Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Zn+]>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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Fc1cccc(C[Zn+])c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (3-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 4 h. The reaction was quenched by addition of methanol (50 mL), diluted with EtOAc and washed with NH4Cl. The organic layer was dried over Na2SO4, filtered and evaporated to yield a yellow oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(3-fluorobenzyl)isonicotinate (6.766 g, 85%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.21 (s, 2H), 6.88-7.00 (m, 2H), 7.02-7.07 (m, 1H), 7.22-7.30 (m, 1H), 7.66-7.73 (m, 2H), 8.68-8.73 (m, 1H). MS m/z 246 (M+H)+
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1.[Cl-].[NH4+]>CCCCCC.CCOCC.O1CCCC1>[CH2:14]1[O:15][C:16]2([CH2:21][CH2:20][C:19]([OH:22])([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]2)[O:23][CH2:13]1
Reactant: Brc1ccncc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccncc2)CCC2(CC1)OCCO2
Yield: 67.2 %

Procedure:
Thirty-five ml of ether was cooled to -78° C., to which 20 ml of a 1.6 mol n-butyl lithium solution in hexane was added. Next, 5 g of 4-bromopyridine was dissolved in 30 ml of ether and the solution was added to the mixture. Then, a solution of 5 g of 1,4-cyclohexanedione monoethyleneacetal in 30 ml of tetrahydrofuran was added to the mixture. After completion of the reaction, the reaction solution was poured into saturated ammonium chloride aqueous solution. The mixture was extracted with chloroform and the extract was purified to give 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone ethyleneacetal.
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]([NH:20][NH:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)=[S:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1COCC1.[Hg](OC(C)=O)OC(C)=O>[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]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[N:21][N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A solution of tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo [3.2.1]octane-2-carbonyl)hydrazinecarbonothioyl)piperazine-1-carboxylate (0.66 g, 1.27 mmol) and Lawesson's reagent (0.36 g, 0.89 mmol) in THF (15 mL) was heated at 66° C. for 1 h, then cooled down to rt Hg(OAc)2 (0.4 g) was added and the mixture was stirred at rt overnight. The solution was then concentrated and the residue was purified by silica gel column chromatography (1:2 EtOAc/petroleum ether) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (0.15 g, 24%) as a light yellow solid. ESI-MS (EI+, m/z): 501 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O>[Si:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
N,N-dimethylformamide (70 ml), was mixed with 5.00 g (36.7 mmol), of 4′-hydroxyacetophenone, 6.64 g (44.1 mmol), of tert-butyldimethylchlorosilane, and 6.00 g (88.1 mmol), of imidazole and the mixture was stirred for 12 hours at room temperature. The reaction mixture was poured onto ice water to stop the reaction and extracted with 100 ml of ethyl acetate. The organic extract was washed with 100 ml of water ten times and then with saturated saline and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform 100%), to obtain 5.23 g (yield: 56.9%), of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]>CN(C)C=O.N1C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:19]=1[C:20]#[N:21]
Reactant: Oc1ccc(F)cc1F
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(COc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
2,4-Difluorophenol (0.11 g, 0.83 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried. Purification by silica gel chromatography (50% hexanes in dichloromethane) yielded 165 mg of 2-(2,4-difluorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:29][C:30]([CH3:32])=O.C([O-])(=O)C.[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:30]([CH3:32])[CH3:29])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCNCC4)c3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(Cl)cc(N4CCN(C(C)C)CC4)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.7 %

Procedure:
To a solution of 2-(3-chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (Example 31, 0.054 g, 0.14 mmol), acetone (0.060 g, 1.4 mmol), sodium acetate (0.023 g, 0.27 mmol), and acetic acid (0.16 g, 2.7 mmol) in 1,2-dichloroethane/methanol (5/5 mL) was added sodium triacetoxyborohydride (0.56 g, 2.7 mmol). The mixture was stirred at room temperature for 16 h and then concentrated. The residue was purified by silica gel chromatography eluting with 0-100% 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2. This material was further purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. The product fractions were concentrated and the residue was dissolved in acetonitrile and water. The mixture was basified with concentrated NH4OH and concentrated. The residue was purified by reverse phase HPLC eluting with 10% to 90% CH3CN in H2O without TFA to afford the title compound (0.011 g, 18%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.52 (s, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.18 (t, J=1.5 Hz, 1H), 6.82 (d, J=2.5 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.35-3.60 (br s, 4H), 2.85-3.15 (br s, 4H), 1.25-1.40 (br s, 1H), 1.23 (d, J=6.5 Hz, 6H); ESI MS m/z 443 [M+H]+.
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:22])([F:24])[F:23])[CH:12]=2)[C:3]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Yield: 55.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (395 mg, 1.04 mmol) and 2-aminothiazole (209 mg, 1.38 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.09 mL, 1.38 mmol) was heated at 110° C. for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded the 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (256.7 mg, 55.1%) as a white solid: mp 95-100° C.; EI-HRMS m/e calcd for C19H21F3N2O3S2 (M+)446.0946, found 446.0944.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:18]=[CH:17][C:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25]CC5C=CC=CC=5)=[N:23][CH:24]=4)=[CH:15][N:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[C].[Pd].CO>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[N:14]=[CH:15][C:16]([C:19]4[CH:20]=[CH:21][C:22](=[O:25])[NH:23][CH:24]=4)=[CH:17][N:18]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc(COc2ccc(-c3cnc(OC4CCN(C5CCCC5)CC4)nc3)cn2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)c[nH]1

Procedure:
10% palladium-carbon (700 mg) was added to a methanol solution (30 ml) of 2-(cyclopentylpiperidin-4-yloxy)-5-(2-benzyloxypyridin-5-yl)pyrimidine (2.22 g), and stirred in a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered to remove palladium-carbon, and the filtrate was concentrated under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1.C1C[O:50][CH2:49]C1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:49]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:50])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCOCC4)ccc3c(OC(C)C)n2)n[nH]1
Temperature: 150 °C

Procedure:
A 2.0˜5.0 mL process vial was charged with trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester (56.2 mg, 1 mmol), Pd(OAc)2 (4 mg), Mo(CO)6 (26.4 mg), morpholine (26.0 mg), DBU (45 mg), and dry THF (2 mL). The vial was immediately capped under air and heated at 150° C. for 15 min under microwave irradiation. After cooling, the reaction mixture was filtered through a short silica gel column, and the solvent was removed under reduced pressure. The residue was sent to prep-HPLC to give 5 mg of [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-morpholin-4-yl-methanone as a yellow solid. LC-MS m/e 396 (MH+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])[NH:13][NH2:14])(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCNC(C)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(=O)NCCNC(=S)NN
Temperature: 4 °C

Procedure:
A solution of methyl N-(2-acetamidoethyl)-dithiocarbamate (57.7 g) and hydrazine hydrate (14.6 cc) in absolute ethanol (300 cc) is heated under reflux for 2 hours. The mixture is then cooled to 4° C. and is filtered, and the insoluble matter is dried at 30° C. under 0.05 mm Hg. 4-(2-Acetamidoethyl)-thiosemicarbazide (39.5 g) is obtained in the form of white crystals (instantaneous m.p. [Kofler]=171° C.).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:11](Cl)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](Cl)=[O:15].C(O)(=O)C(O)=O>[N+](C1C=CC=CC=1)([O-])=O.CCO>[CH:1]1[C:6]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:21])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2ccccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
7.2 g (0.2 mols) of benzene were added at ambient temperature and in a gentle stream of dry nitrogen to 26.6 g (0.2 mols) of anhydrous AlCl3 in 300 ml nitrobenzene. The mixture was heated to 100° C.; after agitation for 15 minutes at this temperature, 20.2 g (0.1 mols) of phthalic acid dichloride dissolved in 100 ml nitrobenzene were added during about 20 minutes. The volume of the solution was made up to 500 ml with nitrobenzene and the temperature was kept at 100° C. with agitation for 30 minutes, after which the reacting substance was cooled and 300 ml of saturated aqueous solution of oxalic acid was added with intense agitation. Three extractions were made, each time with 200 ml ethyl ether and the combined extracts were dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by crystallization from toluene, giving 17.7 g (85% yield) of 9,10-anthraquinone (1), m.p. 285° C. (literature: 286° C., EtOH).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:47])([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])=[O:47])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(C)COC(=O)OC(C)I
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(C)COC(=O)OC(C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
In 80 ml of dimethylacetamide is dissolved 5.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and the solution is cooled to -5° C. With stirring, 4.8 g of 1-iodoethyl 2-methylbutyl carbonate is added at one stroke and stirring is continued for 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice-water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate and these organic layers are combined, water with three 150-ml portions of ice water and three 150-ml portions of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off and isopropyl ether is added to the residue. The thus-obtained white powder is collected by filtration, washed with isopropyl ether and dried to give 2.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[C:10](C)[CH:9]=[C:8]([CH3:13])[CH:7]=1)=[O:5].[OH:19]O>S(=O)(=O)(O)O>[CH3:4][C:6]1[CH:11]=[C:10]([OH:19])[CH:9]=[C:8]([CH3:13])[CH:7]=1.[Br:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[C:4]([OH:5])=[O:19]
Reactant: OO
Reactant: Cc1cc(C)cc(C(=O)c2ccc(F)cc2Br)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(C)cc(O)c1
Product: O=C(O)c1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
30.8 g (0 1 mol) of 2-bromo-4-fluoro-3',5'-dimethylbenzophenone were dissolved in 140 g of 90% sulfuric acid, and 5.7 g of 90% hydrogen peroxide solution were added dropwise (metering time 1 h) between -10° C. and 0° C. After subsequent stirring for 2 h, the mixture was poured on to 500 g of ice and then heated at the boil for 5 h. Isolation as described in Example 8 gave 9.6 g (0.079 mol, 79%) of 3,5-dimethylphenol and 15.6 g (0.071 mol, 71%) of 2-bromo-4-fluorobenzoic acid (crude, purity (GC) ca. 90%, melting point 160°-166° C.)
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].Cl[CH2:21][C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>O1CCCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22](=[O:29])[CH2:21][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][N:5]1[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]2[C:1]1=[O:17])[CH3:28]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
77 g of 2-[2-(phthalimido)ethoxy]ethanol are added, in portions, to a suspension of 31 g of sodium hydride in 400 ml of tetrahydrofuran, while maintaining the temperature in the vicinity of 25° C. The mixture is stirred for one hour and 53.6 g of ethyl chloroacetoacetate are then added, while maintaining the temperature of the mixture at -20° C. The mixture is allowed to stand overnight at ambient temperature and then hydrolyzed with 1 l of 1N hydrochloric acid. Decantation, followed by extraction with ether are carried out and the organic phases are combined. The combined organic phase is washed with water and then dried over magnesium sulfate. It is concentrated and the residue thereby obtained (110 g) is purified by silica column chromatography using a dichloromethane:acetone (95:5) mixture as the eluting solvent.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:12][CH3:13]
Reactant: O=Cc1ccccc1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 94.3 %

Procedure:
To salicylaldehyde (12.2 g) dissolved in DMF (100 ml) were added 1-bromopropane (14.7 g) and potassium carbonate (20.7 g), and the resulting mixture was stirred at room temperature for 21.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 2-propoxybenzaldehyde (15.47 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([O:38]C)[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[C@H:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[CH:32]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To an ice-cooled solution of (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-methoxy-4-methylbenzyl)-piperazine (0.68 g) in dichloromethane (5 ml) was added dropwise a solution of boron tribromide in dichloromethane (1M solution, 3.7 ml) over 20 minutes. After stirring at the same temperature for 2 hours, the mixture was further stirred at room temperature for 12 hours and poured into a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of hexane and ethyl acetate (4:1). Fractions containing the desired compound were collected and the solvent was evaporated under reduced pressure to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3-hydroxy-4-methylbenzyl)piperazine (0.56 g) in the form of a red foam substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[N:13]C#N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCNC1=N)C1C=CC=CC=1.Br[C:30]1[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=2)=[O:37])=[C:33]([CH3:35])[N:34]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:30]2[S:31][C:32]([C:36]([NH:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:9]1=[NH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Agent: N=C1NCCN1Cc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=N)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 5 %

Procedure:
Following the procedure as described in Example 27, making variations as required to replace N-(1-benzylimidazolidin-2-ylidene)cyanamide with 1-benzylimidazolidin-2-imine to react with 2-bromo-N-(3,4-difluorobenzyl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 5% yield: mp 140-142° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.41 (t, J=5.8 Hz, 1H), 7.39-7.23 (m, 7H), 7.12-7.08 (m, 1H), 6.68 (m, 1H), 4.43 (s, 2H), 4.30 (d, J=5.8 Hz, 2H) 3.94 (m, 2H), 3.35-3.27 (m, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.8, 158.3, 153.5, 151.1, 150.4, 148.0, 147.9, 138.2, 137.2, 129.0, 128.2, 127.8, 124.4, 117.7, 116.5, 48.4, 44.4, 43.9, 42.1, 17.6; MS (ES+) m/z 442.2 (M+1).