Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([O:36]CC)=[O:35])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>C(O)C.[OH-].[Na+]>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH2:17][NH:18][C:19]4[CH:40]=[CH:39][C:22]([C:23]([NH:25][C@H:26]([C:34]([OH:36])=[O:35])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])=[C:21]([F:41])[CH:20]=4)[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1F)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2ccc3ccc(CNc4ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c(F)c4)cc3c2c(=O)[nH]1
Yield: 101.1 %

Procedure:
A solution of diethyl N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate (2.3 g, 4.1 mmol) in ethanol (25 ml) and 0.2N NaOH (100 ml) was stirred under nitrogen at room temperature for 3 hours. The solution was adjusted to pH 7 with 1N HCl and reduced in volume under vacuum to remove the ethanol. The product was precipitated by acidifying the solution with 1N HCl to pH 3 with stirring under nitrogen. The suspension was stirred 15 minutes, filtered under nitrogen, washed with water, pressed with a sheet of latex to remove excess water, and dried under high vacuum to give N-(4-(((1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzo-yl)-L-glutamic acid as a white solid (2.1 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.82-2.12 (m, 2H, glu CH2), 2.29 (t, J=7 Hz, 2H, glu CH2), 2.43 (s, 3H, C3 -CH3), 4.32-4.42 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H C9 -CH2), 6.39 (dd, J=15,2 Hz 1H , Ar), 6.53 (dd, J=9,2 Hz, 1H, Ar), 7.30 (t, J=6 Hz, 1H, ArNH), 7.47 (dd, J=9,9 Hz, 1H, Ar), 7.59(d, J=9 Hz, 1H, Ar), 7.61(dd, J=8, 2 Hz, 1H, Ar), 7.73 (t, J=7 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.42 (br s, 2H, CO2H's), 12.53 (s, 1H, N2H). Anal. Calculated for C26H23FN4O6.3/2H2O.1/3 NaCl: C, 56.49; H, 4.74; N, 10.14; Cl, 2.12; Na, 1.37. Found: C, 56.48; H, 4.64; N, 10.20; Cl, 2.01; Na, 1.30.
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[N:15]1([CH2:24]NC2CCCCC2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:15][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:18]1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc2c(c1)nnn2CNC1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a mixture of 13.7 g (0.21 g-atom) of zinc powder (325 mesh) and 200 mL of anhydrous tetrahydrofuran was added 20 mL (0.156 mole) of chlorotrimethylsilane in one portion. After stirring for 5 minutes, a solution of 20.4 mL (0.156 mole) of ethyl bromodifluoroacetate in 50 mL of tetrahydrofuran was added dropwise at a rate to maintain the internal temperature below 35 degrees. The mixture was stirred for 30 minutes and then cooled to −10 to 0 degrees. A solution of 40 g (0.174 mole) of benzotriazol-1-ylmethyl-cyclohexylamine in 400 mL of tetrahydrofuran was added dropwise at a rate to maintain the internal temperature at −10 to 0 degrees. After 10 minutes, the reaction mixture was warmed to room temperature, stirred for another 3 hours and then cooled to −10 to 0 degrees. The reaction was quenched by the addition of 200 mL of saturated aqueous sodium bicarbonate, added at a rate to maintain the internal temperature at −10 to 0. The mixture was stirred at room temperature for 10 minutes, then filtered through Celite, washing with 200 mL of ether. The filtrate was extracted twice with 200 mL of ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 200 mL of hexanes-ether (80:20) was added to the residue, the resulting solid was removed by filtration and the filtrated concentrated under reduced pressure. The residue was distilled under vacuum to give 12.9 g of 3-cyclohexylamino-2,2-difluoropropionic acid ethyl ester as a colorless oil. bp. 85-90 degrees at 1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc3c(c2)CC(C(=O)O)CCO3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (280 mg) in methanol (20 ml)/ethyl acetate (10 ml) was added 10% palladium on charcoal (50% water content, 70 mg). Hydrogen gas was introduced, and the resulting mixture was stirred at room temperature for 17 hours and at 50° C. for 3 hours, and was then filtered to remove the catalyst. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to obtain 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxylic acid (187 mg) as colorless crystals.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2=[CH:18][N:19]=[C:20]([C:22](O)=[O:23])[CH:21]=[C:16]2[CH:15]=[CH:14]1.N>>[ClH:1].[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[CH:21]=[C:16]4[CH:15]=[CH:14][S:13][C:17]4=[CH:18][N:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1cc2ccsc2cn1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccsc2cn1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[2,3-c]pyridine-5-carboxylic acid (Tetrahedron Lett. 1999, 40, 7935) according to methods A and C; yield 73 mg, 0.18 mmol (51%): 1H NMR (300 MHz, methanol-d4) δ 2.12-2.33 (m, 5H), 2.55 (s, 2H), 3.53 (d, J=12 Hz, 2H), 3.59 (s, 2H), 3.99 (d, J=13 Hz, 2H), 4.40 (s, 1H), 7.94 (d, J=5 Hz, 1H), 8.65 (d, J=5 Hz, 1H), 9.15 (s, 1H), 9.59 (s, 1H); MS (DCI/NH3) m/z 296 (M+H)+; Anal. C17H19N3OS.2HCl.0.6H2O: C, H, N.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[CH2:7][CH2:8][C:9]([F:12])([F:11])[F:10])C.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(OCC)C.CCCCCC>[F:10][C:9]([F:12])([F:11])[CH2:8][CH2:7][CH2:6]/[CH:5]=[CH:4]/[OH:3]
Reactant: CCOC(=O)/C=C/CCC(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOCC
Product: O/C=C/CCCC(F)(F)F

Procedure:
A solution of 10 g of 6,6,6-trifluoro-2-transhexenoic acid ethyl ester (see above) in 70 ml of diethyl ether is cooled to 0°-5° and at this temperature 102 ml of 1M diisobutylaluminium hydride solution in hexane are added. The reaction mixture is then stirred for 5 minutes at 0°-5° and carefully hydrolysed with approx. 200 ml of 6N hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted a further 3 times with ether. The combined organic phases are dried over MgSO4, and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) yields the title compound in the form of a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([O:32][CH2:33][C:34](OC)=[O:35])=[CH:27][C:26]=2[CH3:38])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[CH3:39][NH:40][CH3:41]>O1CCCC1>[CH3:39][N:40]([CH3:41])[C:34](=[O:35])[CH2:33][O:32][C:28]1[CH:27]=[C:26]([CH3:38])[C:25]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:24]=[CH:23][C:15]3[C@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:30]([CH3:31])[CH:29]=1
Reactant: CNC
Reactant: COC(=O)COc1cc(C)c(-c2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)N(C)C)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O

Procedure:
The title compound is prepared from 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid and 2 M solution of dimethylamin in tetrahydrofuran following a procedure analogous to that described in example 12. LC (method 9): tR=1.06 min; Mass spectrum (ESI+): m/z=534 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[C:4]([C:15](=O)[C:16](OC)=[O:17])=[CH:3]1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:29]=2)[C:24]([CH2:37][C:38]([NH2:40])=[O:39])=[CH:23]1>>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH:29]=2)[C:24]([C:37]2[C:38](=[O:39])[NH:40][C:16](=[O:17])[C:15]=2[C:4]2[C:5]3[C:10](=[CH:9][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[CH:23]1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(C(F)(F)F)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Product: Cn1cc(C2=C(c3cn(C)c4cc(C(F)(F)F)ccc34)C(=O)NC2=O)c2ccc(N3CCOCC3)cc21
Yield: 54 %

Procedure:
3-(1-Methyl-6-morpholin-4-yl-1H-indol-3-yl)-4-(1-methyl-6-trifluoromethyl-1H-indol-3-yl)pyrrole-2,5-dione (151 mg, 54%) was prepared from methyl (1-methyl-6-trifluromethyl-1H-indol-3-yl)glyoxylate (172 mg, 0.60 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (150 mg, 0.55 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]2[CH2:32][NH:31][CH2:30][CH2:29][NH:28]2)[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:31]3[CH2:30][CH2:29][NH:28][CH:27]([CH2:26][N:23]4[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]4)[CH2:32]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CN1CCN(CC2CNCCN2)CC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CN4CCN(C)CC4)C3)cc21

Procedure:
A 425 mg portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 1.25 g of 1-methyl-4-(2-piperazinylmethyl)piperazine were suspended in 5 ml of pyridine and heated at reflux, under argon, for 18 hours. The solvents were removed and the residue evaporated twice from toluene. The residue was dissolved in dichloromethane, hexane was added, the resulting gum was separated, dissolved in dichloromethane and filtered. Ether was added to the filtrate, the resulting solid collected and recyrstallized, giving 360 mg of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:18])([CH:15]([CH3:17])[CH3:16])[C:12](=[O:14])[CH3:13].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12](=[O:14])[C:11]([CH3:18])([CH3:10])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)(C)C(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
44.4 g (0.316 mol) of 4-chlorobenzaldehyde and 40 5 g (0.316 mol) of 3,3,4-trimethyl-pentan-2-one are dissolved in a mixture of 100 ml of ethanol and 10 ml of water, and a solution of 0.9 g of sodium hydroxide in 10 ml of water is added. The mixture is initially stirred for 1 hour at room temperature, then 0.4 g of solid sodium hydroxide is added and the mixture is stirred for a further 16 hours. The precipitate which results is filtered off with suction and then washed with water. 33.1 g (42% of theory) of 1-(4-chlorophenyl)-4,4,5-trimethyl-1-hexen-3-one are obtained in the form of a low melting, oily-crystalline product. ##STR24##
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[S:14])=[O:11])[CH:7]=[C:6]([Cl:25])[N:5]=1.[CH3:26]I>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][C:13](=[N:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[S:14][CH3:26])=[O:11])[CH:7]=[C:6]([Cl:25])[N:5]=1
Reactant: O=C(NC(=S)Nc1ccc(F)c(F)c1F)c1cc(Cl)nc(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(=Nc1ccc(F)c(F)c1F)NC(=O)c1cc(Cl)nc(Cl)c1
Reaction time: 0.25 h

Procedure:
NaH (2.70 g, 0.06747 mol) was added carefully to a cooled solution (0° C.) of intermediate D9 (28.5 g, 0.04498 mol) in THF (200 ml). The mixture was stirred for 15 minutes and then CH3I (6.38 g, 0.04498 mol) was added. The ice-bath was removed and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the mixture was quenched with H2O and extracted with CH2Cl2 (3×100 ml). The combined organic layers were washed (brine), dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography (eluent: heptane/EtOAc gradiënt from 80/20 to 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 5.7 g of intermediate D10 (32%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100%): 1H NMR (CDCl3, 400 MHz) δ 7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 μL/min) tr 17.82 min; MS: MH+ 172.2
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH2:13]([O:12][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1)[CH3:14]
Reactant: CC[O-]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: CCOc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodium ethoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 5.3 gram (98% yield). Mp: 133.8˜134.9° C.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[C:17]([CH:20]=P(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].C=O.O1CCC[CH2:64]1.C(OCC)(=O)C>C(OCC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:58][O:59][CH3:60])[C:10]([NH:12][CH:13]2[C:56](=[O:57])[N:15]3[C:16]([C:40]([O:42][CH:43]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)=[O:41])=[C:17]([CH:20]=[CH2:64])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: C1CCOC1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
A mixture of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-triphenylphosphoranylidenemethyl-3-cephem-4-carboxylate (syn isomer) (2.2 g), 36% aqueous formaldehyde (20 ml) and tetrahydrofuran (60 ml) were stirred at ambient temperature for 12.5 hours. After addition of ethyl acetate (100 ml) to the reaction mixture, the organic layer was separated out, washed with 10% hydrochloric acid and an aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was pulverized with diethyl ether, and chromatographed on silica gel using chloroform and then a mixture of chloroform and acetone (19:1 and 9:1 by volume) as an eluent. The fractions containing the desired compound were collected and evaporated to give benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.25 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH:17]1([CH:23]=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:8][C:7]1[C:2]2[NH:1][CH:23]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[NH:16][S:13](=[O:15])(=[O:14])[C:3]=2[CH:4]=[C:5]([S:9](=[O:11])(=[O:12])[NH2:10])[CH:6]=1
Reactant: O=CC1CCCCC1
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1cc(Br)c2c(c1)S(=O)(=O)NC(C1CCCCC1)N2

Procedure:
2-Amino-3-bromo-5-sulfamoylbenzenesulfonamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 254-258° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>>[CH2:23]([O:22][C:20]([C:19]1[O:17][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:16][C:13]=2[CH:14]=1)=[O:21])[CH3:24]
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2o1
Yield: 84 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde ((21.5 g, 94.2 mmol) and ethyl bromoacetate (17.3 g, 103.6 mmol) and K2CO3 (19.5 g, 141.3 mmol) and DBU (14.3 g, 94.2 mmol) are reacted analogous to Example 18-A to give the title compound (23.5 g, 84%).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:15][C:16](Cl)=[O:17])[CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16]([N:5]([C:6](=[O:11])[CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:4][C:2]([CH3:1])([CH3:12])[NH2:3])=[O:17])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CC(C)CC(=O)NCC(C)(C)N
Solvent: Cc1ccccc1
Product: CCOC(=O)N(CC(C)(C)N)C(=O)CC(C)C

Procedure:
A mixture of 5.1 parts of 2,2,7,7-tetramethyl-1,4-diazaheptan-5-one, 30 parts of ethylchloroformate and 150 parts of anhydrous toluene were heated at reflux for 16 hours. Removal of the solvent under reduced pressure was followed by addition of 10 parts of water to the residue basification with sodium carbonate solution and chloroform extraction. The yellow oil produced was distilled under reduced pressure to yield 4-ethoxycarbonyl-2,2,7,7-tetramethyl-1,4-diazaheptan-5-one of boiling point 98° - 100°C at 0.2mm pressure. The hydrochloric acid salt of this material gave the following elemental analysis by weight:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[N:12]=1)([CH3:10])([CH3:9])[CH3:8].O>C(O)C>[C:7]([C:11]1[N:12]=[C:13]([CH2:18][CH2:19][O:20][CH3:21])[CH:14]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: C1CNCCN1
Reactant: COCCc1cc(Cl)nc(C(C)(C)C)n1
Solvent: CCO
Solvent: O
Product: COCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of piperazine (45.2 g, 525 mmol) in ethanol (300 mL) was heated to reflux. A solution of 2-tert-butyl-4-chloro-6-(2-methoxy-ethyl)-pyrimidine (20 g, 87 mmol) in ethanol (50 mL) was added dropwise to the above solution. The solution was refluxed for another 3 hrs, cooled to room temperature. Then water was added and the organic layer was extracted with EA (400 mL×3). To the organic layer was added 5% citric acid (1 L), separated, and the aqueous layer was collected and adjusted to alkaline pH>8 with 2 N NaOH. The alkaline aqueous layer was extracted with EA (400 mL×3), and the organic phase was dried over Na2SO4, filtered and concentrated to give the title compound (20 g, 82% yield) as a yellow oil.
Reaction SMILES: [N:1]12[CH2:16][CH:5]([CH:6]([CH:8]([C:14]#[N:15])C(OCC)=O)[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[Na:17].C([O:23][N:24]=O)CC(C)C>C(O)C>[Na:17].[N:1]12[CH2:16][CH:5]([CH:6]([C:8](=[N:24][OH:23])[C:14]#[N:15])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C(C#N)C1CN2CCCC1C2
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)C1CN2CCCC1C2
Temperature: 50 °C

Procedure:
Ethyl (1-azabicyclo[3.2.1]octan-6-yl)cyanoacetate (36 g, 0.16 mol) in abs. ethanol (100 ml) was added to a solution of sodium (4 g, 0.21 mol) in abs. ethanol (100 ml). Isoamylnitrite (25 ml, 0.19 mol) was added over 0.5 h, and the mixture was heated at 50° C. for 4 h. Evaporation of the reaction mixture gave crude sodium salt of the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[OH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[Cl:16][C:10]1[CH:11]=[C:12]([NH:15][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]3)=[CH:32][CH:31]=2)=[CH:7][CH:6]=1
Reactant: Nc1ccc(Nc2ccc(N)cc2Cl)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: O=C(Nc1ccc(Nc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2Cl)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 826 was prepared according to the procedure described in Scheme IV from N1-(4-aminophenyl)-2-chlorobenzene-1,4-diamine and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C36H38ClN5O4: 640.26; found 640.12.