Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=CC=CC(=O)C=CC=CC1OC=CC=1)C1[O:6][CH:5]=[CH:4]C=1.[CH:21](=[O:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.CC(C)=O>>[CH:21](=[O:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.[CH:5](=[O:6])[CH3:4]
Reactant: O=C(C=CC=Cc1ccco1)C=CC=Cc1ccco1
Solvent: O=Cc1ccco1
Solvent: CC(C)=O
Product: CC=O

Procedure:
1,7-Bis-(furfurylidene)-hepta-2,5-dien-4-one is used as the furfuraldehyde derivative. This product is obtained by reaction of one mol of acetone with 2 mols of the aldehyde resulting from the reaction of one mol of furfuraldehyde with 1 mol of acetaldehyde.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH3:8].Cl>O1CCOCC1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C@H:6]([NH2:9])[CH2:7][CH3:8]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCCO1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H](N)[C@H]1CCCO1
Temperature: 70 °C

Procedure:
To a solution of tert-butyl (R)-1-((R)-tetrahydrofuran-2-yl)propylcarbamate (2.67 g, 11.64 mmol) in 1,4-dioxane (80 ml) was added 5M HCl (5 ml). The reaction was then heated at 70° C. for 5.5 hours and after cooling to RT, the mixture was concentrated in vacuo to afford the title compound; 1H NMR (MeOD) δ1.09 (3H, t, CH3), 1.7 (3H, m), 2.0 (2H, m), 2.15 (1H, m), 3.0 (1H, m), 3.88 (3H, m).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:6]([CH2:7][OH:8])[CH2:5][CH:4]1[NH2:9].[CH3:10][C:11]([N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:12]>CO>[OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[CH2:5][C@H:4]1[NH2:9].[CH3:10][C:11]([N:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:12]
Reactant: NC1CC(CO)C1CO
Agent: CC(=O)N(CC(=O)O)c1ccccc1
Solvent: CO
Product: N[C@@H]1C[C@H](CO)[C@H]1CO

Procedure:
913 mg of (1RS, 2RS, 3SR)-2,3-bis(hydroxymethyl)-1-cyclobutylamine was dissolved in 30 ml of methanol. Then 1340 mg of N-acetyl-L-phenylglycine was added thereto to form salt. The reaction mixture was concentrated under reduced pressure. 15 ml of isopropyl alcohol was added to the residue followed by fractional recrystallization. Thus 403.8 mg of (1R, 2R, 3S)-2,3-bis(hydroxymethyl)-1-cyclobutylamine/N-acetyl-L-phenylglycine salt was obtained.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13](C4C=CC(/C=C/C(O)=O)=CC=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1N=O.C([C:64]1[CH:72]=[CH:71][C:67]([C:68]([OH:70])=[O:69])=[CH:66][CH:65]=1)=O>>[CH:30]1([CH2:29][N:10]2[C:11]([NH2:12])=[C:15]([NH2:14])[C:16](=[O:17])[N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:9]2=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1.[CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:66]4[CH:65]=[CH:64][CH:72]=[CH:71][C:67]=4[C:68]([OH:70])=[O:69])[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (1.00 g) and immediately condensed with 4-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367–3370) to give title compound as an off-white solid an off-white solid (720 mg, 54%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>O>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:14]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[CH3:13])=[O:15])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
1-(4-Chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (1.7 g) was added to a pyridine solution of 4-chloro-3-nitroaniline (1 g) and the mixture was stirred at room temperature for 2 h. After the reaction, water was added and the precipitated solid was collected by filtration to give the title compound (2.1 g), melting point:221–225° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[C:23]1(C)C=CC=C[C:24]=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.C=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:17]1([S:14]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([CH:23]=[CH2:24])[CH:3]=3)[NH:7][C:6]=2[C:11]([NH2:13])=[O:12])(=[O:16])=[O:15])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=Cc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Temperature: 100 °C

Procedure:
5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), palladium(II)acetate (12 mg, 0.012 mmol, 0.1 equiv), tri-o-tolylphosphine (31 mg, 0.10 mmol, 0.2 equiv) and triethylamine (150 μL, 1.03 mmol, 2.0 equiv) were dissolved in 5 mL of DMF, the vessel was charged with 1 atm of ethylene and heated to 100° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C15H18N3O4S (M+H+): 336.1013. Found 336.1016.
Reaction SMILES: O=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[P:8]([OH:11])([OH:10])[OH:9].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:6][C:5](=[CH2:7])[CH:4]=[C:2]([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: OP(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C=C(C)C=C(C)P(=O)(O)O

Procedure:
For example, mesityl oxide, was reacted with phosphorous acid in the presence of acetic anhydride and acetic acid under mild conditions to yield 4-methylpenta-2,4-diene-2-phosphonic acid in more than 90% mole purity.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:23])[C:14]=2[N:24]=1>CCO.O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[C:21]3[C:20](=[N:2][OH:3])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:23])[C:14]=2[N:24]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)C(=O)CCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3ccc(Br)nc31)C(=NO)CCC2
Temperature: 25 °C
Yield: 86 %

Procedure:
Hydroxylamine hydrochloride (0.54 g, 7.9 mmol) and sodium acetate (0.65 g, 7.9 mmol) were added to a suspension of 2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.5 g, 5.3 mmol) in EtOH (13 mL) and H2O (5 mL), and the resulting suspension was heated at reflux for 4 h. The reaction was cooled to ambient temperature, and the solids were collected by filtration. The solids were washed with EtOH to provide the title compound (1.34 g, 87%) as an off-white powder: 1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.68 (s, 3H), 2.86 (t, J=6.0 Hz, 2H), 2.68 (t, J=8.0 Hz, 2H), 1.96-1.84 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH3:23])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[NH2:1][C:2]([C@@:4]1([CH3:23])[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[F:24])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@@]1(C)C(N)=O
Reactant: Fc1ccccc1CBr
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]1(C)C(N)=O

Procedure:
The title compound was prepared (80 mg) using a similar procedure as set out earlier in Description 11 starting from 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D22, 55 mg, 0.17 mmol)) and 2-fluorobenzyl bromide; Rt (HPLC): 5.87 min; MS: (ES/+) 451 m/z: [M+Na+]; C24H29FN2O4 requires 428.
Reaction SMILES: [N+](=C)=[N-].N(N[C:7](N)=O)=O.[OH-].[K+].[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:18](=[O:26])[CH2:19][C:20]([CH3:25])([CH3:24])[CH2:21][C:22]=1[OH:23]>C(O)(=O)C.CCOCC>[S:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]1[C:22](=[O:23])[CH2:21][C:20]([CH3:24])([CH3:25])[CH2:19][C:18]=1[O:26][CH3:7]
Reactant: NC(=O)NN=O
Reactant: CC1(C)CC(=O)C(C2CCCS2)=C(O)C1
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC1=C(C2CCCS2)C(=O)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 500 parts by volume of an ether solution of diazomethane prepared using 47 parts of N-nitroso urea and 140 parts by volume of a 40% aqueous solution of potassium hydroxide in a conventional manner, 17.7 parts of 2-(2-tetrahydrothienyl)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one was added little by little over a period of 20 minutes. After stirring for 15 hours at room temperature, the unreacted diazomethane was decomposed by the addition of 5 parts of acetic acid and washed with 1 N aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution followed by drying. After removing ether by distillation, the residue was passed through a column containing a silica gel using a solvent mixture of chloroform and benzene (1:3) as a spreading agent. Upon recrystallization of the raw product from a solvent mixture of benzene and n-hexane, 2-(2-tetrahydrothienyl)-3-methoxy-5,5-dimethyl-2-cyclohexen-1-one was obtained in the form of colorless scale-like crystals. The melting point was 111° to 112° C. The yield was 5.7 parts.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[C:11]=2[CH3:13])[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)P(N(C)C)(N(C)C)=O>[ClH:14].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:11]=2[CH3:13])[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)c(C)c21
Reactant: C1CNCCN1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCn1cc(C(=O)O)c(=O)c2ccc(N3CCNCC3)c(C)c21
Product: Cl
Temperature: 140 °C
Yield: 48.3 %

Procedure:
One hundred milliliter of hexamethylphosphoramide is added to a mixture of 5 g of 1-ethyl-7-chloro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 8.5 g of anhydrous piperazine, and the mixture is heated at 140° C. for 8 hours. After heating, the solvent is removed under reduced pressure and, after 500 ml of water is added to the resultant residue, the mixture is adjusted to pH 4 with glacial acetic acid and the insolubles are filtered out. The filtrate is concentrated under reduced pressure, resulting in a light yellow, solid substance. Recrystallization from isopropanol-water (2:1) mixture yields 3.2 g of 1-ethyl-7-(1-piperazinyl)-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride as the white, needle-like crystals. m.p. not less than 300° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[C:7]1([N:13]=[N+:14]=[N-:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O[C@H:17]([C@@H]1C([O-])=C(O)C(=O)O1)CO.[Na+].O>S([O-])([O-])(=O)=O.[Cu+2].C(O)CCC>[C:7]1([N:13]2[CH:17]=[C:6]([CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[N:15]=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=Nc1ccccc1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: C#C[Si](C)(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: C[Si](C)(C)Cc1cn(-c2ccccc2)nn1
Reaction time: 96 h

Procedure:
Trimethylsilylacetylene, phenylazide, copper (II) sulfate and sodium (R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate were added to a 1:2 solution of water:butan-1-ol. The reaction was stirred for 4 days and t-butanol and water were removed, producing a 1-phenyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazole solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O)=[CH:16][CH:15]=[CH:14][C:13]=2[C:27]([F:30])([F:29])[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[CH3:31][S:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][CH2:22][C:21]1[CH:20]=[C:19]([C:18]2[C:17]3[C:12](=[C:13]([C:27]([F:30])([F:28])[F:29])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CSc1ccccc1CN
Product: CSc1ccccc1CNCc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]benzaldehyde and 2-methylthio benzylamine according to the procedure of Example 66. MS (ES) m/z 543.2.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][O:37]C=O)[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:40].O1CCCC1>CO>[ClH:40].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][OH:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCOC=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCO)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 7.6 h
Yield: 103.4 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.), conc. hydrochloric acid (1.6 g.), tetrahydrofuran (17.0 ml.) and methanol (17.0 ml.) was stirred at room temperature for 7.6 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of methanol and diisopropyl ether. The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 2.3 g.). Water (40 ml.) was added to the product and adjusted to pH 7.0 with sodium bicarbonate. After adjusting the solution to pH 4.0 with 1N hydrochloric acid, the solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.). The column was washed with water and eluted with 20% isopropyl alcohol. The eluate was concentrafted in vacuo and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.50 g.).
Reaction SMILES: COC(=O)[NH:4][C:5]1[O:6][C:7]2[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:8]=2[N:9]=1.[OH-].[Na+]>O1CCOCC1.C(O)CO>[CH3:16][O:15][C:10]1[C:8]2[N:9]=[C:5]([NH2:4])[O:6][C:7]=2[C:13]([NH2:14])=[CH:12][CH:11]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(N)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: COc1ccc(N)c2oc(N)nc12
Temperature: 100 °C
Yield: 19.9 %

Procedure:
To a stirred solution of 100 mg (0.42 mmol) (7-amino-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester in 15 ml dioxane and 5 ml ethylene glycol was added 15 ml of a 5 N aq. sodium hydroxide solution and the mixture was heated at 100° C. for 4 h. After cooling to room temperature the mixture was poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (5/95 methanol/dichloromethane, then 10/89/1 methanol/dichloromethane/triethylamine) followed by trituration in ether afforded 15 mg (20%) 4-methoxy-benzooxazole-2,7-diamine as a brown solid. ES-MS m/e (%): 180 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:12]=[N:11][S:10][N:9]=1)[C:5]([OH:7])=O.[NH2:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:12]=[N:11][S:10][N:9]=1)[C:5]([NH:13][CH:14]1[C:31](=[O:32])[N:16]2[C:17]([C:28]([OH:30])=[O:29])=[C:18]([CH2:21][S:22][C:23]3[S:24][CH:25]=[N:26][N:27]=3)[CH2:19][S:20][C@H:15]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1cnsn1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1cnsn1
Yield: 68.7 %

Procedure:
2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (0.6 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.16 g.) were reacted according to similar manners to those of Examples 12 and 15 to give 7-[2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.10 g.), mp 111° to 120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:23]([NH:27][N:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[C:20](=[O:21])[N:19]([CH3:22])[C:12]2=[N:13][CH2:14]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: CCCCNN1C=c2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2=NC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 0.177 g (0.50 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 10 mL of n-butylamine and 1.0 mL of dimethylformamide was heated with stirring to reflux (110° C. oil bath). After 1 hour, solution was complete. After 20 hours reflux, the excess amine and dimethylformamide were evaporated, and the residue was triturated with water, filtered, washed with water, and dried; wt 0.180 g. Recrystallization from ethyl acetate/petroleum ether gave pure product; wt 0.116 g; mp 184°-186° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]1[CH3:16].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:29][C:19]([F:18])([F:28])[C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:7]2[C:8]3[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=3[C:14]3[C:2]([CH3:17])([CH3:1])[N:3]([CH3:16])[CH2:4][CH2:5][C:6]2=3)=[CH:24][CH:25]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C(C)(C)N(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1(C)C

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-1,1,2,8-tetramethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[NH:24][C:23]=2[C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(N(C(C)C)CC)(C)C>>[CH2:44]([O:43][C:41](=[O:42])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[NH:24][C:23]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCNCCCCc2ccc(OCc3ccccc3)cc2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN(CCCCc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-[2-[4-(4-benzyloxyphenyl)butylamino]ethyl]-2-(3,5-dimethylphenyl)-1H-indol-5-ol (234 mg in 5 mL of dry methylene chloride) at -78° C. was added benzyl chloroformate (0.082 mL) and diisopropylethylamine (0.104 mL) and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate. The organic portion was washed with saturated ammonium chloride, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 3:1 then 2:1) gave the title compound (155 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:19])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[N:6][CH:5]=1.[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:28])=O)=[CH:24][CH:23]=1)#[N:21]>>[ClH:28].[CH:16]([N:13]1[CH2:12][CH2:11][N:10]([C:7]2[N:6]=[CH:5][C:4]([C:3]3[N:19]=[C:26]([C:25]4[CH:29]=[CH:30][C:22]([C:20]#[N:21])=[CH:23][CH:24]=4)[O:1][N:2]=3)=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)([CH3:17])[CH3:18]
Reactant: CC(C)N1CCN(c2ccc(C(=N)NO)cn2)CC1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CC(C)N1CCN(c2ccc(-c3noc(-c4ccc(C#N)cc4)n3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 41, starting from N-hydroxy-6-(4-isopropylpiperazin-1-yl)nicotinamidine and 4-cyanobenzoylchloride.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:13][CH:12]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)(C)O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzoic acid (0.09 g, 0.5 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product (0.11 g, 76%) as a white solid. LRMS (M+H+) m/z: calcd for 314.16. found 314. HPLC Purity (214 nm) 100%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.28-8.26 (m, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 5.86 (s, 1H), 5.08 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 1.41 (s, 6H).