Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7](CN3C(=O)C4=CC=CC=C4C3=O)[O:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:21][NH:22]N>ClCCCl>[NH2:22][CH2:21][N:8]1[CH2:7][O:6][N:5]=[C:4]1[CH:1]1[CH2:2][CH2:3]1
Reactant: CNN
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc(C2CC2)no1
Solvent: ClCCCl
Product: NCN1CON=C1C1CC1

Procedure:
N-[(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]phthalimide (104 g, 387 mmol) was dissolved in 1,2-dichloroethane (500 mL), N-methylhydrazine (22.4 mL, 426 mmol) was added and the solution was refluxed for 5 h. The suspension was cooled in ice, the precipitate (2-methyl-2,3-dihydro-phthalazine-1,4-dione) was filtered off and washed with 1,2-dichloroethane (100 mL). The filtrate was evaporated and the residue distilled at 70° C./0.4 mbar (bath-T 100-150° C). Yield: 39.3 g (73%). m/z 139 (M).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:28])[C@H:15]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([NH:13][CH:8]1[CH2:7][C:6]2[C:11](=[C:2]([NH2:1])[CH:3]=[CH:4][CH:5]=2)[NH:10][C:9]1=[O:12])=[O:28]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N)c2NC1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
3,8-Diamino-3,4-dihydroquinolin-2(1H)-one dihydrochloride (9.0 g) was suspended in N,N-dimethylformaldehyde (90 mL), and triethylamine (15 mL) was added to the suspension under cooling on ice. Subsequently, N-tert-butoxycarbonyl-D-leucine monohydrate (9.87 g), 1-hydroxybenzotriazole (4.86 g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.67 g) were sequentially added to the mixture, followed by stirring at room temperature for one hour. To the resultant mixture were added saturated aqueous sodium bicarbonate solution, ethyl acetate, and water, and the mixture was subjected to extraction. The organic layer was sequentially washed with water and saturated aqueous sodium chloride solution, and was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitates were filtered by use of ethyl acetate, whereby tert-butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (12.4 g) was yielded as a diastereomeric mixture. Subsequently, the thus-obtained tert-butyl (2R)-1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylcarbamate (7.68 g) was dissolved in ethanol (77 mL), and concentrated hydrochloric acid (34 mL) was added thereto, followed by heating to 60° C. while being stirred for 30 minutes. The resultant mixture was neutralized with saturated aqueous sodium bicarbonate solution under cooling on ice and was then subjected to extraction with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (chloroform:methanol=15:1), whereby the title compound (diastereomer of lower polarity: 2.85 g, diastereomer of higher polarity: 2.73 g) was yielded.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][S:14][N:15]=1)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Br[C:2]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[N:17][C:16]3=[O:27])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH:36]1(B(O)O)[CH2:38][CH2:37]1>>[CH:36]1([C:2]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([CH:14]=[C:15]4[S:19][C:18]([N:20]5[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]5)=[N:17][C:16]4=[O:27])=[CH:11][CH:12]=3)[CH:7]=[N:6]2)[CH2:38][CH2:37]1
Reactant: OB(O)C1CC1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4Br)c3)S2)CC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C4CC4)c3)S2)CC1

Procedure:
5-[1-(2-Cyclopropyl-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2-bromo-4-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one and cyclopropyl boronic acid following General Procedure G.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH2:28])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(N)c3C2=O)ccc1OC(F)F
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To the THF solution of 3-(7-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.8 g, 7 mmol) was added cyclopropanyl carbonyl chloride (0.72 ml, 8 mmol) dropwise. The reaction mixture was then heated to reflux for 1 hour. The solvent was removed under vacuo. The mixture was dissolved in EtOAc (50 ml) and washed with water (50 ml×2). The organic layer was dried over Na2SO4 and concentrated under vacuo. The resulted solid was stirred with ether (20 ml) for 1 hour and filtered to give a total of 2.5 g (77% yield) white solid which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>C(#N)C>[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:11]1[C:10](=[O:13])[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:12]1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=c1n(Cc2cccc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F

Procedure:
400 mg (1.30 mmol) of the compound from Example 4A and 635 mg (1.95 mmol) of cesium carbonate were suspended in 3 ml of acetonitrile, and 357 mg (1.43 mmol) of 3-bromobenzyl bromide were added. The mixture was stirred under reflux for 20 h. The precipitated solid was then filtered off, and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml and directly purified chromatographically [Method 19]. This gave 507 mg (82% of theory) of the target compound.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[O:8][CH2+:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]2[CH:16]=[C:15]([O:17]C)[C:14]([O:19]C)=[CH:13][C:11]=2[CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>[N+](C)([O-])=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:19][C:14]1[C:15]([OH:17])=[CH:16][C:10]2[CH2+:9]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[O:8][C:7]([CH3:6])=[CH:12][C:11]=2[CH:13]=1
Reactant: COc1cc2c(cc1OC)[CH2+](c1ccc([N+](=O)[O-])cc1)OC(C)=C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CC1=Cc2cc(O)c(O)cc2[CH2+](c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4 h
Yield: 73 %

Procedure:
44.0 g of 3-methyl-6,7-dimethoxy-1-(4-nitrophenyl)-2-benzopyrylium-perchlorate (C.A. 105, 1986, 152712h) is added to a solution of 46.3 g of AlCl3 in 170 ml of nitromethane and heated to boiling for 4 hours. The solvent is removed, the residue is treated with 500 ml of cooled 50% HCl solution, and the product that is obtained is washed with cold water. 43.5 g of crude product, which is mixed with 130 ml of acetic acid, heated to boiling and mixed with 13.3 ml of 70% HClO4, is obtained. After cooling, 30.0 g of the title compound (73%) with melting point 253°-255° C. (decomposition ethyl acetate) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][CH2:31][OH:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=[O:35].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:29][CH2:30][C:31]([OH:35])=[O:32])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:27])([F:26])[F:28])=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@@H](c1ccc(OCC(F)(F)F)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-2-one (320 mg, 0.7 mmol) in acetone (7 mL) was added Jones reagent (2.5 M□1.05 mL) at 0° C. The mixture was stirred at this temperature for 30 min. The formed mixture was filtered and the filtrate was concentrated. The residue was treated with H2O (10 mL) and CH2Cl2 (10 mL). The mixture was separated, and the organic layer was washed with brine and concentrated. The residue was purified by preparative TLC to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(2,2,2-trifluoroethoxy)phenyl)ethyl)-1,3-oxazinan-6-yl)propanoic acid (290 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[C:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28]C(C)(C)C)=O)[CH2:22][CH2:21]4)=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.F[C:36](F)(F)C(O)=O.C(OC(=O)C)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:34]=[CH:33][C:12]([O:13][C:14]3[C:15]([CH:20]4[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:36])[CH2:22][CH2:21]4)=[N:16][CH:17]=[CH:18][N:19]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(Cl)cn3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(Cl)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(3-(4-(5-chloropyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate (0.14 g, 0.29 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.22 mL, 2.9 mmol) and stirred at room temperature for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (1 mL) was cooled to 0° C. and added acetic anhydride (0.041 mL, 0.43 mmol). The reaction was gradually allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 70% EtOAc/Hexanes) provided a crude crop of the desired product. Further purification via reverse phase HPLC afforded 1-(4-(3-(4-(5-chloropyridin-2-ylamino)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 424.9 (M+1). IC50 (uM) 0.001.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:26][CH2:27][CH2:28][N:29]1[C:33]([SH:34])=[N:32][N:31]=[N:30]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:34][C:33]3[N:29]([CH2:28][CH2:27][OH:26])[N:30]=[N:31][N:32]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: OCCn1nnnc1S
Product: O=C(CCCSc1nnnn1CCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 63 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 1-(2-hydroxyethyl)-5-mercaptotetrazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in a 63% yield.
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.C[Si](Br)(C)C.[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:50]1[N:51]=[C:52]([NH:55]C=O)[S:53][CH:54]=1)[C:27]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]>C(Cl)Cl>[P:18]([CH2:22][CH2:23][O:24][N:25]=[C:26]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)[C:27]([NH:29][CH:30]1[C:48](=[O:49])[N:32]2[C:33]([C:45]([OH:47])=[O:46])=[C:34]([CH2:37][S:38][C:39]3[N:43]([CH3:44])[N:42]=[N:41][N:40]=3)[CH2:35][S:36][C@H:31]12)=[O:28])([OH:21])([OH:20])=[O:19]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCP(=O)(O)O)c3csc(NC=O)n3)[C@H]2SC1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCP(=O)(O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7-[2-{2-(O,O-diethylphosphono)ethoxyimino}-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (6.2 g.) methylene chloride (90 ml.) and bis(trimethylsilyl)acetamide (9.2 g.) was stirred for 30 minutes at room temperature and thereto was added trimethylsilyl bromide (6.9 g.) over a period of 30 minutes with stirring at 20° to 25° C. and then stirring was continued for 5 hours at 25° to 27° C. The reaction mixture containing 7-[2-(2-phosphonoethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) was concentrated and to the residue were added cold methanol (100 ml.) and cold conc. hydrochloric acid (4 ml.) followed by stirring for an hour at room temperature and a further addition of conc. hydrochloric acid (2 ml.). The resulting mixture was stirred for an hour at room temperature and then concentrated. To the residue was added water (300 ml.) and the mixture was adjusted to pH 2 to 3 with sodium bicarbonate and then subjected to column chromatography (non-ion adsorption resin, Diaion HP 20 prepared by Mitsubishi Chemical Industries) (200 ml.). The column was washed with water (1 l.) and then eluted successively with 10% methanol (1 l.), 20% methanol (1 l.), 30% methanol (1 l.) and 40% methanol (2 l.). The fractions containing the desired compound were evaporated to give the title compound (3.7 g.), mp. 180° to 210° C. (dec.)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:23][Cl:24])[C:11]2=[N:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([OH:17])[C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:4][CH2:5][C:6]1([CH2:23][Cl:24])[C:11]2=[N:12][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([O:17][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:16])[N:10]2[CH2:9][CH2:8][O:7]1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2(CCl)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(CCl)COC(C)=O
Reaction time: 16 h

Procedure:
A solution of ethyl 9-(acetoxymethyl)-9-(chloromethyl)-3-hydroxy-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate (2.05 g, 5.68 mmol) in dimethylfomamide (60 mL) was treated with benzyl bromide (1.46 g, 8.5 mmol, Aldrich) and K2CO3 (1.26 g, 9.1 mmol) and stirred for 16 hrs. Solvent was removed in-vacuo and the crude material was dissolved in ethyl acetate (30 mL) and washed with water (30 mL) and brine (30 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to give an amber oil. This was purified by flash column chromatography, eluting with 5% Et2O in CH2Cl2. Product fractions were pooled and concentrated in-vacuo to give the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) δ ppm 7.45 (2H, d, J=7.32 Hz), 7.29-7.39 (3H, m), 4.68 (1H, d, J=1 1.90 Hz), 4.37 (1H, d, J=1 1.90 Hz), 4.31 (2H, q, J=7.22 Hz), 4.16-4.24 (2H, m), 4.09-4.16 (1H, m), 4.06 (1H, d, J=11.29 Hz), 3.95-4.03 (1H, m), 3.89 (1H, d, J=1 1.29 Hz), 2.06 (3H, s), 1.56 (2H, s), 1.29 (3H, t, J=7.17 Hz); 13C NMR (126 MHz, CDCl3) δ ppm 170.16, 164.04, 158.67, 150.65, 141.94, 141.67, 136.51, 128.59 128.52, 128.45, 79.57, 74.51, 65.90, 62.11, 60.59, 49.08, 42.16, 20.83, 14.16; HRMS (ESI) calcd for C21H24N2O7Cl (M+H) 451.1272; found 451.1274.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:7]([NH:9][CH2:10][CH3:11])=[O:8])[CH3:2]>C(O)C.[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:6]([C:7]([NH:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(OCC)c1
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)c1ccc(N)c(OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of 3-ethoxy-N-ethyl-4-nitrobenzamide (0.72 g) obtained in Example 131b) in ethanol (15 ml) was added 10% Pd/C (50% wet) (0.07 g), and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a colorless oil (0.53 g, 84%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][C:7]=1[S:14][C:15]1[C:16]([CH3:21])=[CH:17][CH:18]=[CH:19][CH:20]=1.[Cl-].[Na+]>CS(C)=O>[CH3:4][O:5][C:6]1[C:7]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][C:1]#[N:2]
Reactant: COc1c(CCl)cccc1Sc1ccccc1C
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Sc1ccccc1C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Powdered sodium cyanide (1.5 g) was added all at once to a solution of o-tolyl 2-methoxy-3-chloromethylphenyl thioether (8.3 g) in dimethyl sulfoxide (40 ml), and the mixture was stirred for 15 minutes, poured into saturated aqueous solution of sodium chloride and extracted with diethyl ether. The extract was washed with water, dried and then evaporated under reduced pressure to give oily 2-[2-methoxy-3-(o-tolylthio)phenyl]acetonitrile (7.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10]C([O-])(C)C.[K+].[C:16](C1C=CC=CC=1)(=O)CC.CC(C1C=CC2C(=CC=CC=2)C=1)=O.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(CC(=O)C)C1C=CC=CC=1.C(=O)C1C=CC=CC=1.C(=NC1C=CC=CC=1)C1C=CC=CC=1>>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH2:2][CH3:10].[C:4]1([CH:1]([OH:3])[CH2:2][CH3:16])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: C(=Nc1ccccc1)c1ccccc1
Agent: CC(=O)CCc1ccccc1
Agent: CC(=O)c1ccc2ccccc2c1
Solvent: CCC(=O)c1ccccc1
Solvent: O=Cc1ccccc1
Product: CCC(O)c1ccccc1

Procedure:
As can be seen from Table 3, the electronic properties of the substituents on the phenyl ring of the ketone changed the reduction rate but had less effect on the enantioselectivity (18-33%). An acetophenone substituted in the para position by an electron releasing group, such as 4′-methyl and 4′-methoxy, is reduced more slowly than acetophenone (entries 3, 8 and 9). The chloro substituted acetophenones are all reduced faster, especially for the ortho position (entries 3-7). This trend is opposite to the generally observed trend for Noyori's transfer hydrogenation catalysts in which an ortho-Cl substitution decreases the rate of the reduction (S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 7562). The catalyst (iii) with KOtBu is also efficient for the transfer hydrogenation of propiophenone, 2-acetonaphthone, benzophenone, benzylacetone, benzaldehyde and N-benzylideneaniline (entries 11-15). The hydrogenation of propiophenone gave 1-phenylpropanol in 61% e.e (S) (entry 10). The more difficult ketimine N-phenyl-(1-phenylethylidene)amine (Ph-CMe=N-Ph) was only partially reduced (<5%) after 18 h under the same conditions (entry 16), while cyclohexanone was not hydrogenated (entry 17). Transfer hydrogenation of unsaturated ketones was complicated by some reduction of the C═C double bond (Scheme 2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:4]([F:13])[C:3]=1[OH:14].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=S)=[C:18]([CH3:25])[CH:17]=1>CO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[O:14][C:3]3[C:4]([F:13])=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=3[N:1]=2)=[C:18]([CH3:25])[CH:17]=1
Reactant: COC(=O)Cc1ccc(N)c(O)c1F
Reactant: Cc1cc(F)ccc1N=C=S
Solvent: CO
Product: COC(=O)Cc1ccc2nc(Nc3ccc(F)cc3C)oc2c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 79.1 %

Procedure:
In methanol (30 ml) was dissolved methyl (4-amino-2-fluoro-3-hydroxyphenyl)acetate (1.0 g, 5.02 mmol). To the resulting solution was added 4-fluoro-2-methylphenyl isothiocyanate (0.74 ml, 5.23 mmol). After the mixture was stirred at room temperature for 5 days, mercuric oxide (yellow) (1.14 g, 4.36 mmol) was added thereto. The mixture was stirred at 70° C. for 6 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with methanol. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/ethyl acetate (30/1) eluate fractions, methyl (2-(4-fluoro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.32 g, 91%) was obtained as a colorless solid.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][C:19]([O:21]CC)=[O:20])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:3].[OH-].[Na+]>O1CCOCC1>[C:24]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:3])([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25]
Reactant: CCOC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O

Procedure:
To 350 ml of dioxane, 30 g of Z-Ala-Phe-Gly-OEt was added, followed by addition of 70 ml of lN-NaOH. The reaction solution was dissolved at room temperature. After one hour's reaction, almost all the dioxane was removed by distillation, followed by neutralization with 70 ml of lN-HCl. The resulting mixture was well extracted with ethyl acetate. The extract was dried over MgSO4 and the solvent was removed by distillation to give carbobenzoxy-alanyl-phenylalanyl-glycine having a melting point of 168°-171° C. and [α]D25 =-20.1° (C=1.0, DMF) in yield of 27.0 g (96%).