Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([O-:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([N:11]1[CH:12]=[C:8]([N+:5]([O-:7])=[O:6])[N:9]=[CH:10]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Reaction time: 1 h

Procedure:
430 mL of acetic acid and 188 g of 4-nitroimidazole were charged into a 2 L-volume reactor and stirred. While stirring the mixture, 100% nitric acid(137 mL) was slowly added dropwise to the mixture at the reaction temperature of 35° C. Anhydrous acetic acid(318 mL) was added dropwise thereto at 25° C. over 1 hour. After stirring the reaction mixture at 25° C. for 2 days, 1,4-dinitroimidazole was synthesized. Then, the resultant was poured in 2 L cold water, and extracted three times with 500 mL of methyl chloride for each time. The obtained methylene chloride solution was dried over MgSO4 so as to completely remove the water therefrom, resulting in methylene chloride extract solution containing 1,4-dinitroimidazole. The structure of the obtained 1,4-dinitroimidazole was as same as that of the comparative example.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[CH:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([OH:16])=[O:15].S(=O)(=O)(O)O.[CH3:28][CH2:29]O>O>[CH2:28]([O:15][C:14](=[O:16])[CH:13]([C:3]1[C:4](=[O:12])[O:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:29]
Reactant: CCO
Reactant: O=C(O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C

Procedure:
A solution of (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid in EtOH with a catalytic amount of conc. sulfuric acid was heated to reflux for 5 hours, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was dried over MgSO4 and conc. in vacuo to give (4-Hydroxy-2-oxo-2H-chromen-3-yl)-phenyl-acetic acid ethyl ester as colorless oil, which crystallize upon standing (910 mg). MS: 323[M-H].
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[N:22]=[C:21]2[CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1.[OH-].[Na+]>CCO>[CH2:29]([C:21]1[N:20]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:17]=2[CH:18]=[CH:19][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])=[CH:11]3)[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[N:22]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2cccnc2n1-c1cccc2cc(-c3ccccc3C(=O)O)ccc12
Temperature: 50 °C

Procedure:
To a solution of 2-[5-(2-butyl-imidazo[4,5-b]pyridin-3-yl)-naphthalen-2-yl]-benzoic acid methyl ester (40 mg) in EtOH (1.0 mL) at room temperature was added 2N NaOH (0.5 mL). The reaction mixture was heated at 50° C. for 17 hours. The cooled solution was concentrated in vacuo. The residue was diluted with saturated aqueous NaCl (10 mL) and neutralized with concentrated HOAc. The aqueous solution was extracted with CHCl3 (3×30 mL). The combined extracts were dried MgSO4) and concentrated in vacuo. The residue was azeotroped with heptane (30 mL) and diluted with EtOAc (1 mL) and hexanes (15 mL). The solid that precipitated was filtered and dried. 1H NMR (250 MHz, d6 -DMSO): d 8.15 (m, 4 H), 7.72 (m, 3 H), 7.46 (m, 4 H), 7.30 (dd, 1 H), 6.94 (d, 1 H), 2.63 (m, 2 H), 1.63 (m, 2 H), 1.25 (m, 2 H), 0.74 (t, 3 H).
Reaction SMILES: C(O[C:4](=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([O:18][C:19]1[C:20]([N+:26]([O-])=O)=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])C.[K+]>C(OCC)C>[CH2:8]([O:7][C:5]([C:4]1[NH:26][C:20]2[C:21]([CH:25]=1)=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Yield: 36.1 %

Procedure:
Under agitation, 26.3 g of oxalic acid diethyl ester and, 15 minutes later, a solution of 21.9 g of 3-benzyloxy-2-nitrotoluene in 30 ml of diethyl ether are added dropwise to a suspension of 9 g of potassium ethanolate in 200 ml of diethyl ether. The reaction mixture is heated for 20 hours under reflux; the thus-separated potassium salt of 3-benzyloxy-2-nitrophenylpyruvic acid ethyl ester is vacuum-filtered and washed with diethyl ether. The salt is then dissolved in a mixture of 200 ml of ethanol and 200 ml of concentrated acetic acid, the solution is combined with 50 g of powdered iron and heated under reflux for 90 minutes. The reaction mixture is allowed to cool, poured into 1 liter of ice water, filtered over kieselguhr, and the kieselguhr washed with diethyl ether. The organic phase is separated and the aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed with saturated sodium carbonate solution, dried, and concentrated under vacuum. The residue is recrystallized from ethanol, thus obtaining 9.6 g of 7-benzyloxyindole-2-carboxylic acid ethyl ester, mp 82°-83° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][Zn+])[CH3:38]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[C:31]([CH2:42][CH2:41][C:40]([O:39][CH2:37][CH3:38])=[O:44])[CH:32]=[CH:33][CH:34]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(Br)c2)cc1
Reactant: CCOC(=O)CC[Zn+]
Agent: [Br-]
Product: CCOC(=O)CCc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1

Procedure:
The product from Example 65D and 3-ethoxy-3-oxopropylzinc bromide (purchased from Aldrich) were processed as described in Example 49 to provide the title compound. MS (ESI+) m/z 573 (M+H)+.
Reaction SMILES: [C:1]([C:3](=[N:15][O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])#[N:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>>[OH:23][NH:22][C:1]([C:3](=[N:15][O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:4]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[N:5][O:6][CH:7]([CH3:9])[CH3:8])=[NH:2]
Reactant: NO
Reactant: CC(C)CON=C(C#N)C(=NOC(C)C)n1cncn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)CON=C(C(=N)NO)C(=NOC(C)C)n1cncn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
(6.04 mmol) of the 1-[2-cyano-2-isobutoxyimino-1-isopropoxyiminoethyl]-1H-1,2,4-triazole produced based on Example 1 were added 0.46 g (6.62 mmol) of hydroxylamine hydrochloride and 0.54 g (6.58 mmol) of sodium acetate, followed by stirring at 50° C. for 3 hours. The solvent in the reaction mixture was distilled off under reduced pressure. The resulting crystal was washed with water and isopropyl ether, to obtain 0.91 g (yield: 48%) of 1-[2-(N-hydroxyamidino)-2-isobutyloxyimino-1-isopropoxyiminoethyl]-1H-1,2,4-triazole.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:7][C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]([OH:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: Cc1ccc(C(N)=S)cc1
Product: Cc1ccc(-c2nc(O)c(-c3ccccc3)s2)cc1

Procedure:
The title compound was prepared according to the method of Scheme II in a manner analogous to Example 31 except 4-methylthiobenzamide was used instead of thiobenzamide and 2-chloro-2-phenylacetyl chloride was used instead of 2-bromopropionate.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[CH2:10]([N:12]=[C:13]=[O:14])[CH3:11]>ClCCCl>[CH2:10]([NH:12][C:13](=[O:14])[O:7][CH2:6]/[CH:5]=[CH:4]/[C:3](/[CH2:1][CH3:2])=[CH:8]/[CH3:9])[CH3:11]
Reactant: CCN=C=O
Reactant: C/C=C(/C=C/CO)CC
Solvent: ClCCCl
Product: C/C=C(/C=C/COC(=O)NCC)CC
Yield: 80 %

Procedure:
A solution of (E,E)-4-ethyl-2,4-hexadien-1-ol (2.0 g) and ethyl isocyanate (1.13 g) in 1,2-dichloroethane (12 ml) was stirred at 0° C. for 3 hours and at room temperature for 12 hours. The reaction mixture was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (chloroform) to give (E,E)-4-ethyl-2,4-hexadien-1-yl ethylcarbamate (2.5 g) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[N:24]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:25]=[O:26]>ClCCl>[C:30]1([CH2:29][CH2:28][CH2:27][NH:24][C:25]([N:13]2[CH2:12][C:11]3([N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1ccc(CN2CCC23CNC3)cc1
Reactant: O=C=NCCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of 1-benzyl-1,6-diaza-spiro[3.3]heptane (41 mg, 217 μmol) in dichloromethane (2 mL) was added diisopropyl-ethyl-amine (112 mg, 868 μmol)) followed by (3-isocyanato-propyl)-benzene (84 mg, 521 μmol) and the reaction mixture was allowed to stir at ambient temperature for 16 h. After complete consumption of starting material the reaction mixture was diluted with dichloromethane and was washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. Purification by HPLC afforded the title compound (9 mg, 12%) as an off-white solid. MS m/e: 350 (M+H)+.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1O>>[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[CH3:17])=[O:13]
Reactant: CC1CCCCC1O
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: CS(=O)(=O)O
Product: CC1CCCCC1OC(=O)c1cc(N)ccc1Cl
Reaction time: 6 h
Yield: 81.4 %

Procedure:
Methanesulfonic acid (99%, 100 g, 1.0 mole) was added slowly to a stirred mixture of 5-amino-2-chlorobenzoic acid (85%, 100 g, 0.5 mole) in 2-methylcyclohexanol (200 g, 1.85 mole). The mixture was heated under reflux with stirring for 6 hours, then the excess 2-methylcyclohexanol was evaporated under reduced pressure. The residue was then dissolved in methylene chloride (800 ml), washed with water (300 ml), 5% sodium bicarbonate solution (300 ml), water (300 ml), dried (magnesium sulfate), and filtered. The solvent was then evaporated to give 109 g of 2-methylcyclohexyl 5-amino-2-chlorobenzoate as a light brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.N1CCCCC1>CCO>[CH3:12][N:13]([CH3:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[CH:16][CH:15]=1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CN(C)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Temperature: 25 °C

Procedure:
A general procedure for the preparation of 3-benzylideneindolin-2-ones: A mixture of 5-fluoroindolin-2-one (151 mg, 1 mmol), 4-(dimethylamino)benzaldehyde (149 mg, 1 mmol), and piperidine (12.7 mg, 0.15 mmol) in 4 mL EtOH was heated at reflux for 15 h and cooled to rt. The solid was collected via filtration and washed with ether (10 mL), and dried under vacuum. The crude product was further purified with silica chromatography (hexane/EtOAc) to afford 3-(4-(dimethylamino)benzylidene)-5-fluoroindolin-2-one as a orange solid (220 mg, 78%, E/Z ratio 7:1). For the major E/Z isomer: 1H NMR (400 MHz, acetone-d6) δ 9.41 (s, 1 H), 7.68-7.64 (m, 3 H), 7.58 (dd, J=9.6, 2.4 Hz, 1 H), 6.98-6.86 (m, 4 H), 3.09 (s, 6 H); MS (ESI) m/z 283 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:34][Si](CC)(CC)CC)[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]2[C:28]3[C:23](=[C:24]([C:29]([O:31]C)=[O:30])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[CH:11][C:10]=1[NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:34])[CH2:16][NH:17][C@H:18]([CH3:33])[CH2:19][C:20]2[C:28]3[C:23](=[C:24]([C:29]([OH:31])=[O:30])[CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[CH:11][C:10]=1[NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Temperature: 40 °C
Reaction time: 9 h
Yield: 91.6 %

Procedure:
To a solution of methyl 3-[(2R)-2-({(2R)-2-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenyl}-2-[(triethylsilyl)oxy]ethyl}amino)propyl]-1H-indole-7-carboxylate (400 mg, 0.601 mmol) in methanol (20 ml) is added a solution of potassium hydroxide (336 mg, 6.01 mmol) in water (2.0 ml), and the mixture is stirred at 40° C. for 9 hours. The reaction solution is neutralized with 1N hydrochloric acid at 0° C., and thereto is added a pH standard solution (pH 6.8, 5.0 ml). The resultant is purified by reversed phase column (octadecylsilyl, water/methanol 95/5→40/60) to give the title compound (296 mg, yield: 92%).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=O>CO.O>[F:10][C:11]([F:19])([F:18])[S:12][C:13]([CH3:17])([CH3:16])[CH:14]=[N:2][OH:3]
Reactant: NO
Reactant: CC(C)(C=O)SC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C=NO)SC(F)(F)F

Procedure:
A mixture of hydroxylamine hydrochloride (0.09 mole) in methanol (230 ml), sodium carbonate (4.8 g, 0.045 mole) in 50 ml of water and 2-trifluoromethylthio-2-methylpropionaldehyde (14.85 g, 0.086 mole) from Step 1 was stirred at room temperature overnight. The reaction mixture was poured into water, the oxime was extracted into diethyl ether, the combined ether extracts were washed with water and then dried. The drying agent was removed by filtration and the filtrate was distilled to provide 2-trifluoromethylthio-2-methylpropionaldehyde oxime, b.p. 80°C/18 mm. The structure of this product was confirmed by elemental and spectroscopic analyses.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:49](=[O:50])[N:24]3[CH:25]([C:33]([O:35][CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[C:26]([CH:29]=[C:30]([Cl:32])[Cl:31])=[CH:27][S:28][C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:12]1([CH2:18][C:19]([NH:21][CH:22]2[C:49](=[O:50])[N:24]3[C:25]([C:33]([O:35][CH:36]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:34])=[C:26]([CH:29]=[C:30]([Cl:31])[Cl:32])[CH2:27][S:28](=[O:9])[C@H:23]23)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Cl)Cl)=CS[C@H]12
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(Cl)Cl)CS(=O)[C@H]12
Yield: 42.6 %

Procedure:
A solution of m-chloroperbenzoic acid (7 g) in ethyl acetate (35 ml) was added to a solution of benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-2-cephem-4-carboxylate (15 g) in ethyl acetate (75 ml) under ice-cooling and the mixture was stirred at the same temperature for an hour. The precipitates were collected by filtration to give benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-3-cephem-4-carboxylate-1-oxide (6.57 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]1>CS(C)=O.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:13]2[CH:12]=[C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:34][C@H:35]5[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37][CH2:36]5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[S:15][C:14]=2[CH:16]=1
Reactant: COc1ccc2cc(-c3cnc4ccc(Cl)nn34)sc2c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2cc(-c3cnc4ccc(N[C@H]5CC[C@H](O)CC5)nn34)sc2c1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-3-(6-methoxybenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.111 mmol, 1.0 equiv) in DMSO (2.0 mL) was added p-toluene sulfonic acid monohydrate (30 mg, 0.111 mmol, 1.0 equiv) and trans-4-aminocyclohexanol (0.803 mmol, 5.0 equiv) and heated to 100° C. for 24 h. The reaction mixture was diluted with water and extracted with ethyl acetate. Purification by column chromatography using 5% methanol in dichloromethane elution gave 33 mg of the yellow solid, 75%.
Reaction SMILES: C([NH:8][C:9](=[O:22])[CH2:10][NH:11][C:12](=[O:21])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1C(O)=O)C1C=CC=CC=1.[ClH:23].[H][H]>C(O)(=O)C.[Pd]>[ClH:23].[NH:14]1[CH2:15][CH2:16][CH2:17][C@H:13]1[C:12]([NH:11][CH2:10][C:9]([NH2:8])=[O:22])=[O:21]
Reactant: [H][H]
Reactant: O=C(CNC(=O)[C@@H]1CCCN1C(=O)O)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)CNC(=O)[C@@H]1CCCN1

Procedure:
A solution of 2-[(N-carboxy-L-prolyl)amino]acetamide N-benzyl ester (Ex. 9, 610 mg, 2 mmoles) in glacial acetic acid (8 ml) containing hydrogen chloride (2 mmoles) is agitated with palladium on charcoal (5%, 50 mg) in an atmosphere of hydrogen in the same manner as described in Example 6 until one molar equivalent of hydrogen has been consumed. Filtration, evaporation of the filtrate and drying of the residue under reduced pressure gives the title compound which is used as such in the subsequent step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:20][C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[N:25][CH:26]=1>CN(C=O)C.O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:24]2[N:23]=[CH:22][C:21]([CH2:20][O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]4)=[CH:26][N:25]=2)=[CH:33][CH:32]=1
Reactant: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccc2cc(OCc3cnc(Nc4ccc(Cl)cc4)nc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.8 %

Procedure:
A mixture of 6-hydroxyquinolin-2(1H)-one (0.057 g, 0.354 mmol), Cs2CO3 (0.192 g, 0.590 mmol) and 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine (0.1 g, 0.394 mmol) in DMF (2.5 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and the resulting suspension filtered. The bright yellow filter cake was taken up in methanol and the mixture was stirred for 1 h. The suspension was filtered and the yellow solid was washed with methanol and dried. The solid was further stirred in DCM/MeOH for 2 days. The mixture was filtered, and the filter cake washed with methanol and dried to give 6-((2-(4-chlorophenylamino)pyrimidin-5-yl)methoxy)quinolin-2(1H)-one as a brown solid (0.04 g, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.68 (1H, s), 9.95 (1H, s), 8.64 (2H, s), 7.72-7.92 (3H, m), 7.12-7.47 (5H, m), 6.52 (1H, d, J=9.54 Hz), 5.04 (2H, s). LCMS: R.T.=3.77 min; [M+H]+=378.93.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]([CH3:14])[C:3]1=[O:15].O[N:17]=[C:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.N>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:13][N:25]=[C:18]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[N:17]=3)=[CH:10][C:5]=2[N:4]([CH3:14])[C:3]1=[O:15]
Reactant: Cn1c(=O)n(C)c2cc(C(=O)O)ccc21
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Cn1c(=O)n(C)c2cc(-c3nc(-c4cccnc4)no3)ccc21

Procedure:
The title compound was prepared according to Method C using 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid (Matrix) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 3.49 (s, 3 H), 3.53 (s, 3H), 7.36 (d, J=8.3 Hz, 1 H), 7.64 (ddd, J=8.0, 5.1, 0.8 Hz, 1 H), 7.98 (d, J=1.6 Hz, 1 H), 8.08 (dd, J=8.3, 1.6 Hz, 1 H), 8.55 (dt, J=8.0, 1.9 Hz, 1 H), 8.73 (dd, J=4.8, 1.6 Hz, 1 H) 9.29 (d, J=1.2 Hz, 1 H). MS (DCI/NH3) m/z 308 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1.[CH3:31][NH:32][CH3:33]>CN1C(=O)CCC1.CO>[CH3:31][N:32]([CH3:33])[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:17]=[CH:18][C:19]=3[CH3:20])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][N:3]=1
Reactant: CNC
Reactant: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1ccc(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(N(C)C)cc2n(C)c1=O
Temperature: 100 °C

Procedure:
1-(3-(7-chloro-1,2-dihydro-1-methyl-2-oxo-1,6-naphthyridin-3-yl)-4-methylphenyl)-3-phenylurea A6 (50 mg, 0.12 mmol) is dissolved in NMP (1 mL) and treated with dimethyl amine (0.60 mL of a 2.0 M solution in methanol). The reaction mixture is heated to 100° C. for 12 h. Upon cooling to rt the reaction is purified by preparative LCMS.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:7](B(O)O)[CH:8]=1.[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2Br)[CH:27]=1)[CH3:23]>>[CH2:22]([O:24][C:25](=[O:39])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([C:33]2[CH2:37][CH2:36][CH2:35][C:34]=2[C:7]2[CH:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[CH:5][C:6]=2[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1cc(C)cc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Product: CCOC(=O)c1cc(C)cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)c1

Procedure:
Prepared by general procedure B(iii) but using [5-trifluoromethyl-2-(benzyloxy)phenyl]boronic acid instead of (5-chloro-2-benzyloxyphenyl)boronic acid and 3-(2-bromocyclopent-1-enyl)-5-methylbenzoic acid ethyl ester instead of 3-(2-bromocyclopent-1-enyl)-6-methylbenzoic acid ethyl ester.