Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: c1c[nH]cn1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(-n2ccnc2)n1
Yield: 71 %

Procedure:
Similarly to Example 63, reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole and imidazole at 120° C. for 1 hr gave 2-(difluoromethyl)-1-[4-(1H-imidazol-1-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole in 71% yield: mp (CH2Cl2/hexanes) 272-275° C.; 1H NMR (DMSO-d6) δ 8.74 (s, 1H), 8.04 (t, J=1.4 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.78 (t, JHF=52.5 Hz, 1H), 7.50 (t, J=8.3 Hz, 1H), 7.22 (dd, J=1.5, 0.8 Hz, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.03 (m, 2H), 4.00 (s, 3H), 3.94 (m, 2H), 3.80-3.75 (m, 4H); Anal. Calcd. for C19H18F2N8O2: C, 53.3; H, 4.2: N, 26.2. Found: C, 53.6; H, 4.3; N, 26.7%.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=O)[CH3:28])=[CH:18]1>C(O)C>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C:27](=[N:2][OH:3])[CH3:28])=[CH:18]1
Reactant: NO
Reactant: CC(=O)Cc1cn(-c2ccccc2Cl)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(Cc1cn(-c2ccccc2Cl)c2ccccc12)=NO
Reaction time: 8 h

Procedure:
2.1g (0.03 mole) of hydroxylamine hydrochloride and 2.1g of sodium acetate dissolved in 10 ml. of water are added to 5.8g (0.02 mole) of 1-(2-chlorophenyl)-3-(2-oxopropyl)indole dissolved in 50 ml of ethyl alcohol. Stirring is carried out overnight at room temperature, the oxime which has precipitated is filtered (without heat), washed with water and dried. It is recrystallised from 30 ml of di-isopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:20]=[C:21]([CH:24]=O)[S:22][CH:23]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CO.O.C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:18])([CH3:17])[C:14]([C:19]4[CH:20]=[C:21]([CH2:24][N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)[S:22][CH:23]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1csc(C=O)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1csc(CN2CCC(O)CC2)c1
Reaction time: 16 h

Procedure:
A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde (120 mg, 0.34 mmol), 4-hydroxypiperidine (69 mg, 0.68 mmol) and 100 mg of 4 Å molecular sieves in 5 mL of anhydrous DMF was stirred under nitrogen for 16 hours. Acetic acid (20 mg) and 1M sodium cyanoborohydride (0.68 mL, 0.68 mmol) were then added. The mixture was diluted with 5 mL of anhydrous methanol and stirred at room temperature for 3 hours. The mixture was poured into 100 mL of water with stirring, and basified to about pH 8 with saturated NaHCO3 solution. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 10-20% MeOH/CHCl3 to give (3E)-6-fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as yellow powder. Yield: 38 mg, 26%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[N:5]=1
Reactant: COCc1n[nH]cc1C(=O)OC
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 29 (1) in N,N-dimethylacetamide (50 mL) were added 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.1 g, 23%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(=O)c1ccc(C)cc1N
Temperature: 60 °C
Reaction time: 16 h
Yield: 107.9 %

Procedure:
A solution of 4-methyl-2-nitrophenylethanone (5.0 g, 28 mmol) in methanol (100 mL) is treated with ammonium formate (9.6 g, 140 mmol) and 5% palladium on carbon (1.5 g). The mixture is heated to 60° C. for 6 h then stirred at ambient temperature for 16 hours. The reaction mixture is filtered through Celite and the filtrate is concentrated in vacuo. The concentrate is treated with sodium bicarbonate and partitioned between water and ethyl acetate. The organic layer is separated, dried with sodium sulfate and concentrated to give crude title compound (4.5 g, 30.2 mmol) which is used without further purification. MS m/z: M+=149; 1H NMR (CDCl3, 300 MHz) δ8.05 (d, 1H), 7.4 (d, 1H), 7.25 (s, 1H), 2.8 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13](Cl)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].[O:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][C:27]#[N:28])=[CH:25][C:20]=2[O:19][CH2:18]1.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[S:16][C:9]2[N:10]=[C:11]([NH2:15])[N:12]=[C:13]([CH:26]([C:24]3[CH:23]=[CH:22][C:21]4[O:17][CH2:18][O:19][C:20]=4[CH:25]=3)[C:27]#[N:28])[C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Cl)nc(N)nc2s1
Reactant: N#CCc1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2c(C(C#N)c3ccc4c(c3)OCO4)nc(N)nc2s1
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chloro-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (1 equiv.) and benzo[1,3]dioxol-5-yl-acetonitrile (1 mole eq.) in DMF at room temperature, sodium hydride (1.1 mole eq., 60% in mineral oil) was added. The mixture was stirred at this temperature overnight under argon. After that, it was diluted with brine and extracted with ethyl acetate. The combined organic portions were washed with brine and water and dried with sodium sulphate. After filtration and evaporation of the solvent, brown solids were obtained which were purified either by preparative TLC or preparative HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1)=[O:7])[CH3:2]>CO>[CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([CH3:22])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CO
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(O)cc1
Reaction time: 5 h
Yield: 99.8 %

Procedure:
The 3-(4-benzyloxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (1.0 g, 3.07 mmol) was taken up in methanol (10 mL) and ethyl acetate (10 mL), nitrogen gas was bubbled though the solution for 15 min, and 10% Pd/C catalyst was added. The reaction was charged with hydrogen to 40 PSI and shaken for 5 h. The reaction was filtered though Celite® and concentrated to give 3-(4-hydroxy-phenyl)-2,2-dimethyl-3-oxo-propionic acid ethyl ester (0.724 g, 100%) as an oil. MS found: (M+H)+=237.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH:19](I)([CH3:21])[CH3:20]>O1CCCC1>[CH2:11]([O:10][C:8](=[O:9])[C:7]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)([CH:19]([CH3:21])[CH3:20])[C:6]([O:5][CH2:3][CH3:4])=[O:18])[CH3:12]
Reactant: CC(C)I
Reactant: CCOC(=O)C(C(=O)OCC)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(c1ccco1)C(C)C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
24 g (1 mol) of sodium hydride were suspended in 100 ml of absolute tetrahydrofuran. A solution of 218.4 g (0.97 mol) of 2-furylmalonic acid diethyl ester in 200 ml of absolute tetrahydrofuran was added dropwise. The temperature rose to 30° (blue suspension). After stirring at 30° for 30 minutes, 340 g (200 ml; 2 mol) of isopropyl iodide were added dropwise within 30 minutes. The reaction mixture was heated to reflux overnight, thereafter evaporated under reduced pressure, and dissolved in ether. After evaporation of the solvent, the remaining oily residue was distilled in a high vacuum, to obtain 240.6 g (92.5%) of 2-furyl-2-isopropylmalonic acid diethyl ester (purity 93.6%) in the form of a yellowish oil, boiling point 85°-88°/13 Pa.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C:10]([CH3:14])([CH3:13])[S:11](=O)[C@H:7]23)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.S(Cl)(Cl)=[O:28]>C(Cl)(Cl)(Cl)Cl>[C:4]1(=[O:21])[N:5]([CH:6]2[C:19](=[O:20])[N:8]3[CH:9]([C:15]([O:17][CH3:18])=[O:16])[C@:10]([CH3:14])([OH:28])[CH2:13][S:11][C@H:7]23)[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: COC(=O)C1N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2S(=O)C1(C)C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1N2C(=O)C(N3C(=O)c4ccccc4C3=O)[C@H]2SC[C@@]1(C)O

Procedure:
A solution of methyl 6-phthalimido-2,2-dimethylpenam-3-carboxylate-1-oxide (2.25 g., 6 mmol) and thionyl chloride (0.47 ml., 6.5 mmol) in 90 ml. dry carbon tetrachloride was refluxed for 1 hour, cooled and evaporated in vacuo to dryness. An nmr spectrum of the crude product showed a 2:3:3 mixture of methyl 7-phthalimido-3α-methyl-3β-hydroxycepham-4-carboxylate, methyl 6-phthalimido-2β-chloromethylpenam-2α-methyl-3-carboxylate, and methyl 6-phthalimido-2α-chloromethylpenam-2β-methyl-3-carboxylate, respectively. The products were separated by chromatography on silica gel and fully characterized by spectroscopy.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:20][C:11]([F:10])([F:19])[C:12]1[N:13]=[CH:14][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][N:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 130 °C
Yield: 71.6 %

Procedure:
A mixture of 4-fluorobenzaldehyde (0.196 mL, 1.828 mmol), 2-(trifluoromethyl)-5-pyrimidinol (300 mg, 1.828 mmol), and K2CO3 (505 mg, 3.66 mmol) in DMF (2 mL) was heated with a microwave reactor at 130° C. for 1 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (351 mg, 1.309 mmol, 71.6% yield). LCMS: rt=2.97 min, [M+H+]=269
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.CON(C)[C:21](=[O:29])[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CON(C)C(=O)c1ccc(C)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(C)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with N-methoxy-N-methyl-4-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O.O>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][N:8]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c2cc(Br)ccc12
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(=O)OC(C)(C)C)c2cc(-c3ccc([N+](=O)[O-])cc3)ccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.7 %

Procedure:
The mixture of 1-tert-butyl 3-ethyl 6-bromo-1H-indazole-1,3-dicarboxylate (1.3 g), p-nitrophenyl boronic acid (666 mg), Pd (dppf)Cl2 (92 mg), and potassium carbonate (1 g) in N,N-dimethylformamide/water (4:1, 20 Ml) was stirred at room temperature for 24 h. Ethyl acetate and water were added. The organic layer was separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EA only) to give 1-tert-butyl 3-ethyl 6-(4-nitrophenyl)-1H-indazole-1,3-dicarboxylate (1.3 g).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>CCCCCC.[Pt]>[CH2:1]=[CH:2][CH:3]=[CH:4][CH2:5][CH2:6][CH3:7].[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=CCCCCC
Agent: [Pt]
Solvent: CCCCCC
Product: C=CC=CCCC

Procedure:
The charge is a mixture of 3.5 ml of 1-heptene (25 mmole) which is diluted with 14.5 ml of n-hexane to about 20% (volume to volume) concentration. Reaction conditions, platinum catalyst solution and other variables are the same as described in Example 1. The results follow:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH2:23]([N:30]=[C:31]=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH2:23]([NH:30][C:31](=[O:32])[N:5]([CH2:4][C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[Br:1])[CH2:6][CH3:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (2.35 g, 8.33 mmol) in CH2Cl2 (24 mL) was added triethylamine (1.8 mL, 12.5 mmol), followed by benzyl isocyanate (1.22 mL, 10.0 mmol), and the reaction was stirred at room temperature for 50 minutes. The mixture was worked up with CH2Cl2 and H2O, and the combined organic layers were dried, filtered, and concentrated. The residue was dissolved in CH2Cl2 and filtered to remove solids, and the filtrate was purified by silica gel chromatography to give 3-benzyl-1-(2-bromo-5-trifluoromethyl-benzyl)-1-ethyl-urea.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH:14]2[CH2:16][CH2:15]2)[C@H:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[C:20]([O:19][C:18](=[O:24])[NH:17][C@H:10]1[C@H:11]([CH:14]2[CH2:15][CH2:16]2)[CH2:12][CH2:13][NH:8][CH2:9]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C1CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-cyclopropylpiperidin-3-ylcarbamate (1.20 g, 3.63 mmol) and 10% Pd/C (0.39 g, 0.36 mmol) in methanol (20 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 18 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate (0.87 g, 100%) as a solid.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].O.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][C:2](=[O:11])[CH2:3][CH2:4]2)([O-:15])=[O:14]
Reactant: O=C1CCc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reaction time: 0.08 h

Procedure:
3,4-Dihydro-2(1H)-quinolinone (1.0 g, 6.70 mmol) is dissolved in 20 mL of concentrated sulfuric acid at −10° C., and then 5 mL of water is added slowly to the solution. After 5 minutes, 61% nitric acid (0.5 mL, 6.70 mmol) is added dropwise to the solution. The reaction mixture turns from yellow to dark red, and eventually solidifies. After 1 hour, water (50 mL) is added slowly at −10° C. and precipitate appears. The solution is poured into a separatory funnel, extracted with ethyl acetate (20 mL×2) and washed with saline (20 mL). The organic layers are collected and dried over MgSO4. Solvent is removed and the title compound is obtained as a pale yellow solid (1.0 g, 76%); 1H NMR (300 MHz, DMSO) δ 10.66 (s, 1H), 8.08-8.01 (m, 2H), 6.96 (d, 1H), 2.98 (t, 2H), 2.49 (dd, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:6]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][S:8][C@H:3]12.C[Si](NC(N[Si](C)(C)C)=O)(C)C.Cl.[CH2:45]([O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51](Cl)=[O:52])[CH:46]=[CH2:47].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:45]([O:48][N:49]=[C:50]([C:54]1[N:58]=[C:57]([NH2:59])[S:56][N:55]=1)[C:51]([NH:1][CH:2]1[C:30](=[O:31])[N:4]2[C:5]([C:14]([O:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:15])=[C:6]([O:9][S:10]([CH3:13])(=[O:11])=[O:12])[CH2:7][S:8][C@H:3]12)=[O:52])[CH:46]=[CH2:47]
Reactant: C=CCON=C(C(=O)Cl)c1nsc(N)n1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1nsc(N)n1
Yield: 92.1 %

Procedure:
To a solution of benzhydryl 7-amino-3-mesyloxy-3cephem-4-carboxylate (6.91 g) and bis(trimethylsilyl)-urea (18.4 g) in methylene chloride (69 ml) was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetyl chloride hydrochloride (syn isomer) (4.08 g) at -10° C. under stirring and the mixture was stirred at the same temperature for 30 minutes. After the reaction mixture was added to a stirred mixture of water and methylene chloride, the solution was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-mesyloxy-3-cephem-4-carboxylate (syn isomer) (8.90 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:36])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])[CH:25]=2)[CH:18]=1)[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]#[C:38]Br>C(O)C>[CH2:1]([O:8][C:9](=[O:36])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:25]=[C:26]3[C:27](=[CH:28][CH:29]=2)[N:30]=[C:38]([NH2:37])[N:32]([CH2:33][CH2:34][CH3:35])[CH2:31]3)[CH:18]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(N(C(=O)OCc4ccccc4)C4CCCCC4)c3)ccc2N=C1N

Procedure:
A mixture of [3-(4-amino-3-propylaminomethyl-phenoxy)-phenyl]-cyclohexyl-carbamic acid benzyl ester (0.0018 mol) and cyanogen bromide (0.00234 mol) in ethanol (60 mL) was stirred and refluxed for 3 hours and then was cooled. The ethanol solvent was evaporated. The residue was triturated under diisopropyl ether and ethanol, filtered off, and dried to yield the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34].C(N(CC)CC)C.C(O)C>O>[NH2:23][C:22]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[N:34]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:4](=[O:21])[C:3]=12
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3ccccc32)cc1
Reactant: COc1ccccc1NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccccc4OC)nc3c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (500 mg), 2-methoxyphenylhydrazine hydrochloride (321 mg), triethylamine (627 μl) and ethanol (5 ml) was stirred at room temperature for 1 hour and at 90° C. for 2 hours. After cooling, water was added to the mixture and the precipitated solid was collected by filtration, washed with water-ethanol and dried to obtain the target compound (421 mg).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[O-]CC.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH:37]=[CH:38][C:39](OCC)=[O:40])=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1>C(O)C>[CH3:18][O:17][C:15]1[CH:14]=[C:13]([CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH:37]=[CH:38][C:39](=[O:40])[NH:1][C:2]([NH2:4])=[O:3])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)[C:21]([OH:23])=[O:22])[CH:12]=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C=Cc1ccc(Oc2ccc(C(=Cc3cc(OC)cc(OC)c3)C(=O)O)cc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc(C=CC(=O)NC(N)=O)cc3)cc2)cc(OC)c1

Procedure:
Urea (0.21 g, 3.58 mmol) was dissolved in sodium ethoxide (2.7 M, 2.2 mL, 5.92 mmol) at 80° C. under argon, and to this a solution of 4 (1.14 g, 2.37 mmol) in anhydrous ethanol (15 mL) was added and heated at this temperature for 13 hr. Ethanol was evaporated under reduced pressure, water (20 mL) was added, acidified to pH 1 by 5% aqueous HCl and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2×25 mL), brine (2×20 mL), dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (3:7) containing acetic acid (1%), followed by recrystallization from ethanol. Yield: 167 mg, 14.4%.