Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH2:20][C:19]2=[O:23])=[CH:14][CH:13]=1.Cl>O1CCCC1.CCCCCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([C:3]([O:7][CH2:8][CH3:9])=[O:10])[C:19]2=[O:23])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCN1c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(c2ccc(Cl)cc2)C1=O
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a suspension of 25 g of sodium hydride (60% oil dispersion) in 100 mL of tetrahydrofuran was added 37 g of diethyl carbonate. Under reflux, to the mixture was added dropwise a solution of 52.0 g of 1-(4-chlorophenyl)-2-pyrrolidinone in 150 mL of tetrahydrofuran over about 1.5 hours. After refluxing for 4.5 hours, the reaction mixture was cooled, and carefully poured into ice-water. The mixture was made to weakly alkaline with diluted hydrochloric acid and extracted with 300 mL of ethyl acetate. The organic layer was washed sequentially with water, aqueous sodium bicarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated to give an oil. To the residue was added 200 mL of n-hexane, and the precipitated crystals were collected by filtration. The crystals were washed with n-hexane and dried in vacuo to give 60 g of the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=2[O:18][CH3:19])=[C:4]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[O:23][C:22]2=[O:41])[CH:3]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:50]>>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([C@H:24]2[O:23][C:22](=[O:41])[N:21]([CH2:20][C:4]3[CH:3]=[C:2]([Br:50])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=3[O:18][CH3:19])[C@H:25]2[CH3:26])[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=1
Reactant: BrC(Br)Br
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CC(C)(C)ON=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution (4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl nitrite (186 mg, 1.80 mmol). The resulting mixture was stirred at 80° C. for 20 min. An aliquot indicated completion of the reaction. The reaction crude was purified silica gel to afford the title compound as a yellow glass. LC-MS: 650.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.85 (s, 1 H), 7.69 (s, 2 H), 7.60 (s, 0.5 H), 7.48-7.53 (m, 1.5H), 7.07-7.11 (m, 1 H), 6.93-6.99 (m, 1 H), 6.62-6.67 (m, 1H), 5.59 (d, J=8.0 Hz, 0.5H), 5.39 (d, J=7.0 Hz, 0.5H), 4.82 (d, J=6.5 Hz, 0.5H), 4.75 (d, J=6.5 Hz, 0.5 H), 3.98 (d, J=16.0 Hz, 0.5 H), 3.76-3.85 (m, 1.5 H), 3.75 (s, 1.5 H), 3.74 (s, 1.5 H), 3.13-3.23 (m, 1H), 1.13-1.29 (m, 6 H), 0.52 (d, J=6.5 Hz, 1.5H), 0.34 (d, J=7.0 Hz, 1.5 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[N:3]1.S(Cl)(Cl)=O.[CH2:27](Cl)Cl>>[CH3:1][C:2]1([CH3:22])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:27])=[O:20])=[CH:15][CH:14]=2)=[N:3]1
Reactant: ClCCl
Reactant: CC1(C)COC(c2ccccc2-c2ccc(C(=O)O)cc2)=N1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2ccccc2C2=NC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
10.0 g (33.8 mmol) of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline was dissolved in methylene chloride (200 ml). 4.8 g (40.3 mmol) of thionyl chloride was added thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was subjected to vacuum concentration. Methanol (100 ml) was added to the residue, followed by stirring for 3 hours. After distilling out the solvent under a reduced pressure, methylene chloride and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue and obtained mixture was caused liquid-liquid separation. After washing with water and drying, vacuum concentration was conducted. The residue was purified by silica gel column chromatography (an ethyl acetate/n-hexane system) to give 9.53 g of the title compound as an oil (yield 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>C(Cl)Cl>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])=[S:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-amino-5-bromopyridine (200.0 g, 1.156 mol) in DCM (2.0 L) cooled to 5° C. was added ethoxycarbonyl isothiocyanate (134.9 mL, 1.156 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temperature (20° C.) and stirred for 16 h. Evaporation in vacuo gave a yellow solid which was collected by filtration, thoroughly washed with petrol (3×500 mL) and air-dried to afford the title compound (351.5 g, quantitative). No further purification was required.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>O>[C:27]([NH:2][C@H:3]1[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH3:20])[N:12]=2)=[O:10])[CH2:4]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@H]1N
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N[C@@H]1CN(C(=O)c2nn(C)c3ccccc23)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To 200 mg (0.68 mmol) of cis-3-amino-4-methyl-1-(1-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride was added 0.7 ml of pyridine, and 0.07 ml (0.75 mmol) of acetic anhydride was added dropwise under ice cooling. Then, after heated to room temperature, the mixture was stirred overnight. To the reaction mixture was added water, and then the solution was extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure to obtain crude oil. This was subjected to silica gel column chromatographic purification (methylene chloride:acetone=10:1) to obtain 176 mg (86.3%) of aimed compound. m.p. 202°-204° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7](=S)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>CCCCO>[CH3:15][C:14]1[N:6]2[C:5]3[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=3[NH:3][CH:2]([CH3:1])[CH2:8][C:7]2=[N:18][N:17]=1
Reactant: CC(=O)NN
Reactant: CC1CC(=S)Nc2ccccc2N1
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccccc1NC(C)C2
Yield: 44.9 %

Procedure:
A solution of 4-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (200 mg, 1.04 mmol) and acetohydrazide (150 mg, 2.07 mmol) in n-BuOH (10 mL) was heated at 130° C. overnight. The reaction mixture was evaporated, and then water (10 mL) was added, extracted with ethyl acetate (10 mL), dried with Na2SO4, and concentrated to give the crude product, which was purified by prep-TLC to give 1,5-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (100 mg, 45%).
Reaction SMILES: CN(C)CCN(C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([SH:22])[CH:19]=[CH:20][CH:21]=1.CON(C)[C:26](=[O:35])[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1CCCCC1>[SH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[C:17]=1[C:26](=[O:35])[CH:27]=[CH:28][CH:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH2:34]1
Reactant: COc1cccc(S)c1
Reactant: CON(C)C(=O)CCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: COc1cccc(S)c1C(=O)C=CC1C=CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
To a solution of N,N,N′,N′-tetramethylethylenediamine (4.31 mL) in cyclohexane (50 ml) were added n-butyl lithium (2.46 mol/L n-hexane solution 12.2 mL) and 3-methoxythiophenol (2 g) successively under ice-cooling. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added N-methoxy-N-methyl-3-phenylpropionamide (2.76 g) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give the title compound (1.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[O:6][CH:23]=[N:22][CH:21]=1
Reactant: COc1ccccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1cnco1
Yield: 70.4 %

Procedure:
A mixture of 2-methoxybenzaldehyde (10.0 g, 73.4 mmol), tosylmethylisocyanide (14.34 g, 73.4 mmol) and potassium carbonate (10.14 g, 73.4 mmol) in 220 ml methanol is heated at reflux for 6 hours. The solvent is removed under reduced pressure and the residue poured into ice-water (800 ml). The precipitate is collected by filtration, washed with water, and dried in vacuo to give 9.05 g of 5-(2-methoxyphenyl)oxazole (70%). Boron tribromide (1M in dichloromethane, 36 ml) is added slowly to a cold solution (0° C.) of the above oxazole (3.0 g, 17.1 mmol) in dichloromethane (215 ml). After stirring overnight at room temperature, ice-water (50 ml) is added carefully. The aqueous layer is extracted with dichloromethane (50 ml), and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The precipitate which formed after addition of dichloromethane (70 ml) is collected by filtration, heated with dichloromethane (15 ml), and filtered again to give 3.16 g of 2-(5-oxazolyl)phenol. This phenolic product is reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to give 400 mg of the title epoxide (9.5%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1COCC1>[CH:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexylamine (8.5 mL, 0.1 mole) was added drop wise to a solution of benzoylchloride (1.17 mL, 10 mmol) in 35 mL of dry THF at 0° C. The reaction was then stirred at room temperature for 3 hours. After that time water was added and the mixture was poured onto crushed ice. A white solid precipitated. It was collected by filtration and rinsed thoroughly with water. The solid was then dried under vacuum (1.63 g, 80%). NMR 1H (ppm, CDCl3): 7.72 (d, J3=6.78 Hz, 2H), 7.48-7.36 (m, 3H), 6.02 (br. d., J3=6.58 Hz, 1H), 4.00-3.89 (m, 1H), 2.03-1.99 (m, 2H), 1.79-1.71 (m, 3H), 1.44-1.37 (m, 2H), 1.25-1.15 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](C)[C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15](Br)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.O.[CH3:30]S(C)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:30][C:25]1[NH:24][CH:28]=[CH:27][N:26]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CS(C)=O
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc(C)c2[nH]c3cccc(Br)c3c2c1COC
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ncc[nH]4)c3c2c1COC

Procedure:
5-Bromo-methyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (0.35 g) is left with imidazole (0.13 g) in dimethyl sulfoxide (4 ml) for three days at room temperature. The precipitate resulting after addition of water (40 ml) is recrystallized from ethanol and chromatographed on silica gel with a mixture of 19 parts of dichloromethane and one part of methanol. Thus 0.2 g of 5-(1-imidazolylmethyl)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester with a melting point of 220°-222° C. is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][C:19]1[C:24]([NH:25][C:26](OC(C)(C)C)=[O:27])=[CH:23][CH:22]=[C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:20]=1)C(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:27]=[C:26]1[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:20]=2)[NH:25]1
Reactant: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1Cc2nc(-c3ccccc3)ccc2NC1=O)OCc1ccccc1
Yield: 102.6 %

Procedure:
A solution of 1L (145 mg, 0.287 mmol) in TFA (1 mL) and CH2Cl2 (1 mL) was stirred at RT for 1 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (110 mg, 100%). LC/MS (method A): retention time=3.09 min, (M+H)+=374.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Yield: 20.8 %

Procedure:
A solution of 1-(4-pyridinyl)piperazine (1.63 g), N-[4-(2-methylsulphonyloxyethyl)phenyl]methanesulphonamide (2.93 g) and triethylamine (1.01 g) in ethanol (25 ml) was heated under reflux for 18 hours and then evaporated. The resulting oil was partitioned between dichloromethane and water (some insoluble material remained in the aqueous layer). The aqueous layer was washed with dichloromethane and the organic layers were combined, washed with water and dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed in silica gel. Elution with dichloromethane/methanol (19:1) first gave some impurity followed by a solid which was crystallised from methanol/ethyl acetate to give the title compound (0.75 g), m.p. 208°-210° C.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=[O:33].[K+].[K+].OO>CS(C)=O>[CH:29]1([C:27]([NH:26][C:24]2[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:6]5[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[N:8][CH:7]=5)=[CH:16][CH:15]=4)[N:22]3[N:23]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
To a solution of cyclopropanecarboxylic acid{5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (30 mg, 0.073 mmol, 1 equiv) and K2CO3 (10 mg, 0.073 mmol, 1 equiv) in DMSO (0.2 mL) at 10° C., 30% H2O2 (17 μL, 0.146 mmol, 2 equiv) was added dropwise. After stirring at room temperature the mixture for 4 h, the mixture was diluted with DMSO and filtered. The filtrate was submitted for preparative HPLC purification: HPLC system (XBridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; isolating the final product (25 mg, 81% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](O)(=[O:23])[CH3:22]>C1COCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CC(=O)O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)Cc1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred solution of diisopropylamine (14.22 ml, 101.43 mmol) cooled to −78° C. is added dropwise butyllithium (60 ml). The reaction mixture is stirred and allowed to warm to 0° C. over 15 minutes after which time 2-chloro-4-methylpyridine is added to the stirred solution. After 1 hour, ethyl acetate (18.88 ml) and THF (78 ml) are added over 45 minutes followed by acetic acid (11.4 ml, 193.2 mmol) and stirring continued for 20 minutes. The reaction mixture is concentrated in vacuo and the crude product dissolved in with water (200 ml). The aqueous is extracted with chloroform (3×300 ml) and the combined organic portions washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield the crude product as a brown oil. Purification by chromatography on silica, eluting with ethyl acetate-hexane affords the titled compound.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[N:15]=[N:16][CH:17]=1>>[ClH:11].[CH3:24][C:20]1[N:19]([CH2:18][C:14]2[N:15]=[N:16][CH:17]=[C:12]([C:2]3[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=3)[CH:13]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1ccc(-c2cnnc(Cn3ccnc3C)c2)cc1
Product: Cl

Procedure:
The title compound, MS: m/e=265.3 (M+H+), was prepared from p-tolylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH2:37]([P:41]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH3:40]>C(OCC)(=O)C>[I-:1].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C:9]([C:8]2[N:7]3[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C@H:6]3[S:5][CH2:4][C:3]=2[CH2:2][P+:41]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCP(CCCC)CCCC
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12
Solvent: CCOC(C)=O
Product: CCCC[P+](CCCC)(CCCC)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Product: [I-]
Reaction time: 0.75 h
Yield: 53.3 %

Procedure:
A solution of diphenylmethyl 3-iodomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (4.9 g.) in ethyl acetate (90 ml.) was stirred in the dark at room temperature and treated, over 15 minutes, with a solution of tri-n-butylphosphine (3.1 g., ca. 2 equivs.) in ethyl acetate (50 ml.). The solution was stirred for a further 45 minutes and precipitated into petroleum-ether to give the phosphonium iodide (3.448 g.), m.p. 120°-125° (decomp), [α]D - 43°(N,N-dimethylformamide), RF 0.0, inflexion (EtOH) at 259 nm. (ε 7,100), νmax. (CHBr3) 3410 (-NH), 1786 (β-lactam), 1708 (ester), and 1686 and 1510 cm. -1 (-CONH-), τ (CDCl3) 4.22 (C(7) -H, dd, J 5 and 9 Hz.), 4.87 (C(6) -H d, J 5 Hz), 5.80 and 6.11 (C(2) -CH2, two dd, JH-H 18 Hz., JP-H 3-4 Hz). [Found: C, 55.3; H, 6.0; I, 15.7; N, 3.1; P, 3.7 C39H50IN2O4PS2 (832.8) requires C, 56.2; H, 6.1; I, 15.1; N, 3.4; P, 3.7%].
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Cl:23])[CH:17]=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:2]=[O:4])=[C:18]([Cl:23])[CH:17]=1
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N=C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 260 %

Procedure:
To an ice cold solution of triphosgene (59 mg, 200 μmol) in CH2Cl2 (1.5 ml) was added 4-amino-3-chloro-benzoic acid methyl ester (100 mg, 540 μmol; [84228-44-4]) and a solution of Et3N (150 μl, 1.1 mmol) in CH2Cl2 (0.5 ml) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 min. The solvent was removed under reduced pressure. The residue was triturated with EtOAc, the solid was filtered off and the filtrate was evaporated to dryness under reduced pressure to give the title compound (111 mg, 520 μmol; 97%) as brown solid which was used in the next step without further purification. MS: m/e=228.9 [M+H+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH:10](OCC)(OCC)OCC.[C:20](#[N:24])[CH2:21][C:22]#[N:23]>C(O)C.O>[C:22]([C:21](=[CH:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[C:20]#[N:24])#[N:23]
Reactant: N#CCC#N
Reactant: CCOC(OCC)OCC
Reactant: CNc1ccc(O)cc1
Solvent: CCO
Solvent: O
Product: CN(C=C(C#N)C#N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A mixture of 62.5 grams (0.5 mole) of N-methyl-p-aminophenol, 74.0 grams (0.5 mole) of triethyl orthoformate, and 33.5 grams (0.5 mole) of malononitrile in 400 milliliters of 99.5% ethanol was prepared under a nitrogen atmosphere and heated at 75°-78° C. for 17 hours. The reaction mixture was cooled to room temperature, diluted with 1.5 liters of water plus ice and allowed to stand 1/2 hour. The precipitate was filtered to obtain 44 grams of α-cyano-β-(N-methyl-p-hydroxyanilino)acrylonitrile, melting point 187°-189° C. Five grams of this precipitate was treated with diethylsulfate in aqueous sodium hydroxide to obtain 0.5 gram of α-cyano-β-(N-methyl-p-ethoxyanilino)acrylonitrile (Formula II, supra) as a solid which melts at 147°-148° C. after recrystallization from ethyl acetate.