Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1)C1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of 1-(3-(benzylamino)-4-nitrophenyl)piperidine-4-carboxylic acid (0.2 g, 0.56 mmol) and aniline (0.052 mL, 0.56 mmol) in DMF (5 mL) was added diisopropylethylamine (0.198 mL, 1.12 mmol) under argon. The mixture cooled to 0° C., HATU (0.212 g, 0.56 mmol) was added at that temperature and then stirred at room temperature for 4 h. After completion of reaction (by TLC), H2O (5 mL) was added drop by drop. The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish 1-(3-(benzylamino)-4-nitrophenyl)-N-phenyl piperidine-4-carboxamide (0.21 g), 87% yield. 1H NMR (500 MHz, DMSO): δ 1.57 (m, 2H), 1.82 (m, 2H), 2.65 (m, 1H), 2.99 (m, 2H), 3.98 (m, 2H), 4.60 (d, J=5.7 Hz, 2H), 5.97 (d, J=2.5 Hz, 1H), 6.44 (dd, J=2.5 Hz, 1H), 7.03 (m, 1H), 7.29 (m, 3H) 7.37 (m, 2H), 7.43 (m, 2H), 7.60 (m, 2H), 7.92 (d, J=9.7 Hz, 1H), 8.84 (m, 1H), 9.9 (bs, 1H). HRMS (ESI) calculated for C25H27N4O3: 431.2078, Found: 431.2005.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH:11]1([C:17]2[CH:18]=[CH:19][C:20]([NH:21][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])=[CH:22][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(C2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(C2CCCCC2)cc1

Procedure:
The product (280 mg) is obtained according to the method of stage 1 of Example 4, by using 400 μL of 2-fluoro-nitrobenzene and 1 g of 4-cyclohexylaniline in the presence of 683 mg of potassium tert-butanolate in 4 mL of DMSO.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br)[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[Cl:1])[CH3:18]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25 g (0.162 mol) of 6-chloropurine was dissolved in 500 ml of dimethylformamide and 89.4 g (0.647 mol) of potassium carbonate was added to this solution. 23.4 ml (0.162 mol) of 4-bromobutyric acid ethyl ester was added dropwise over a period of 4 hours. The solution was stirred for 16 h at room temperature. The solvent was removed in vacuo, the residue was dissolved in EE and the solution was washed three times with water and once with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/EE (1/1). Yield: 28.7 g.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH2:14](N)[CH2:15][CH2:16][CH3:17].N>O1CCOCC1>[CH2:14]([NH:1][C:2]1[C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN
Reactant: NC1=NS(=O)(=O)c2cccc(Cl)c21
Agent: N
Solvent: C1COCCO1
Product: CCCCNC1=NS(=O)(=O)c2cccc(Cl)c21
Reaction time: 2 h

Procedure:
A solution of 2.17 g of the 3-amino-4-chlorobenzo[d]isothiazole-1,1-dioxide prepared according to Example II and 2 ml of n-butylamine in 15 ml of dioxane was boiled for approx. 2 hours, ammonia escaping. After distilling off the solvent, the residue was stirred with water, sucked off, washed successively with water and petroleum ether and dried. The desired product was obtained in a yield of 2.4 g, melting-point 136°-138° C.
Reaction SMILES: C(Cl)Cl.[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][CH2:17][OH:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([O:18][CH2:17][CH2:16][C:6]1[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:9][C:5]=1[CH3:4])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reaction time: 0.25 h

Procedure:
To methylene chloride (200 ml) were added 2-(5-methyl-2-phenyl-oxazol-4-yl)ethanol (20 g) and triethylamine (19.2 ml). Thereto was dropwise added methanesulfonyl chloride (9.52 ml) at 0° C. and the mixture was stirred at the same temperature for 15 min. The mixture was washed with 10% aqueous citric acid solution (200 ml), saturated aqueous sodium hydrogencarbonate solution (100 ml) and saturated brine (100 ml) and dried over Na2SO4. Methylene chloride was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (21.45 g).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N+]=[N-])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[CH:8][CH:9]=1)[O:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:18]
Reactant: CCOC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: OC1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
Ethyl 2-(4-cyclopropylsulfonylphenyl)-2-diazo-acetate (36 g, 121.62 mmol) was dissolved in DCM (608 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (12.75 mL, 133.78 mmol) was added followed by rhodium(II)acetate dimer (1.12 g, 0.021 mmol). Mixture was stirred at 25° C. for 1 hr. Reaction mixture was diluted with DCM (500 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a product (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid ethyl ester (50 g).
Reaction SMILES: [H-].[Na+].[Br-].[CH2:4]1[CH2:35][O:34][CH2:33][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:5]1.CC1(CCCCCCCBr)OCCO1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:69]([O:76][C:77]1[CH:78]=[C:79]([CH:82]=[CH:83][C:84]=1[O:85][CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)[CH:80]=O)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CS(C)=O.O>[CH2:69]([O:76][C:77]1[CH:78]=[C:79]([CH:80]=[CH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[O:5][CH2:4][CH2:35][O:34][CH2:33]2)[CH:82]=[CH:83][C:84]=1[O:85][CH2:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)[C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1
Reactant: c1ccc([P+](CCCCCCCC2COCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CC1(CCCCCCCBr)OCCO1
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Solvent: O
Product: C(=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)CCCCCCC1COCCO1
Reaction time: 0.75 h
Yield: 36.6 %

Procedure:
A mixture of 640 mg of oily sodium hydride (60%) and 10 mg of dimethyl sulfoxide was stirred for 45 minutes at 75° to 80° C. After cooling the mixture, a mixture of 50 ml of dimethyl sulfoxide and 8.2 g of 8-ethylenedioxynonyl triphenylphosphonium bromide prepared from 2-methyl-2-(7-bromoheptyl)-1,3-dioxolan and triphenylphosphin was added to the mixture. After 10 minutes, a mixture of 2.5 g of 3.4-dibenzyloxybenzaldehyde and 10 ml of dimethyl sulfoxide was added to the mixture at room temperature and the resultant mixture was stirred overnight. To the reaction mixture was added 500 ml of water and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide an oily product. The product was applied to the silica gel (200 ml) column chromatography and eluted with a mixture of n-hexane and ether (1:1) to provide 1.4 g of 1-(3,4 -dibenzyloxyphenyl)-9-ethylenedioxy-1-decene.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[OH:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:43]=1
Reactant: NCCc1ccc(O)cc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-(2-aminoethyl)-phenol. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 90% yield, m.p. 190-194° C. MS [(+)ESI, m/z]: 572 [M+H]+
Reaction SMILES: [CH3:1][C:2]([N+:7]([O-:9])=[O:8])([CH2:5][OH:6])[CH2:3][OH:4].[C:10]1(=O)OCC[O:11]1>C(OCC)(=O)C>[CH3:1][C:2]1([N+:7]([O-:9])=[O:8])[CH2:5][O:6][C:10](=[O:11])[O:4][CH2:3]1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: O=C1OCCO1
Solvent: CCOC(C)=O
Product: CC1([N+](=O)[O-])COC(=O)OC1

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol and ethylene carbonate is heated overnight. The reaction mixture is diluted with ethyl acetate and the solution is washed with water. The organic phase is dried and concentrated to obtain 5-methyl-5-nitro-1,3-dioxan-2-one. This is dissolved in methanol and hydrogenated under pressure to give the 5amino compound which is acylated with dodecanoyl chloride to give the product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:13](Cl)(Cl)[C:14](Cl)=[O:15].C(=O)([O-])O.[Na+].[Cl-].[NH4+]>[Cu].[Zn].[Zn].CCCCCCC.C(OCC)(=O)C.C(COC)OC.C(OCC)C>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:13][C:14](=[O:15])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C1CC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a diethyl ether (100 mL) solution of allyl benzyl ether (11.1 g, 75.0 mmol), was added zinc copper couple (74.5 g, 33.0 mmol) while stirring at room temperature, a dimethoxyethane (100 mL) solution of trichloroacetyl chloride (43.6 mL, 375 mmol) was added dropwise, and the mixture was stirred at mom temperature for six hours. The reaction mixture was poured into ice-cooled aqueous sodium hydrogencarbonate (500 mL), extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1). The obtained dichloro product was dissolved in methanol (200 mL), ammonium chloride (20.0 g, 375 mmol) was added and zinc powder (30.0 g, 450 mmol) was added little by little while vigorously stirring. After the reaction was completed, the insoluble matters were filtered off with Celite, the filtrate was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent in the filtrate was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=15/1 then 12/1) to obtain the title compound (7.20 g, 37.9 mmol).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[CH3:9][S:10]SC>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([S:10][CH3:9])[CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CSSC
Solvent: Cc1ccccc1
Product: CSc1cc(C)ccc1O
Temperature: 160 °C
Yield: 49.1 %

Procedure:
A mixture of para-cresol (65 grams, 0.60 moles) and toluene (20 ml) was distilled until the mixture was free of toluene. Aluminum turnings (1.1 grams, 0.04 gram atoms) were then added to the dried para-cresol and this mixture was heated at 150°-160° C. until cessation of hydrogen evolution. Methyldisulfide (36 ml, 0.4 moles) was added and the mixture heated at reflux (about 160° C.) overnight. The mixture was refluxed for another additional 4 hours and was then flashed under a vacuum. The flashed mixture was then distilled through a 0.7×30 cm packed column to yield 30.3 grams of 4-methyl-2-(methylthio)-phenol, a 55 percent yield. Subsequently, MMR analysis verified the identity of the compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH2:24][C:25](Cl)=[O:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:25](=[O:26])[CH2:24][C:17]2[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(OC)c(CC(=O)Cl)c1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(OC)c(CC(=O)NCCc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with 2,5-dimethoxyphenyl acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[N+:9]([O-])[C:8]([C:13]#[N:14])=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:13]#[N:14])[CH:7]=1
Reactant: Cc1ccc2ccc(C#N)[n+]([O-])c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(Cl)cc(C#N)nc2c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 7-methylquinoline-2-carbonitrile 1-oxide (11.5 g, 63 mmol) and phosphorus oxychloride (47 mL, 500 mmol) was heated at 100° C. for 10 min then at 200° C. for 20 min. The reaction mixture was poured into crushed ice and the precipitate was filtered. The crude material was then purified by flash chromatography on silica gel (eluting solvent: 3% acetone in dichloromethane) to provide the title compound. 1HNMR (400 MHz, acetone-d6): δ 8.25 (d, 1H), 8.10 (s, 1H), 8.00 (d, 1H), 7.82 (dd, 1H), 2.65 (s, 3H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:12]([Si:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)Cl)([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[Si:16]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])([C:12]([CH3:15])([CH3:14])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45 %

Procedure:
In DMF (120 ml), 1,4-butanediol (4.0 g) was dissolved. The solution was added with imidazole (3.02 g) and t-butyldiphenylchloro silane (12.2 g), and the whole was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure and then added with a saturated aqueous ammonium chloride solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate) thereby obtaining the subject compound (6.56 g) as a colorless oily substance.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[CH3:21][O:20][CH:18]1[CH2:17][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:6][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:8]3)[S:10][CH:11]=2)=[O:15])[CH2:19]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: COC1CN(C(=O)c2csc(N3CC(SC(C)=O)C3)n2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1CN(C(=O)c2csc(N3CC(SC4=C(C(=O)OCc5ccc([N+](=O)[O-])cc5)N5C(=O)[C@H]([C@@H](C)O)[C@H]5[C@H]4C)C3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 3-acetylthio-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (350 mg, 1.07 mmol) (obtained as described in Reference Example 31) in dimethylformamide (18 ml) was added hydrazine acetate (118 mg, 1.28 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (636 mg, 1.07 mmol) in acetonitrile (32 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (746 μl, 4.28 mmol). The mixture was stirred for 6 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (95:5 and 9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (636 mg, yield 94%) as a pale yellow solid.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:15][CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9].Cl[C:45]([O:47][CH2:48][CH3:49])=[O:46]>>[CH2:7]([C:10]1[N:23]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:29][CH:30]=2)[C:13]2[CH:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:15]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:16][CH2:17][C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Reactant: CCOC(=O)Cl
Agent: O=C(O)C(=O)O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)OCC)CC2
Yield: 84.6 %

Procedure:
The compound obtained in Example 62 (1.00 g) is treated in the same manner as in Example 64 with using ethyl chloroformate (0.27 g) instead of acetic anhydride to give ethyl 2-n-propyl-5-ethoxycarbonyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.82 g) as a white foam.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:42]=[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH:40]=O)=[CH:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:46]([O:45][C:43]1[CH:42]=[C:27]([CH:26]=[C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](/[CH:40]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sodium hydride (60%, oily, 2.11 g) was added to a mixture of ethyl diethylphosphonoacetate (10.5 ml) and tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 30 minutes. A solution of 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (22.7 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (21.9 g, yield: 84%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.