title compound as a white solid (4.34 g, 96%). 1H NMR (DMSO-d6, 300 MHz) δ 7.34-7.33 (d, 1H), 7.21-7.18 (dd, J=8.28 Hz, 1.81 Hz, 1H), 7.06-7.03 (d, J=8.18 Hz 1H), 5.09 (br s, 2H), 4.28-4.26 (q, J=7.43 Hz, 2H), 3.11-3.07 (m, 1H), 2.97-2.88 (m, 1H), 2.47-2.3 (m, 1H), 1.83-1.65 (m, 6H), 1.32 (t, J=7.43 Hz, 3H). LC/MS (Method B): 263.2 (M+H)+. HPLC (Method A) Rt 2.60 min (Purity: 97.8%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:10]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:9]1[S:37]([CH3:40])(=[O:39])=[O:38])=O)(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[CH2:30]([C:10]1[C:11]2[C:16](=[C:15]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]=1[S:37]([CH3:40])(=[O:39])=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:43]([OH:45])([C:42]([F:47])([F:46])[F:41])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c(Cc4ccccc4)c(S(C)(=O)=O)n(C(=O)OC(C)(C)C)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1[nH]c2c(N3CCNCC3)cccc2c1Cc1ccccc1

Procedure:
To a solution of 3-benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methylsulfanyl-indole-1-carboxylic acid tert-butyl ester (277 mg) in CH2Cl2 (10 ml) was added MCPBA (296 mg) at 0° C. The reaction was allowed to warm up to room temperature overnight. After adding 150 mg of PPh3, the reaction was stirred for another 30 minutes and was then poured into a mixture of EtOAc/H2O. The organic layer was separated and washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and the resulting residue was purified by flash chromatography to give 3-Benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methanesulfonyl-indole-1-carboxylic acid tert-butyl ester as yellow solid. MS: (M+H)+ 570.4. 3-Benzyl-7-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-methanesulfonyl-indole-1-carboxylic acid tert-butyl ester was then dissolved in dichloromethane and treated with trifluoroacetic acid to give 3-benzyl-2-methanesulfonyl-7-piperazin-1-yl-1H-indole as a TFA salt, MS: (M+H)+ 370.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([F:25])=[C:19]([F:18])[CH:20]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(F)c(F)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 23 %

Procedure:
Example 6 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3,4-difluorophenyl)acetic acid (0.034 g) to give the title compound (0.0195 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 1 h
Yield: 20.8 %

Procedure:
To a solution of the above alcohol (0.437 g, 2.03 mmol) in CH2Cl2 (10 mL), at room temperature, was added sequentially 3 Å molecular sieves (1.07 g), N-methylmorpholine N-oxide (0.365 g, 3.11 mmol), and tetrapropylammonium perruthenate (70 mg, 0.20 mmol). After 1 hour, the mixture was filtered through a short column of silica gel and the cake was washed with ethyl acetate. The solvent was removed from the filtrate under reduced pressure. Purification of the crude material by column chromatography on silica gel (4:1 hexanes-ethyl acetate) provided 90 mg (20%) of 1-(tert-butoxycarbonyl)-piperidine-4-carboxaldehyde as a colorless oil. 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.51-1.62 (m, 2H), 1.85-1.93 (m, 2H), 2.37-2.46 (m, 1H), 2.88-2.97 (m, 2H), 3.94-4.00 (m, 2H), 9.66 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[C:9](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:24][CH3:25])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.O>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][CH2:36][O:23][C:20]1[CH:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH2:24][CH3:25])[C:7]=3[N:8]=2)=[CH:22][CH:21]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)cc3)n2C)n(CC)c1=O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCBr)cc3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
Compound 184 (200 mg, 0.59 mmol) obtained in Reference Example 181 was dissolved in 4 ml of dimethylformamide. To the solution were added 163 mg (1.18 mmol) of potassium carbonate and 0.56 ml (1.18 mmol) of 1,4-dibromobutane, and the mixture was stirred at 50° C. for 4 hours. Water was added thereto under ice cooling to dissolve potassium carbonate and the deposited crystals were collected by filtration. The obtained crude crystals were recrystallized from hexane/ethyl acetate to give 170 mg (yield 61%) of Compound 186 as pale yellow grains.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([OH:36])[CH:31]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:36][C:32]1[CH:31]=[C:30]([CH3:29])[CH:35]=[CH:34][N:33]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1ccnc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)ccn2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 27.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.45 g), 4-methylpyridin-2-ol (0.19 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 25%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4]>[Ti]>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Ti]
Product: O=C(O)c1ccc2cc(C(=O)O)ccc2c1

Procedure:
The hydrolysis of dimethyl-2,6-naphthalenedicarboxylate was conducted in the batch-mode in a 2 liter, stirred, titanium-lined reactor. The reaction time, temperature, pressure and analysis of the resulting 2,6-naphthalenedicarboxylic acid are provided in Table 5.
Reaction SMILES: [Br:1][C@@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11]>C1COCC1>[Br:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@H:8]1[OH:7]
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1

Procedure:
(1R,4S,5R)-4-Bromo-6-oxabicyclo[3.2.1]octan-7-one (a) (2.13 g, 10.4 mmol) was taken up in THF (20 mL) and treated with 0.88 ammonia (5.3 mL) at 20° C. for 24 hours with stirring. The solvent was then removed in vacuo to give a white solid (2.31 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:33]1[C:32]2[C:36]3[C:19]4([C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[NH:17][C:18]4=[O:37])[CH2:26][O:27][C:28]=3[CH:29]=[CH:30][C:31]=2[NH:35][O:34]1
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Agent: BrCC1CCCCO1
Product: O=C1Nc2ccccc2C12COc1ccc3c(c12)N(Cc1ccccn1)ON3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [CH:1]1(N[C@H](C(O)=O)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N[C@H:14]([C:22]([OH:24])=[O:23])CC1C=CC=CC=1.C1(NCC(O)=O)CCCCC1.C1C=CC([C@@H](N)C(O)=O)=CC=1>[Pt]=O.[OH-].[Pd+2].[OH-].C(O)(=O)C>[C:22]([O:24][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)(=[O:23])[CH3:14]
Reactant: C[C@H](NC1CCCCC1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=[Pt]
Agent: [Pd+2]
Agent: N[C@@H](C(=O)O)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)OC1CCCCC1
Yield: 24 %

Procedure:
Specific examples of the production of an amino acid which is optically active and contains a cyclohexyl group include the production of cyclohexylalanine by reducing L-phenylalanine in an aqueous acetic acid solution using a platinum oxide catalyst (J. Org. Chem., 1988, 53, 873 and Tetrahedron, 1992, 48, 307), and the production of cyclohexylglycine by reducing (R)-phenylglycine in a carbon-containing aqueous solution using a palladium hydroxide catalyst (Synth. Commun., 1978, 8, 345). However, in the former case, the optical purity of the product is unclear. In the latter case, the yield is as low as between 24 and 66%, and cyclohexyl acetate is formed as a by-product at a ratio of from 27 to 68%. Further, the optical purity of the resulting cyclohexylglycine is between 66 and 84% ee, which is not satisfactory. Accordingly, these methods are not useful on an industrial scale.
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[CH:16]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[CH:29](=O)[C:30]1[C:31](=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:32]>O>[CH:23]1([NH:22][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1.[CH:29](=[N:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12)[C:30]1[C:31](=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:32]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=Cc1ccccc1O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: O
Product: O=C(O)C1=C(CO)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
7-Amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (9.21 g) was suspended in water (200 ml) and neutralized to pH 7.5 with dicyclohexylamine (7 g). To the resultant solution was added dropwise salicylaldehyde (5.42 g). After stirring at ambient temperature for 2 hours, the precipitates were collected by filtration and dried to give 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylic acid dicyclohexylamine salt (17.4 g).
Reaction SMILES: [CH2:1]([C:17](Cl)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.[NH2:20][C:21]1[C:29]2[O:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH3:32].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][C:27]1([CH3:31])[CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH3:32])=[C:21]([NH:20][C:17](=[O:18])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:29]=2[O:28]1
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc2c(c1N)OC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Nc1c(C)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 171 mg amount of hexadecanecarboxylic acid chloride was added to a solution of 100 mg of 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran and 63 mg of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for one hour. A 10 ml amount of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was extracted twice with 20 ml of ethyl acetate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([NH:15][C:16]([O:18][CH3:19])=[O:17])[N:14]=1)=O>C1(C)C=CC=CC=1>[CH3:19][O:18][C:16]([NH:15][C:13]1[N:14]2[CH:6]=[N:8][CH:9]=[C:10]2[S:11][CH:12]=1)=[O:17]
Reactant: COC(=O)Nc1csc(CNC=O)n1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Nc1csc2cncn12
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 81.4 %

Procedure:
A 1.17 ml portion of phosphorus oxychloride was added to a suspension formed by adding 2.8 ml of dry toluene to 560 mg of 2-(formylamino)methyl-4-methoxycarbonylaminothiazole, and the mixture was then stirred at an oil temperature of 100° C. for 45 minutes. Then, the solvent was evaporated under reduced pressure, and 30 ml of dichloromethane and 10 ml of a 15% aqueous potassium carbonate solution were then added to the resulting residue to adjust the solution to pH 9.5. The organic layer was separated, and the aqueous layer was then salted out with sodium chloride. Afterward, extraction was carried out three times with 30 ml of dichloromethane, and the extract was then combined with the above organic layer. The solution was dried (magnesium sulfate), and then filtered. Further, the solvent was evaporated under reduced pressure to obtain a milky white powder, and this powder was then purified by a silica gel column chromatograph to obtain 417.5 mg of the title compound as a colorless powder.
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][CH:32]=[CH:31][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:20](=[O:21])[CH2:19][C:18](=[O:22])[NH:17][C:16]3[C:23]4[C:28]([CH:29]=[CH:30][C:15]2=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br.N>ClCCl>[OH:2][C:3]1[CH:34]=[CH:33][CH:32]=[CH:31][C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:20](=[O:21])[CH2:19][C:18](=[O:22])[NH:17][C:16]3[C:23]4[C:28]([CH:29]=[CH:30][C:15]2=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:12][CH:13]=1)=[O:6]
Reactant: COc1ccccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3O)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
5-[4-(2-Methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (56 mg, 0.124 mmol) obtained in Example 12 was dissolved in dichloromethane (1.2 mL), the solution was added with a 1 M solution of boron tribromide in dichloromethane (0.37 mL, 0.37 mmol) on an ice bath, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was added with 25% aqueous ammonia, and the mixture was extracted with chloroform. Then, the organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to give the title compound (39 mg, yield 72%).
Reaction SMILES: P(Cl)(Cl)(OC)=O.[Cl:7][CH2:8][CH2:9][CH2:10][CH:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23])[C:12]([NH2:14])=O.N12CCCN=C1CCCCC2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH:11]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]([F:25])([F:23])[F:24])[C:12]#[N:14]
Reactant: NC(=O)C(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Agent: COP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: N#CC(CCCCl)c1ccc(Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.6 %

Procedure:
Methyl dichlorophosphate (1.9 mL) was added dropwise at 20° C. or less to an ice-cooled solution of 5-chloro-2-(4-chloro-2-trifluoromethylphenyl)pentanoic acid amide (3.0 g) and 1,8-diazabicyclo[5,4,0]undec-7-ene (6.4 mL) in methylene chloride (30 mL). After completion of the dropwise addition, the reaction solution was stirred at room temperature for one hour and 25 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction solution. After stirring for five minutes, the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Wakogel C-200; elution solvent:heptane:ethyl acetate=49:1→19:1) to obtain 2.25 g of the title compound.