Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:9]([O:11][CH3:12])=[O:10])(=O)C>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(COC(C)=O)c1
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(CO)c1
Temperature: 25 °C

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and nitrogen inlet, was placed 318 g of the previously prepared methyl 3-acetoxymethyl -4-nitrobenzoate and 3.2 l of anhydrous methanol. To the resulting solution was bubbled in 40 g of hydrogen chloride and the resulting mixture was refluxed for 3 hours. After cooling to room temperature the solvent was removed using a rotary evaporator yielding 273 g of methyl 3-hydroxymethyl-4-nitrobenzoate as a yellow solid containing traces of methanol, which was used as such in the next step.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[F:14].[CH3:16][OH:17]>>[CH3:2][O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:17][CH3:16])=[CH:7][C:6]=1[F:14]
Reactant: CO
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: [Na]
Product: COC(=O)c1cc([N+](=O)[O-])c(OC)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
A mixture of sodium metal (1.27 g, 0.055 mol) and MeOH (250 mL) was stirred at 0° C. for 10 minutes. This solution was added to a solution of 2-fluoro-5-nitrobenzoic acid methyl ester (10.0 g, 0.046 mol) in MeOH (250 mL), and the mixture was stirred for 20 minutes at 0° C. to 5° C. The reaction mixture was then allowed to warm to room temperature and stir for 2 hours. The mixture was then filtered to give an off-white precipitate. Recrystallization with CHCl3 (70 ml) yielded an off-white crystalline solid, 1.825 g (0.008 mol, 17%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[CH2:9]([O:11][C:12]([NH:14][C:15]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[S:16])=[O:13])[CH3:10]
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(Br)cn1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-bromopyridin-2-amine (14.7 g, 85.0 mmol) and ethoxycarbonyl isothiocyanate (11.1 g, 10.0 ml, 85.0 mmol) in dioxane (300 ml) was stirred for 18 hours at 25° C. under nitrogen atmosphere. The solvent was evaporated under reduced pressure, the solid yellow residue was diluted with ethyl acetate and washed with water and brine, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated to dryness. 26.2 g (quant.) light yellow solid. Mp.: 159-161° C. MS: m/z=304.0/305.9 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
3-methyl pyrazole 1-carboxylic acid tert-butyl ester (4.0 g, 21.95 mmol) was dissolved in 73 mL of CCl4. N-bromosuccinimide (5.47 g, 30.73 mmol) and benzoyl peroxide (744 mg, 3.07 mmol) were added. This solution was warmed to reflux for 5.5 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution. The phases were separated, and the organic phase was extracted with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (SiO2, ISCO chromatography system, elution with 5 to 10% ethyl acetate in hexanes) provided 3-bromomethyl pyrazole 1-carboxylic acid tert-butyl ester (53-2) as a pale yellow oil (2.94 g, 51% yield). 1H NMR was consistent with desired product.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][C:29]=1[F:42])[CH2:2][CH2:3][CH3:4].C([Sn](=O)CCCC)CCC.[N:53]([Si](C)(C)C)=[N+:54]=[N-:55].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([OH:25])([CH3:23])[CH3:24])[CH2:16][CH2:15]2)[C:7](=[O:26])[C:6]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[NH:55][N:54]=[N:53][N:41]=2)=[CH:30][C:29]=1[F:42])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12

Procedure:
A mixture of 4′-({7-butyl-4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile (0.76 g), dibutyltin oxide (0.17 g), azidotrimethylsilane (4.60 g) and toluene (15 mL) was refluxed overnight. 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. To a solution of the residue in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3 mL) at room temperature, and the mixture was refluxed for 3 hr. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.58 g, 71%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:8][CH2:7][N:6]1[C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([CH3:17])[N:12]=1)=[O:10])=[O:4].[Li+].[OH-].Cl>CO.O>[CH3:17][N:13]1[C:14]([CH3:16])=[CH:15][C:11]([C:9]([N:6]2[CH2:7][CH2:8][C@H:5]2[C:3]([OH:4])=[O:2])=[O:10])=[N:12]1
Reactant: COC(=O)[C@@H]1CCN1C(=O)c1cc(C)n(C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N2CC[C@H]2C(=O)O)nn1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of (2S)-methyl-1-[(1,5-dimethylpyrazol-3-yl)carbonyl]azetidine-2-carboxylate (398.4 mg, 1.68 mmol) in methanol (12 mL) was added 1N LiOH in water (3.1 mL) at about 0° C. The mixture was stirred under argon at about 0° C. for about 30 minutes and then at about room temperature overnight. The pH was adjusted to about pH 1 by adding 1 N HCl and then the mixture was diluted with water and extracted with dichloromethane. The organic layers were washed with brine, dried over sodium sulfate and then concentrated to give 315.2 mg (84% yield) of the product as a white solid. 1H NMR (CDCl3) δ 2.32 (s, 3H); 2.49-3.89 (series of m, 2H); 3.84 (s, 3H); 4.40-4.71 (series of m, 2H); 5.20 (t, 1H, J=7.7); 6.57 (s, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH3:29][N:30]([CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH2:36])[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][CH:39]=1)[NH:36]/[C:18](=[C:6]1\[C:5](=[O:28])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(C)Cc1cccc(N)c1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1cccc(CN(C)C)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 3-(dimethylaminomethyl)-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/ethanol=30:1) C27H27N3O3
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].[Cl-].[NH4+]>CS(C)=O>[N:4]1([CH2:3][CH:2]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[O:1][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:31]([CH3:32])[CH3:33])=[O:29])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: COc1ccc(COCC(O)Cn2ccnc2)cc1
Reactant: CC(C)OC(=O)CCCCCBr
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc(COCC(Cn2ccnc2)OCCCCCC(=O)OC(C)C)cc1
Reaction time: 0.5 h

Procedure:
1-[2-Hydroxy-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 1b; 10 g, 0.038 mol) was added to a stirred suspension of powdered potassium hydroxide (8 g, 0.14 mol) in dimethylsulphoxide (20 ml) at 18° C. and stirred for 0.5 hours. Isopropyl 6-bromohexanoate (10.5 g, 0.044 mol) was then added and the mixture was stirred for 0.5 hours at 18° C. The mixture was poured into saturated aqueous ammonium chloride (1500 ml) and extracted with dichloromethane. The combined extracts were dried (Na2SO4) and the solvent was evaporated off under reduced pressure to give the crude product which was purified by column chromatography (silica gel, 2% ethanol in chloroform) to give isopropyl 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoate as a pale-yellow oil.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Na].[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](=O)[CH3:15])=[CH:10][CH:9]=1>CO>[Cl:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[CH:14]([NH2:5])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(=O)C(C)Oc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: CO
Product: CC(N)C(C)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.3 %

Procedure:
82 g of ammonium acetate and 6.7 g of sodium cyanoborohydridc were added to a solution containing 21 g of 3-(4-chlorophenoxy)-2-butanone dissolved in 500 mL of methanol, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was then concentrated under reduced pressure, and 180 mL of concentrated hydrochloric acid and 100 mL of water were added to the residue. The whole mixture was extracted with 300 mL of diethyl ether. The obtained water layer was alkalifled using a 5% aqueous solution of sodium hydroxide, and then extracted with 500 mL of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulphate, and then concentrated under reduced pressure. A fraction possessing a low boiling point was removed from the obtained oily products to afford 18 g (yield 86%) of the desired product. Refractive index: 1.5360.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[H-].[Na+].[Cl:16][CH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[N:30][C:31]([Cl:37])=[CH:32][CH:33]=2)[N:28]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[ClH:16].[Cl:37][C:31]1[N:30]=[C:29]2[C:34]([CH:35]=[CH:36][C:27]([N:18]3[CH:17]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:3]4[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:26])=[N:28]2)=[CH:33][CH:32]=1
Reactant: CC1CCCC(C)N1CCCCO
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCC(C)N1CCCCOC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 11.9 %

Procedure:
The procedure is as in Example 7, but starting with 4-(2,6-dimethyl-1-piperidyl)butanol (8 g) in anhydrous tetrahydrofuran (220 cc), an oily suspension (50% by weight; 1.9 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (8.6 g). The residue obtained is taken up with ethyl acetate (20 cc); the insoluble product is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue obtained is taken up with water (50 cc) and 4N aqueous hydrochloric acid solution (20 cc); the remaining insoluble product is removed by filtration. The filtrate is neutralized with 4 N aqueous sodium hydroxide solution and then extracted with methylene chloride (3×100 cc); the organic extracts are combined and washed with water, dried and concentrated to dryness under reduced pressure (3 kPa) at 40° C. The residue obtained is recrystallized successively in ethyl acetate and 2-propanol, and 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[4-(2,6-dimethylpiperidino)butoxy]-1isoindolinone hydrochloride (1.6 g) is thereby obtained.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:37])[CH2:11][CH:12]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH2:35][CH3:36])[CH:27]=1)[N:13]1[C:17](=[O:18])[C:16]2=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]2[C:14]1=[O:25])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[CH2:35]([O:34][C:28]1[CH:27]=[C:26]([CH:12]([N:13]2[C:17](=[O:18])[C:16]3=[C:19]([CH3:24])[C:20]([CH3:23])=[CH:21][CH:22]=[C:15]3[C:14]2=[O:25])[CH2:11][C:10]([NH:9][OH:8])=[O:37])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33])[CH3:36]
Reactant: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C)c(C)c3C2=O)ccc1OC
Yield: 83.4 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide was prepared by the procedure of Example 16 from N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-(3,4-dimethylphthalimido)propanamide (0.63 g, 1.25 mmol), Pd(OH)2/C (100 mg) and hydrogen (50 psi) in ethyl acetate and methanol (30 mL each) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(3,4-dimethylphthalimido)propionamide as a white solid (430 mg, 84% yield): mp, 197.0–202.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H, CH3), 2.35 (s, 3H, CH3), 2.56 (s, 3H, CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.65 (t, J=7.9 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.00 (br s, 1H, Ar), 7.59 (br s, 2H, Ar), 8.78 (br s, 1H, OH), 10.56 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 13.22, 14.65, 19.33, 34.21, 49.88, 55.43, 63.72, 111.75, 112.40, 119.62, 120.39, 127.76, 129.33, 131.36, 134.71, 136.50, 145.13, 147.62, 148.48, 166.02, 167.32, 168.65; Anal Calcd for C22H24N2O6+0.3 H2O: C, 63.24; H, 5.93; N, 6.70. Found: C, 63.11; H, 5.88; N, 6.67.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31](O)=[O:32])=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH:29]=[CH:30][C:31]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:32])=[CH:34][CH:35]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1ccc(F)cc1
Yield: 68.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (3.1 mL), 4-fluorocinnamic acid (1.9 g), WSC.HCl (2.1 g), and methylene chloride (100 mL), to give the captioned compound (2.5 g, 69%) as an amorphous solid product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[N:19]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ccc(OCc3cc(-c4ccc(C(F)(F)F)cc4)nn3C)cc21
Temperature: 0 °C
Reaction time: 14 h
Yield: 30 %

Procedure:
To an ice cold solution of (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (35 mg, 160 μmol; example 2 e]), [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-methanol (41 mg, 160 μmol) and tributylphosphine (50 μl, 19 μmol) in tetrahydrofuran (3.5 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (33 mg, 19 μmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a brown oil which was purified by column chromatography (silica gel, heptane/AcOEt) to obtain 22 mg (50 μmol, 30%) of the title compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][O:8][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (3.00 g, 13.6 mmol) in DMF (10 ml) was added under a nitrogen atmosphere imidazole (2.89 g, 42.0 mmol). After cooling to 0° C. tert-butyldimethylchlorsilan (3.37 g, 22.3 mmol) was added and the reaction mixture was stirred for 18 h in a thawing ice bath. It was diluted with water (20 ml) and extracted with EtOAc (20 ml). The aqueous layer was extracted with ethyl acetate (20 ml) and the organic layers were washed with water (20 ml) and brine (20 ml) and were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (4.35 g, 96%) as a colorless liquid. MS m/e: 279.0 [M−tBu]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]#[N:17])=[C:4](F)[CH:3]=1.CC([O-])(C)C.[K+].[CH:25]1([OH:29])[CH2:28][CH2:27][CH2:26]1.Cl>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([C:16]#[N:17])=[C:4]([O:29][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: CCc1ccc(-c2cc(Br)cc(F)c2C#N)cc1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: CCc1ccc(-c2cc(Br)cc(OC3CCC3)c2C#N)cc1
Reaction time: 5 h

Procedure:
1-Bromo-4-cyano-3-fluoro-5-(4-ethyl-phenyl)-benzene (1.2 g) is added to a flask charged with a stir bar, KOtBu (0.5 g) and cyclobutanol (3.0 g). The solution is stirred at room temperature overnight, before another portion of KOtBu (0.2 g) is added. The solution is stirred for another 5 h and then neutralized with 1 M aqueous HCl solution. The resulting mixture is extracted with ethyl acetate, the combined organic phases are dried (sodium sulphate) and the solvent is removed to give the title compound.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39]O)=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23].N1C=CC=CC=1>C(#N)C>[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39][Br:1])=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CO)cc3C(F)(F)F)cc12
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.273 g (3.02 mmol) of triphenylphosphine dibromide are added under argon in portions at 0° C. to a solution of 0.97 g (2.32 mmol) of benzyl alcohol derivative from Example VI in 15 ml of acetonitrile and 0.3 ml (3.72 mmol) of pyridine. After 15 minutes the cooling bath is removed and the mixture is stirred for 2 hours at room temperature. The reaction solution is concentrated in vacuo, and the residue is dissolved in a little toluene and purified by chromatography on silica gel 60 by means of toluene.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:38]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:9][CH:8]=1)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Product: CN(CCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1)C(=O)c1ccccc1

Procedure:
Acylation of tert-butyl (3RS,4RS)-4-[4-(3-methylamino-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride analogously to the procedure described in Example 22(k) gave tert-butyl (3RS,4RS)-4-[4-[3-(benzoyl-methyl-amino)-propoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 609 (M+H)+.
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:24])=[C:18]([CH2:21][CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[C:11]([NH:13][CH:14]2[C:39](=[O:40])[N:16]3[C:17]([C:23]([O:25][CH:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[S:24])=[C:18]([CH2:21][CH3:22])[CH2:19][S:20][C@H:15]23)=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of benzhydryl 7-[2-(6-formamidopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.5 g) in methanol (100 ml) and tetrahydrofuran (25 ml) was added conc. hydrochloric acid (1.5 ml). The solution was stirred for 90 minutes at 30° to 35° C. The resultant solution was adjusted to pH 5.0 with a saturated aqueous solution of sodium bicarbonate and then methanol was evaporated under reduced pressure. The residual oil was dissolved in ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.4 g), mp. 121° to 128° C. (dec.).