Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:15]Br.S([O-])([O-])=O.[Na+].[Na+]>CO>[Br:15][C:11]1[CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=1[O:13][CH3:14]
Reactant: BrBr
Reactant: CCCCCCc1ccc(OC)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCc1ccc(OC)c(Br)c1
Temperature: 25 °C

Procedure:
26.4 g (0.137 mol) of 4-n-hexyl-1-methoxybenzene was dissolved in 200 ml of methanol. 26.4 g (0.156 mol) of bromine was added while stirring under cooling with ice. The mixture was stirred for 2 hours, while raising the temperature to room temperature. Sodium sulfite was added to the reaction mixture to decompose an excess amount of bromine, whereupon the mixture was extracted with chloroform-water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 20:1 mixture of n-hexane and ethyl acetate) to obtain 35.18 g (yield, 95.8%) of a colorless oil of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[C:4]([F:22])[CH:3]=1.CCN(CC)CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][CH:10]1[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:4]=1[F:22])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)c(F)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 124.5 %

Procedure:
To a stirred solution of 1-bromo-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzene (549.4 mg, 1.468 mmol) in DMSO (6 mL) and MeOH (5 mL) was added Et3N (448 ul, 3.229 mmol), Pd(OAc)2 (36.2 mg, 0.161 mmol), and 1,3-bis(diphenylphosphino)propane (66.4 mg, 0.161 mmol). To the mixture was induced CO gas for 10 min. The resulting mixture was stirred at 70° C. for 2 days under a current of CO. After the mixture was concentrated, the residue was diluted with EtOAc. The solution was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel eluting with n-hexane:EtOAc (5:1, v/v) as eluent to afford 323.0 mg (62%) methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-fluorobenzoate as a pale yellow oil. 1H-NMR (400 m/z, CDCl3) δ1.47 (s, 9H), 1.87(br s, 1H), 1.95-2.10 (m, 3H), 3.34-3.44 (br m, 2), 3.89 (s,. 3H), 3.94 and 4.11-4.26 (br m each, 3H), 7.03-7.11 (m, 1H), 7.75-7.80 (m, 2H); MS (FAB) m/z 354 (M++1).
Reaction SMILES: [CH2:1]([NH:3][C:4](F)=[O:5])[CH3:2].[C:7]([N:11]1[CH:15]=[C:14]([OH:16])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([NH:3][C:4](=[O:5])[O:16][C:14]1[CH:13]=[N:12][N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:15]=1)[CH3:2]
Reactant: CC(C)(C)n1cc(O)cn1
Reactant: CCNC(=O)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC(=O)Oc1cnn(C(C)(C)C)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
4.6 g (0.05 mol) of N-ethylcarbamoyl fluoride were added to a mixture of 7 g (0.05 mol) of 1-tert.-butyl-4-hydroxypyrazole, 10.4 g (0.075 mol) of potassium carbonate and 100 ml of acetonitrile. The mixture was stirred for a further 3 hours at 20° C. It was then filtered under suction. The filtrate was concentrated by evaporation in vacuo. 9 g (85% of theory) of 1-tert.-butyl-pyrazol-4-yl N-ethylcarbamate were obtained in the form of beige crystals with a melting point of 77° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN1CCC(ON)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.150 g, 0.543 mmol, US 2005/20572 A1) in DCM (10 mL) were added 4-(aminooxy)-1-methylpiperidine 50 (0.129 g, 0.99 mmol), 1-hydroxybenzotriazole (0.110 g, 0.814 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.156 g, 0.814 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 h, diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated to provide a residue which was subjected to chromatography to give 51 (0.065 g, 31%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=2[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>ClCCl>[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=3[CH3:22])=[CH:23][CH:24]=2)=[O:38])=[CH:35][CH:34]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Yield: 40.6 %

Procedure:
In a dry reaction vessel, ethyl 2-[3-(4-aminobenzyl)-2-methyl-1H-indol-1-yl]acetate (1.0 g, 3.10 mmol) was added, and dissolved in 15 mL dichloromethane. Triethylamine (1.3 mL, 9.34 mmol) was added, in an ice bath a dichloromethane solution dissolving 4-chlorobenzoyl chloride (0.544 g, 3.11 mmol) was added slowly. After completion of dropwise addition, it was reacted in an ice bath for 4 h. It was filtered. An aqueous solution of sodium bicarbonate was added, extracted with dichloromethane, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 0.580 g, at a yield of 40.6%.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1)#[CH:2].[OH-].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CC(O)C.CO.Cl[Cu].C([O-])([O-])=O.[K+].[K+]>[C:1]([C:3]1([OH:13])[CH2:12][CH2:11][CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1)#[C:2][CH2:18][CH:17]=[CH2:16]
Reactant: C#CC1(O)CCC2CCCCC2C1
Reactant: C=CCBr
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: C=CCC#CC1(O)CCC2CCCCC2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A solution of 2-ethynyldecahydronaphthalen-2-ol (100.6 g, 0.56 mol) in iPrOH (300 ml) was added slowly at 0° C. under a nitrogen atmosphere to a mixture of KOH (47.5 g), K2CO3 (6.5 g), and CuCl (4.4 g) in MeOH (300 ml). After stirring for additional 30 minutes at 0° C., allylbromide (102 g, 0.85 mol) was added slowly over a period of 25 minutes. The reaction mixture was stirred overnight at RT, quenched with NH4Cl and concentrated in vacuo. The residue was taken up in saturated NH4Cl (500 ml) solution, extracted with MTBE (2×400 ml). The combined organic phases were washed with saturated NH4Cl solution (500 ml), H2O (2×500 ml), saturated NaCl solution (500 ml) until neutral pH was achieved, dried (MgSO4), and evaporated in vacuo to yield quantitatively 120 g of crude product which was used without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9](Br)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br-].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[Zn+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[C:19]1[S:18][CH:22]=[CH:21][CH:20]=1
Reactant: [Zn+]c1cccs1
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2cccs2)c(C(=O)OC)cc1-c1cccs1
Temperature: 67 °C
Yield: 87.2 %

Procedure:
Dimethyl 2,5-dibromoterephthalate (6.09 g, 17.30 mmol) is dissolved in anhydrous THF (100 cm3), followed by the addition of 2-thienylzinc bromide (0.50 M in THF, 90 cm3, 45.0 mmol) and Pd(PPh3)4 (0.50 g, 0.43 mmol). The mixture is heated at 67° C. for 2 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and washed with water, methanol and diethyl ether then dried in vacuo, to yield the product as a pale yellow solid (5.41 g, 87%). 1H NMR (300 MHz, CDCl3): δ(ppm) 7.82 (s, 2H, Ar—H), 7.40 (dd, J=4.8 and 1.4 Hz, 2H, Ar—H), 7.07-7.12 (m, 4H, Ar—H), 3.78 (s, 6H, CH3); 13C NMR (75 MHz, CDCl3): δ(ppm) 168.1 (C═O), 140.3 (q), 133.6 (q), 133.4 (q), 131.9 (CH), 127.5 (CH), 127.0 (CH), 126.7 (CH), 52.6 (CH3); MS (m/e): 358 (M+, 100%), 327, 299, 240, 195.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](C(=O)C=O)[NH2:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].O.[C:21]([OH:25])(=[O:24])[CH:22]=O.Cl>C(#N)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][N:15]=[CH:22][C:21]([OH:25])=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=CC(=O)O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N(N)C(=O)C=O)cc1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc(S(=O)(=O)NN=CC(=O)O)cc1

Procedure:
The subject compound is prepared using the general method of Example 1 except that 4.58 g (20 mmol) of glyoxylic acid p-acetamidobenzenesulfonylhydrazide was reacted with 2.4 g (26 mmol) of glyoxylic acid monohydrate in the presence of 1/2 cc conc. HCl and 200 cc acetonitrile. The desired product was obtained in a yield of 5.4 g, m.p. 136° (dec.).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:12]2[CH2:13][C:14](=[O:16])[CH2:15][CH:11]2[CH2:10][NH:9]1.[N:17]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[N:17]1([C:22]([N:9]2[CH2:10][CH:11]3[CH2:15][C:14](=[O:16])[CH2:13][CH:12]3[CH2:8]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(Cl)N1CCCC1
Reactant: O=C1CC2CNCC2C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C1CC2CN(C(=O)N3CCCC3)CC2C1
Yield: 58.5 %

Procedure:
Hexahydro-cyclopenta[c]pyrrol-5-one trifluoroacetate 1f (478 mg, 2 mmol) was dissolved in 20 mL of dichloromethane followed by addition of pyrrolidine-1-carbonyl chloride (0.276 mL, 2.5 mmol) and triethylamine (0.84 mL, 6 mmol). The reaction mixture was reacted overnight at room temperature. The mixture was adjusted to pH 4 with a solution of 10% citric acid. The mixture was extracted with dichloromethane (50 mL×3). The combined organic extracts were washed with 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 2-(pyrrolidine-1-carbonyl)-hexahydro-cyclopenta[c]pyrrol-5-one 8a (0.26 g, yield 58.5%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:52][O:53][C:54](=[O:59])[C@H:55]([OH:58])[CH2:56][NH2:57]>CN(C=O)C.C(N(C(C)C)CC)(C)C.O>[CH3:52][O:53][C:54](=[O:59])[C@H:55]([OH:58])[CH2:56][NH:57][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H](O)CN
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)c1ccc(C2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C3CCCCC3)cc2)cc1
Reaction time: 0.75 h

Procedure:
4-{[tert-Butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoic acid was dissolved in DMF (10 mL) and HOBt (0.40 g, 2.93 mmol) and EDAC (0.52 g, 2.73 mmol) were added. The reaction mixture was stirred for 45 min. Then a solution of (R)-3-amino-2-hydroxypropionic acid methyl ester in DMF (8 mL) and diisopropylethylamine (0.46 mL) were added. The mixture was stirred overnight. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (75 mL). The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×30 mL), water: saturated sodium chloride (3×30 mL), dried with magnesium sulphate and concentrated in vacua. The residue was purified by column chromatography on silica gel (100 g) using mixtures of ethyl acetate and n-heptane (1 L (1:1) and 0.5 L (7:3)) as eluents to afford 0.77 g (R)-3-(4-{[tert-butoxycarbonyl-(4-cyclohexylphenyl)amino]methyl}benzoylamino)-2-hydroxypropionic acid methyl ester.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:17]([C:15]2[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]3[CH2:12][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[O:9][C:10]=3[CH:16]=2)=[O:19])=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.6 mmol) in CH2Cl2 (15 mL) were added 1-methyl-1H-pyrazol-3-ylamine (0.16 g, 1.7 mmol), EDCI (0.46 g, 2.4 mmol), HOBt (0.32 g, 2.4 mmol) and N-methylmorphiline (0.81 g, 8 mmol) sequentially. The mixture was stirred at room temperature overnight. The reaction solution was washed with water (5 mL), aq. HCl (1 N, 5 mL) and sat. NaHCO3. The organic phase was dried over Na2SO4 and concentrated to give a yellow oil. The crude oil was purified by prep. HPLC to give the product as a white solid (98.6 mg, 16% yield, TFA salt). 1H NMR (400 MHz, CDCl3): δ 10.71 (s, 1H), 7.58 (s, 1H), 7.30-7.48 (m, 5H), 7.01˜7.19 (d, 2H), 6.57 (s, 1H), 5.08 (d, 1H), 4.74 (m, 1H), 3.74 (s, 3H), 2.66 (d, 2H), 2.17 (m, 1H), 1.96 (m, 1H), 1.28 (d, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH:10]2[CH:5]([CH2:6][C:7](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:9]2)[C:4](=[O:21])[NH:3]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][NH2:30])=[CH:25][CH:24]=1>CO.C(O)(=O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[N:30][C:7]2[CH2:6][CH:5]3[CH:10]([CH2:9][C:8]=2[NH:30][NH:29][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=2)[C:2](=[O:1])[NH:3][C:4]3=[O:21])=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC2C(=O)NC(=O)C2C1
Reactant: NNc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NC(=O)C2CC(NNc3ccc(Cl)cc3)=C(N=Nc3ccc(Cl)cc3)CC12

Procedure:
8 g (24.4 mmole) 1,3,3a,4,7,7a-hexahydro-1,3-dioxo-5,6-bis(trimethylsiloxy)-isoindole and 11.4 g (80 mmole) 4-chlorophenyl hydrazine are boiled under reflux for 16 hours in 50 ml methanol and 50 ml glacial acetic acid. The crystals precipitated out after cooling are filtered off, after-washed several times with methanol, and dried. One obtains 5-[(4-chlorophenyl)-azo]-6-[N'-(4-chlorophenyl)-hydrazino]-1,3,3a,4,7,7a-hexahydro-1,3-dioxoisoindole in the form of yellow-green crystals.
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].[CH3:18][Mg]I>C1COCC1>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([Cl:13])[C:7]=1[CH2:6][CH2:5][C:4](=[O:16])[CH3:18]
Reactant: CON(C)C(=O)CCc1c(Cl)cc(Cl)cc1Cl
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)CCc1c(Cl)cc(Cl)cc1Cl
Reaction time: 2 h
Yield: 59 %

Procedure:
To the stirred and cold solution (0° C.) of N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide (1 g, 3.37 mmol) in THF (15 ml) kept under nitrogen atmosphere, MeMgI (1.3 mL of 3M ether solution, 3.9 mmole) was added and stirring was continued at 0° C. for 2 hours. Reaction mixture was quenched with 5% of HCl (10 ml) at 0° C. and aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layer was washed with 20 ml of brine and dried over sodium sulfate; concentrated under vacuum to give off-white solid. The residue was purified by chromatography over silica gel. 0.50 g (60.0% of theory) of 4-(2,4,6-trichloro-phenyl)-butan-2-one was obtained in form of a solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].C(N(CC)CC)C.[CH2:36]([OH:47])[C@H:37]1[O:43][C:41](=[O:42])[C@H:40]([OH:44])[C@@H:39]([OH:45])[C@@H:38]1[OH:46]>CN(C=O)C>[OH:42][CH:41]1[O:43][C@H:37]([C:36](=[O:9])[OH:47])[C@@H:38]([OH:46])[C@H:39]([OH:45])[C@H:40]1[OH:44].[NH2:2][C@H:3]([C:8]([NH:10][C@H:11]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[C@H](C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of HCl, H-Ile-Phe-OBzl (1.41 g, 3.5 mmol) in freshly distilled DMF (2 ml) neutralized with triethylamine (0.49 ml, 3.5 mmol), δ-gluconolactone (1.25 g, 7 mmol) and TEA (0.98 ml, 7 mmol) were added. The mixture was stirred at 60° C. for 24 hr. δ-gluconolactane (0.63 g, 3.5 mmol) and TEA (0.43 ml, 3.5 mmol) were then added and the mixture was stirred for 24 h more. The mixture was then filtered and the filtrate evaporated under reduced pressure. The residue was purified by preparative chromatography on a silica gel column eluted with the system chloroform-methanol-water (16:6:1): yield 1.1 g (58%) after precipitation in ether-petroleum ether (1:1, v/v); mp 175°-176° C.; [α]54625 =+1.3° (c=1, DMF); Rf(A) =0.53.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.C(Cl)(=O)C1C=CC=NC=1.[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[C:37]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=O)[CH3:35]>>[CH2:34]([N:36]([C:45]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:46]=1[CH:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][CH:57]=[C:58]([O:63][CH3:64])[CH:59]=2)[CH2:54]1)[CH2:37][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[CH3:35]
Reactant: CCN(C(=O)c1cccnc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(Cl)c1cccnc1
Product: CCN(Cc1cccnc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 19.2 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and nicotinoyl chloride hydrochloride according to an analogous synthetic method to Preparation Example 86, pyridine-3-carboxylic acid ethyl [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amide (162 mg) was used according to an analogous synthetic method to Example 337 described below to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]pyridin-3-ylmethylamine (30 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 described below to provide the title compound (23 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([O-:19])=[O:18]
Reactant: N#Cc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 100 °C
Yield: 95.5 %

Procedure:
In 50 ml of N,N-dimethylformamide were dissolved 5.0 g of 3-cyanophenol and 5.93 g of 2-fluoronitrobenzene followed by addition of 8.71 g of potassium carbonate, and the mixture was stirred with heating at 100° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water 3 times, dried and concentrated. The residue was crystallized from diisopropyl ether to give 9.63 g of the title compound as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6]
Reactant: O=Cc1cc(F)cc(Br)c1
Solvent: CO
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-fluorobenzaldehyde(22.25 g, 0.11 mole) in methanol at rt was added NaBH4,(2.07 g, 0.055 mole) stirred at rt for 2 hr. The reaction was quenched with H2O, and concentrated. The residue was diluted with diethyl ether, washed with 1 N HCl, brine, dried over MgSO4, and concentrated. 3-Bromo-5-fluorobenzyl alcohol was obtained as a colorless oil was collected (14.6 g, 65%). 1H NMR (DMSO-d6) δ 4.50 (m, 2H), 5.44(t, 3H, J=5.93 Hz), 7.16 (dd, 1H, J=1.09, 8.79 Hz), 7.36 (s, 1H), 7.38 (dd, 1H, J=2.99, 6.15 Hz); Anal. Calc. For C7H6Br2FO: C, 41.01; H, 2.95. Found: C, 41.30; H, 3.01.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CS(O)(=O)=O.B(OC)(OC)OC.N>C(Cl)Cl>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: CS(=O)(=O)O
Agent: N
Solvent: ClCCl
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 25.9 %

Procedure:
10 g of 7-aminocephalosporanic acid was added to 80 ml of methylene chloride and the resulting mixture was cooled to 0° C., and then, 36.2 m of methanesulfonic acid was added slowly thereto. 7.4 ml of trimethyl borate was added thereto at the above temperature and the resulting mixture was stirred at 0 ° C. for 5 hours, and then, the resulting mixture was added to ice-water. The pH of the mixture was adjusted to 3.5 with aqueous ammonia. The ocherous solid formed was isolated by filtration and washed with water. The wet solid was dispersed in water and adjusted the pH to 8 with aqueous ammonia to dissolve the solid in water. Thereafter, the pH of the resulting mixture was adjusted to 3.5 with 3N hydrochloric acid. The resulting mixture was filtered to obtain crystals and the crystals were washed with water and then, dried overnight in a vacuum to give 2.32 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid as an ocherous solid (Yield: 26% and Purity: 95.5%). H-NMR data was equal to that of the compound prepared in Example 1.