Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[CH:7]=[C:6]([C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[CH:15]=3)[N:5]=[CH:4][N:3]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(-c2cc(-c3cccc(C)c3)ncn2)c1
Yield: 15 %

Procedure:
First, into a recovery flask equipped with a reflux pipe were put 4.99 g of 4,6-dichloropyrimidine, 9.23 g of 3-methylphenylboronic acid, 7.18 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.31 g of 3-methylphenylboronic acid, 1.82 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Then, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained organic layer was washed with saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and was dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 20:1, so that a pyrimidine derivative H5mdppm, which was the objective substance, was obtained (pale yellow powder, yield of 15%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme (d-1) of Step 1 is shown below.
Reaction SMILES: C(O)(=O)C.[C:5]([C:7](=[N:11][O:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:15])[CH3:14])[C:8]([NH2:10])=[NH:9])#[N:6].C(N(CC)CC)C.BrBr.[S-:30][C:31]#[N:32].[K+]>CO.O.CN(C)C=O>[NH2:32][C:31]1[S:30][N:10]=[C:8]([C:7](=[N:11][O:12][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:15])[CH3:14])[C:5]#[N:6])[N:9]=1
Reactant: CCOC(=O)C(C)(C)ON=C(C#N)C(=N)N
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C(C)(C)ON=C(C#N)c1nsc(N)n1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of 2-cyano-2-(1-ethoxycarbonyl-1-methylethoxyimino)acetamidine acetate (685 g) in methanol (6.85 l) was added triethylamine (557 g) at -13°~15° C. over a 20-minute period and then bromine (344 g) was added thereto at the same temperature over the same period. The solution was stirred at -13°~15° C. for 15 minutes, then N,N-dimethylformamide (685 ml) was added to the solution at the same temperature, and a solution of potassium thiocyanate (209 g) in methanol (2.09 l) was added thereto at -13°~15° C. over a 30-minute period. After being stirred at -5°~0° C. for an hour, the solution was poured into a cold water (5°~10° C.) and stirred for an hour under ice-cooling. The resulting precipitates were collected by filtration, washed with cold water and dried to give 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-ethoxycarbonyl-1-methylethoxyimino)acetonitrile (390 g).
Reaction SMILES: C(O)(C)C.C(=O)=O.[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][CH3:17])=[O:15])=[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1.C([Li])(CC)C.[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](Cl)=[O:49])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2([OH:49])[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[C:13](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[C:14](=[O:15])[N:16]2[CH3:17])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(c1ccccc1)C(O)(C1CCN(C(=O)OCc3ccccc3)CC1)N(C)C2=O
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To an isopropanol/dry ice cooled solution of 4-Methoxy-N-methyl-2-(phenylmethyl)benzamide (250 mg, 0.980 mmol) in THF (50 mL) under argon was added sec-butyllithium solution (1.3M, 1.55 mL, 2.00 mmol) dropwise. After 10 min. a THF (10 mL) solution of benzyl-4-(chlorocarbonyl)piperidine-1-carboxylate (275 mg, 980 mmol) was quickly added to the reaction solution. After 10 min. the reaction was quenched with water then warmed to room temperature. Saturated sodium bicarbonate was added and the resulting mixture extracted with ethyl acetate (3×) and dried with anhydrous magnesium sulfate. Filtration followed by evaporation of solvent in vacuo gave the crude product which was subjected to flash column chromatography (hexane:ethyl acetate 50:50) to afford benzyl-4-(3-hydroxy-6-methoxy-2-methyl-1-oxo-4-phenyl-1,2,3,4-tetra-hydroisoquinolin-3-yl)piperidine-1-carboxylate as a white foam (242 mg, 0.484 mmol, 49%). MS [M+H]+ 501.2
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.C(ON1C(=O)N2C[C@H]1CC[C@H]2C(O)=O)C1C=CC=CC=1.C(NN)=O.[CH2:37]([O:44][N:45]1[C:51](=[O:52])[N:50]2[CH2:53][C@H:46]1[CH2:47][CH2:48][C@H:49]2[C:54]([NH:56][NH:57][CH:58]=[O:59])=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C1COCC1.[Cl-].[Na+].C(Cl)Cl.N1C=CC=CC=1>[CH2:37]([O:44][N:45]1[C:51](=[O:52])[N:50]2[CH2:53][C@H:46]1[CH2:47][CH2:48][C@H:49]2[C:54]1[O:59][CH:58]=[N:57][N:56]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: NNC=O
Agent: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N2C[C@@H](CC[C@H]2c2nnco2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.3 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a 0° C. solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL). The reaction mixture was allowed to warm to rt then was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with saturated sodium chloride and extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+. Step 2: To a −10° C. solution of (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (11 g) in dry DCM (200 mL) was added pyridine (28 mL), followed by dropwise addition of (CF3SO2)2O (28 mL). The reaction mixture was allowed to warm to rt and was stirred for 3 hrs. The reaction mixture was then cooled to −10° C. and quenched with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 1:3 to 2:1 EtOAc/hexanes) to give (2S,5R)-6-(benzyloxy)-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (4.6 g, 86% for two steps) as a slightly yellow solid. ESI-MS (EI+, m/z): 301.0 [M+H]+. Step 3: To a solution of (2S,5R)-6-(benzyloxy)-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (4.6 g, 15.3 mmol) in THF (150 mL) was added 10% Pd/C (1 g). The mixture was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was then filtered and concentrated to afford the compound of Formula (I): (2S,5R)-6-hydroxy-2-(1,3,4-oxadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (2.9 g, 91%). ESI-MS (EI+, m/z): 211.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[O:11]=[C:12]([CH2:18][CH3:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].CC(C)([O-])C.[Na+]>>[CH3:17][O:16][C:14](=[O:15])[CH:13]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12](=[O:11])[CH2:18][CH3:19]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCC(=O)C(C(=O)OC)C(=O)c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 2 using 4-bromobenzoyl chloride and methyl 3-oxovalerate; sodium tert-butoxide was used in place of pyridine.
Reaction SMILES: Cl[C@H:2]1[N:5]([C:6](=[C:11]([CH3:13])[CH3:12])[C:7]([O:9][CH3:10])=[O:8])[C:4](=[O:14])[C@@H:3]1[C@@H:15]([O:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:19])[CH3:16].[CH2:31]([Si](C)(C)C)[CH:32]=[CH2:33].[Cl-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C.F[B-](F)(F)F.[Ag+]>[CH3:12][C:11]([CH3:13])=[C:6]([N:5]1[C@H:2]([CH2:33][CH:32]=[CH2:31])[C@@H:3]([C@@H:15]([O:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[CH3:16])[C:4]1=[O:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H]([C@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1Cl
Reactant: C=CC[Si](C)(C)C
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H]([C@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-[(3S,4R)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (180 mg) and allyltrimethylsilane (0.12 ml) in dichloromethane (2 ml) was added silver tetrafluoroborate (240 mg) at -78° C. under a nitrogen atmosphere. The stirring mixture was allowed to warm to 0° C. during 45 minutes and kept at the same temperature for one hour. The mixture was diluted with ethyl acetate (10 ml) and a saturated aqueous sodium chloride was added. The mixture was neutralized with a saturated aqueous sodium bicarbonate, diluted with additional ethyl acetate (20 ml) and filtered through a pad of cellurose powder. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (11 g) eluting with 3-30% ethyl acetate in dichloromethane to give methyl 3-methyl-2-[(3S,4R)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-4-allylazetidin-1-yl]but-2-enoate (47 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.[Na].[H-].[Na+]>CN(C)C=O>[N:23]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCn1ccnc1

Procedure:
A 99.0 g amount of 2-(10-bromodecyl)-1H-isoindole-1,3(2H)-dione (prepared as described above) was dissolved in 300 ml of warm N,N-dimethylformamide with stirring. This solution was added to a stirred solution of 1H-imidazole, sodium salt (prepared by stirring a mixture of 20 g of imidazole and 14.0 g 50% sodium hydride in 500 ml of N,N-dimethylformamide at room temperature for 48 hours). The resulting mixture was heated on a steam bath for 14 hours, then taken to dryness in vacuo. The residue was partitioned between 500 ml of dichloromethane and 250 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and gave 85.4 g of 2-[10-(1H-imidazol-1-yl)decyl]-1H-isoindole-1,3(2H)-dione as an oil which solidified on standing at room temperature.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1([F:30])[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][NH:18][CH2:17]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:15][C:16]1([F:30])[CH2:22][N:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[CH2:20][CH2:19][NH:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCNCC(F)(F)C1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: FC1(F)CNCCN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Temperature: 135 °C
Reaction time: 6 h
Yield: 56.7 %

Procedure:
A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol), tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (1.06 g, 4.49 mmol) and DIPEA (1.56 ml, 8.99 mmol) in DMA (15 mL) was stirred at 135° C. for 6 hours. The reaction mixture was concentrated to dryness and DCM (30 mL) was added. The solution was cooled in an ice bath and TFA (15 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness, diluted with water, basified with 6M aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in DCM to give 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.820 g, 56.6%) as a beige solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>C(O)C>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[CH3:14]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspenson of 2,6-dichloro-3-nitropyridine (1.0 g, 0.00518 mole) and glycine ethyl ester hydrochloride (0.725 g, 0.00518 mole) in absolute ethanol (10 ml) was added triethylamine (1.05 g, 0.0104 mole). The resulting solution was stirred overnight at room temperature under nitrogen. An additional portion of absolute ethanol (10 ml) was added and the suspension was filtered and the solid was washed with 3-10 ml portions of absolute ethanol. The combined filtrate and washings were evaporated under reduced pressure at room temperature to give a yellow solid which was triturated in water (30 ml) collected by filtration, and rinsed with additional water. The solid was recrystallized from isopropyl ether/light petroleum ether, and the resulting solid was purified by column chromatography (10 g of silica gel) with 1:1 isopropyl ether/light petroleum ether as the eluting solvent. The appropriate fraction was recrystallized from isopropyl ether and dried under high vacuum to give the title compound, mp 77.5°-80° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[N:10]=2)[CH:5]=[CH:6][N:7]=1.O1CCC[CH2:20]1.CC(C)=O.C(=O)=O.C[Mg+].[Br-]>CCOCC.CO.CN1CCCC1=O>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:3]2[C:2]([CH3:20])=[N:7][CH:6]=[CH:5][N:4]2[CH:8]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(-c2cn3ccnc(Cl)c3n2)c(F)c1
Agent: C[Mg+]
Agent: O=C=O
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Cc1nccn2cc(-c3ccc(F)cc3F)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Into a 3-neck reaction flask equipped with a mechanical stirrer, was added 8-chloro-2-(2,4-difluorophenyl)imidazo[1,2-a]pyrazine (40.00 g, 150.6 mmol), ferric acetylacetonate (2.66 g, 7.53 mmol), tetrahydrofuran (970 mL) and N-methylpyrrolidinone (86 mL). The flask was charged with nitrogen and cooled to about −5-0° C. (acetone/DriKold cooling bath) before the drop-wise addition of 3M MeMgBr in Et2O (150 mL) over about 20 min. After the addition was complete, the reaction was stirred at this temperature for about 15 min before the cooling bath was removed. The reaction mixture was allowed to warm to ambient temperature over about 1 hour and then stirred overnight. The reaction was concentrated and the residue was stirred with water (1000 mL) and EtOAc (1000 mL) for about 15 min. The mixture was filtered through a Celite® pad to remove salts. The Celite® pad was scraped and stirred with EtOAc (3×250 mL). The basic aqueous phase was separated and extracted with EtOAc (3×250 mL). The organic layers were combined, washed with water (3×350 mL), dried over MgSO4, and filtered through a Florisil® pad to remove origin material. The solvent was removed to yield a yellow solid that was treated with boiling MeOH (125 mL), cooled to about 15° C. and petroleum ether [bp 30-60° C.] (250 mL) was added with stirring. The solid was filtered, washed with petroleum ether [bp 30-60° C.] (3×50 mL), and dried in vacuo at 70° C. to yield the title compound as a pale yellow powdery solid (23.25 g, 64%): LC/MS (Table 1, Method g) Rt=2.42 min; MS m/z: 246.1 (M+H)+.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]([CH3:24])[C:15]1[N:20]=[C:19]([CH3:21])[C:18]([O:22][CH3:23])=[CH:17][N:16]=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>C1COCC1.CCCCCC.C(OCC)(=O)C.O>[CH3:24][N:14]([CH3:13])[C:15]1[N:20]=[C:19]([CH2:21][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18]([O:22][CH3:23])=[CH:17][N:16]=1
Reactant: COc1cnc(N(C)C)nc1C
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1nc(N(C)C)ncc1OC
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
A three-necked 150 ml flask fitted with a septum, a low temperature thermometer and an addition funnel was charged under nitrogen with 11.6 ml (18.6 mmol) of 1.6 M n-butyllithium. After cooling the flask to 5° C., a solution of 2.6 ml (18.6 mmol) of diisopropylamine in 20 ml dry THF was added dropwise over 5 minutes. After addition was completed, the mixture was stirred at 5° C. for 15 minutes and then cooled to -70° C. To the reaction mixture was added a solution of 1.56 g (9.3 mmol) of 2-dimethylamino-4-methyl-5-methoxypyrimidine in 20 ml dry THF over ten minutes. The reaction mixture was then stirred at -70° C. for 1.5 hour, and a solution added of 2.0 g (18.6 mmol) of ethyl chloroformate in 20 ml dry THF over five minutes. The reaction mixture was stirred at -70° C. for a half hour and then allowed to warm to -15° C. over 15 minutes. The reaction mixture was poured into 100 ml of water, the aqueous mixture brought to pH 8.5 with 1N HCl and extracted with three 25 ml portions of chloroform. The combined extracts were dried over Na2SO4, filtered and evaporated leaving an oil. Chromatography over 100 g of silica gel with hexane/ethyl acetate (9:1) yielded 47% (1.05 g) of the title compound as a colorless liquid. NMR(CDCl3) 8.0 (s, 1H), 4.19 (q, J=7 Hz, 2H), 3.75 (s, 3H), 3.65 (s, 2H), 3.05 (s, 6H), 1.1 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]>C(O)(C(F)(F)F)=O.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:6]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]=1[CH3:20]
Reactant: COc1nc(CC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(CC(=O)O)c([N+](=O)[O-])cc1C
Yield: 94.4 %

Procedure:
A solution of tert-butyl 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetate (83.0 g, 294 mmol) in TFA (200 mL) was heated in a hot water bath for 1 h. The solution was concentrated in vacuo to give a brown oil. The oil was diluted with hexane and stirred. The resulting solid was collected by filtration and air dried to give 2-(6-methoxy-5-methyl-3-nitropyridin-2-yl)acetic acid (62.8 g, 94% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.70 (s br, 1H), 8.20 (s, 1H), 4.25 (s, 2H), 4.03 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.59, 163.80, 146.52, 139.16, 135.30, 121.53, 54.86, 42.88, 15.32. An analytical sample was recrystallized from hexane: mp 135-137° C. Anal. calcd. for C9H10N2O5: C, 47.79; H, 4.46; N, 12.39. Found: C, 47.65; H, 4.14; N, 12.30.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([C:10](O)=[O:11])=[CH:7][S:8][CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[NH:4][C:5]1[C:6]([CH2:10][OH:11])=[CH:7][S:8][CH:9]=1
Reactant: O=C(O)c1cscc1Nc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cscc1Nc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
57.63 g (0.2 mole) of 4-(2,6-dichloroanilino)-3-thiophencarboxylic acid (dissolved in 350 ml of tetrahydrofuran) are added dropwise to a suspension of 7.59 g (0.2 mole) of lithium aluminum hydride in 170 ml of absolute tetrahydrofuran at 15° in the course of one hour, while stirring and under nitrogen. Stirring is then continued at room temperature for one hour. The reaction mixture is hydrolyzed with 2 liters of ice-cold water, acidified to pH 5 with dilute sulfuric acid and extracted with 1.5 liters of ethyl acetate. The extract is washed with 100 ml of 2 N sodium bicarbonate solution, dried over sodium sulfate and concentrated, 4-(2,6-dichloroanilino)-3-thiophenmethanol being obtained in almost quantitative yield as a viscous oil which slowly solidifies. Recrystallization from cyclohexane gives pure 4-(2,6-dichloroanilino)-3-thiophenmethanol (m. 96° to 97°).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45](OC(C)(C)C)([CH3:50])[CH2:46]C(O)=O)/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:38]([OH:40])=[O:39])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([Cl:33])[C:26]=5[CH2:34][C:35]([OH:37])=[O:36])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)[C:58]([OH:60])=[O:59]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45]([C:58]([OH:60])=[O:59])([CH3:50])[CH3:46])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:38]([OH:40])=[O:39])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([Cl:33])[C:26]=5[CH2:34][C:35]([OH:37])=[O:36])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(C)(CC(=O)O)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3cc(O)c(O)c(Cl)c3CC(=O)O)CS[C@H]12)c1csc(N)n1
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3cc(O)c(O)c(Cl)c3CC(=O)O)CS[C@H]12)c1csc(N)n1)C(=O)O

Procedure:
7-[2-(2-Aminothiazol-4-yl)-2-((Z)-1-t-butoxycarboxy-1-methyl ethoxyimino)acetamido]-3-[(1-(2-carboxymethyl-3-chloro-4,5-dihydroxyphenyl)-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid (0.875 g) was treated with trifluoroacetic acid (10 ml) at room temperature for 1 hour. The mixture was evaporated and the residue triturated with ether to give a solid which was collected by filtration and purified by HPLC (AMICON C18 15 μm), eluting with methanol/water/acetic acid (35:65:1 to 40:60:1) [Dimethylformamide was necessary for dissolution of the crude product.] Thus was obtained the title product (0.38 g); NMR (DMSO-d6 /CD3CO2D/CF3CO2D) 1.55(s,6H, --C(CH3)2 --); 3.35(s,2H,--CH2COOH); 3.60 and 3.85(2d, J=18 Hz, --SCH2 --); 4.30 and 4.65 (2d,J=11.5 Hz, 2H, --CH2 --S--tetrazole); 5.20 and 5.85(2d, J=4.5 Hz, 2H, H6 and H7); 6.85 (s,1H, aromatic); 7.05(s,1H, thiazole).