Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C(OC)OC)C.[N:9]1[C:14]2[CH:15]=[CH:16]NC(=O)[C:13]=2[CH:12]=[N:11][CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1.OO.C(O)(C(F)(F)F)=O>CN(C=O)C.C(O)(=O)C>[NH:9]1[C:14]2[CH:15]=[CH:16][CH:1]=[N:2][C:13]=2[CH:12]=[N:11][C:10]1=[O:28]
Reactant: O=c1[nH]ccc2ncncc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(OC)N(C)C
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=c1ncc2ncccc2[nH]1

Procedure:
Substituted dialkyl methylenemalonate of general formula A can be reacted with S-methylisothiouronium sulfate in the presence of appropriate bases in ethanol at reflux to give B. Compounds B can be converted to phenols C by reaction with benzoyl peroxide in the presence of appropriate bases in refluxing carbon tetrachloride or other solvents (for example dioxane). Treatment of compounds C with POCl3 at reflux produces chloropyrimidines D, which are coupled with appropriate anilines in the presence of bases in DMF at a temperature between 50° C. and 120° C. Pyrimidine esters E are converted to amides using a two-step sequence (hydrolysis and amide formation). Reaction of amides G with lithiumhexamethyldisilazane in DMF at a temperature between 100° C. and 140° C. gives pyrido[4,3-d]pyrimidin-5(6H)-one derivatives H. Alternatively, compounds H can be prepared by reaction of compounds G with DMF-DMA in DMF at a temperature between 80° C. and 120° C. followed by refluxing the resulting enamine in acetic acid. Oxidation of the sulfide of compounds H with oxidation reagents (i.e. mCPBA, H2O2-TFA) followed by displacement of the sulfone with appropriate amines and deprotection produce desired pyrimidopyridone analogs I.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH2:24]([Sn:23]([CH2:22][O:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=1)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)COc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A solution of 1,1-dimethylethyl 4-hydroxybenzoate (0.20 g, 1.04 mmol) in N,N-dimethylformamide (4 ml) was treated with powdered anhydrous potassium carbonate (0.4 g) followed by iodomethyltributyltin (0.60 g, 1.4 mmol) [D. E. Seitz, et al, Synth. Commun. (1983) 13, 129-134] and the resulting mixture was stirred at 65° C. for 1 hour. The cooled reaction mixture was diluted with a mixture of hexane and ethyl acetate (9:1), washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent and chromotography of the residue on silica gel (elution hexane-toluene, 1:1) gave 0.494 g (96%) of the title material as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]([C:5]1[N:30]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: CSc1ccc(CN)cc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 83 and using 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester and 4-(methylthio)benzylamine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH2:22][O:23][CH3:24])([CH3:21])[CH2:19][OH:20])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2].[CH2:28](Br)[C:29]#[CH:30].[H-].[Na+]>C1COCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:25][CH3:26])[C:15]([NH:17][C:18]([CH3:21])([CH2:19][O:20][CH2:30][C:29]#[CH:28])[CH2:22][O:23][CH3:24])=[O:16])=[CH:8][C:7]=2[CH3:27])#[CH:2]
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(CO)COC)cc2c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(C)(COC)NC(=O)C(Oc1cc(C)c2ncc(C#C)cc2c1)SC
Temperature: 55 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methoxymethyl-1-methyl-ethyl)-2-methylsulfanyl-acetamide (120 mg) in dry THF (10 ml) NaH (27 mg, 60% in oil) was added at room temperature under a nitrogen atmosphere. After 30 minute propargyl bromide (115 mg) was added to the reaction mixture. After stirring during 5 h one equivalent of NaH and one equivalent of propargyl bromide were added. The mixture was stirred during 4 h at 55° C., then quenched with water and diluted with ethyl acetate. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography (cyclohexane/ethyl acetate, 3:2) to give 2-(3-Ethynyl-8-methyl-quinolin-6-yloxy)-N-(2-methoxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (66 mg) as a light brown oil as a mixture of diastereoisomers.
Reaction SMILES: C([NH:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[N:16](CC3C=CC=CC=3)[C@@:10]1([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])C1C=CC=CC=1.[H][H]>[Pd].CO.C(O)(=O)C>[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]2[NH:16][C@@:10]1([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:11][C@H:12]2[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2N
Yield: 99.3 %

Procedure:
(1R*,2R*,5S*,6R*)-2-Benzylamino-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Description 18; 7.07 g, 14.7 mmol) and 10% palladium on activated charcoal (2 g) were taken up in methanol (100 mL) and acetic acid (100 mL), and the mixture was hydrogenated at 50 psi hydrogen for 16 hours at room temperature. The suspension was filtered and the filtrate concentrated in vacuo. The residue was then suspended in saturated aqueous sodium hydrogen carbonate solution (200 mL) and extracted with dichloromethane (2×400 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a brown oil (4.4 g, 14.6 mmol).
Reaction SMILES: [CH2:1]([I:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(OCC)(=O)C>[I-:4].[CH2:1]([N+:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCI
Reactant: CCCCCCCCCCCCCCCCN(C)C
Solvent: CCOC(C)=O
Product: C=CC[N+](C)(C)CCCCCCCCCCCCCCCC
Product: [I-]
Temperature: 25 °C

Procedure:
16.8 grams of allyl iodide were dissolved in 44.6 grams of ethyl acetate and 27.8 grams of dimethyl hexadecyl amine were added slowly with stirring at room temperature. Within 15 minutes after the addition of the amine was complete, the viscosity of the solution increased and crystallization occurred. After 24 hours the crystals were filtered, washed with ethyl acetate, and dried. The colorless crystalline product contained 88% of the theoretical amount of iodide ion.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[Cl:29][C:30]1[N:35]=[N:34][C:33]([NH2:36])=[C:32]([CH3:37])[C:31]=1[CH3:38].C(N(CC)C(C)C)(C)C>C(#N)CCC>[Cl:29][C:30]1[C:31]([CH3:38])=[C:32]([CH3:37])[C:33]2[N:34]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[N:35]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Cc1c(N)nnc(Cl)c1C
Solvent: CCCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1C
Temperature: 125 °C
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (237 mg, ˜80% purity, 0.430 mmol, 1.0 eq), 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 67.2 mg, 0.430 mmol, 1.0 eq) and N,N-diisopropylethylamine (70 μL, 0.430 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1→hexane/EtOAc 3/2) to give 185 mg (78% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccc(F)cc4)nc3)cc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-({4-[({6-[(4-fluorophenyl)oxy]-3-pyridinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D16) (32.39 g, 0.0606 mol) in DCM (150 mL) was cooled in an ice/water bath and TFA (80 mL) was added drop-wise over 10 minutes. The reaction mixture was stirred at room temperature overnight then concentrated to a yellow gum. The gum was dissolved in MeOH (100 mL) and loaded onto SCX resin (150 g, pre-washed with MeOH). Elution with MeOH (750 mL) gave unchanged TFA salt of the title compound, and elution with 2M NH3 in MeOH (750 mL) gave title compound free base. The recovered TFA salt was treated in a similar manner to that described above using further SCX resin (100 g) to give a further batch of title compound free base. The two batches of the free base were combined in DCM and concentrated to give the title compound as a pale yellow gum (26.78 g). δH (CDCl3, 400 MHz) 8.07 (1H, d), 7.65 (1H, dd), 7.22 (2H, d), 7.04 (6H, m), 6.70 (1H, d), 3.48 (3H, s), 3.42 (2H, s), 2.89 (3H, m), 2.68 (2H, d), 1.97 (1H, m), 1.64 (1H, t), 1.49 (1H bs), 1.00 (3H, d). MS (ES): MH+ 435.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([CH3:18])[C:15]([C:19]([OH:21])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[C:37]([C:41]1[CH:46]=[C:45]([NH2:47])[C:44]([O:48][CH3:49])=[CH:43][N:42]=1)([CH3:40])([CH3:39])[CH3:38].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C)C=O>[C:37]([C:41]1[CH:46]=[C:45]([NH:47][C:19]([C:15]2[N:16]([CH3:18])[C:17]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[C:44]([O:48][CH3:49])=[CH:43][N:42]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Cn1c(C(=O)O)cc2cccc(OCc3ccccc3)c21
Reactant: COc1cnc(C(C)(C)C)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(C)(C)C)cc1NC(=O)c1cc2cccc(OCc3ccccc3)c2n1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.2 %

Procedure:
To a slurry of 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (163 mg, 0.58 mmol) in methylene chloride (2 mL) at 0° C. was added oxalyl chloride (72 microL, 0.84 mmol) followed by a drop of N,N-dimethylformamide. The solution immediately bubbled and became clear after a period of 0.75 h. The mixture was concentrated and redissolved in methylene chloride (1.5 mL). The acid chloride solution was added to a solution of N,N-diisopropylethylamine (202 microL, 1.16 mmol) and 2-tert-butyl-5-methoxy-pyridin-4-ylamine (95 mg, 0.52 mmol) in methylene chloride (1.5 mL). The solution was stirred at room temperature for 3 h then poured onto saturated aqueous NaHCO3. The aqueous layer was extracted with methylene chloride and the combined extracts were washed with saturated aqueous NaHCO3, followed by saturated aqueous KH2PO4, and again with saturated aqueous NaHCO3. The organic extracts were dried over sodium sulfate, filtered through a plug of silica-gel with diethyl ether, and concentrated in vacuo to provide pure 7-benzyloxy-1-methyl-1H-indole-2-carboxylic acid (2-tert-butyl-5-methoxy-pyridin-4-yl)-amide (231 mg, 99%) as a white solid.
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31](OC1C=CC=CC=1)=[O:32])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:51][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:32])(=[O:28])=[O:29])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Reactant: CCCCCCCCN
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 97.6 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sufonyl]phenyl]benzamide produced in Example 45 and 0.15 mol (0.88 mmol) of octylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel chromatography to obtain 210 mg (yield: 98.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:11](Cl)=[N:12][OH:13])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([Cl:28])[CH:17]=1.C(=O)([O-])O.[Na+]>CC(O)C>[Br:1][C:2]1[C:10]2=[N:9][S:8][N:7]=[C:6]2[C:5]([C:11]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([Cl:28])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: ON=C(Cl)c1ccc(Br)c2nsnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c3nsnc23)=NO1
Temperature: 65 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a solution of 7-bromo-N-hydroxy-benzo[1,2,5]thiadiazole-4-carbimidoyl chloride (Example 5.5) (10.01 g) in 2-propanol (140 ml) was added 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (6.87 g) and sodium hydrogen carbonate (5.99 g). The reaction mixture was stirred at 65° C. for 3 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (heptane/ethyl acetate 9:1) to give 4-bromo-7-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzo[1,2,5]thiadiazole (7.4 g). 1H-NMR (DMSO-d6, 400 MHz): 8.17-7.53 (m, 5H), 4.70 (d, 1H), 4.49 (d, 1H) ppm.
Reaction SMILES: [C:1]1([O:7][P:8]([O-:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([O:21][C:22](=[O:25])[CH2:23]Br)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>ClCCl>[O:9]([P:8]([CH2:23][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:25])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diphenylphosphite (2.25 mL) in dichloromethane at 0° C. was added t-butylbromoacetate (1.48 mL) followed by triethylamine (1.95 mL). The mixture was stirred at 0° C. for 15 min and then at rt for 1 h before being quenched with water and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 7.40-7.18 (m, 10H); 3.22 (s, 1H); 3.18 (s, 1H); 1.50 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-])=O.I[CH2:15][CH3:16].[CH3:17][CH2:18][OH:19]>>[CH2:15]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH:1][C:18](=[O:19])[CH3:17])[CH2:9]1)[CH3:16]
Reactant: CCO
Reactant: O=[N+]([O-])c1cccc2cnccc12
Reactant: CCI
Product: CCN1CCc2c(cccc2NC(C)=O)C1

Procedure:
A solution of 5-nitroisoquinoline (25 g, 0.144 mol) in 250 mL of EtOH was treated with iodoethane (26.9 g, 0.172 mol) and the resulting solution heated at reflux for 24 hours. The reaction mixture was cooled and the material which formed was collected and dried. The material obtained was converted to the title compound by the procedures described in Example 1. A white solid was obtained (4.42 g, 17%).
Reaction SMILES: [C:1]1(C)[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].[C:14](O)(=O)C>[Pd].O>[C:9]([O:12][C:6]1[CH:1]=[C:2]([CH3:7])[CH:3]=[CH:4][C:5]=1[CH3:14])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: Cc1ccccc1C
Reactant: CC(=O)[O-]
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: CC(=O)Oc1cc(C)ccc1C

Procedure:
xylene, 390 mls of potassium acetate, 0.6 M acetic acid and 0.87 g of palladium catalyst on carbon (10% Pd) are electrolyzed in a cell without diaphragm having a graphite anode (area 140 cm2), steel cathode, magnetic stirrer and water jacket. The electrolysis is carried out at 18° C. with a current of 1.40 A. After the flow of 4 F/mol of electricity, the content of the cell is filtered and extracted with dichloromethane. The organic phase is washed with a solution of NaHCO3 and dried over MgSO4. After having distilled off the solvent under atmospherical pressure, the liquid is transferred into a microdistillation apparatus in which 4.30 g of unreacted p.xylene are recovered together with 3.41 g of pure 2,5-dimethylphenyl acetate. The molar values of the yield of current and the stoichiometric yields relative to the synthesis of 2,5-dimethylphenyl acetate from p.xylene are thus 12.8% and 51.3%, respectively.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[CH:27]([C:31]([O:33][CH:34]([CH2:40][O:41][CH:42]([CH3:44])[CH3:43])[CH2:35][O:36][CH:37]([CH3:39])[CH3:38])=[O:32])[CH:28]=[CH:29][S:30][C@H:25]23)=[O:22])[N:19]=1)=[O:13].CSC>C(Cl)Cl>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:47][O:48][CH3:49])[C:21]([NH:23][CH:24]2[C:45](=[O:46])[N:26]3[C:27]([C:31]([O:33][CH:34]([CH2:35][O:36][CH:37]([CH3:38])[CH3:39])[CH2:40][O:41][CH:42]([CH3:43])[CH3:44])=[O:32])=[CH:28][CH2:29][S:30](=[O:9])[C@H:25]23)=[O:22])[N:19]=1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)C=CS[C@H]12)c1csc(NC=O)n1
Solvent: CSC
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(COC(C)C)COC(C)C)=CCS(=O)[C@H]12)c1csc(NC=O)n1
Reaction time: 0.33 h

Procedure:
A solution of m-chloroperbenzoic acid (70% purity: 3.2 g) in methylene chloride (50 ml) was dropwise added to a stirred solution of 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer, 7.5 g) in methylene chloride (75 ml) at 2° to 5° C. over 25 minutes, and stirred at 0° to 5° C. for 20 minutes. Dimethylsulfide (1 ml) was added to the resultant mixture. The resultant mixture was washed with an aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride in turn. After drying the solution over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was triturated with diethylether (100 ml), and then the precipitates were collected by filtration to give 2-isopropoxy-1-isopropoxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate-1-oxide (syn isomer, 6.77 g).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17].[S:28]1[CH2:34][C:32](=[O:33])[NH:31][C:29]1=[S:30].C1(C)C=CC=CC=1>CCOC(C)=O>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:34]2[S:28][C:29](=[S:30])[NH:31][C:32]2=[O:33])[CH3:14])=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1cc(C(C)=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CSC(=S)N1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C(C)=C2SC(=S)NC2=O)ccc1OCc1ccc(C(F)(F)F)cc1C(F)(F)F
Reaction time: 8 h
Yield: 62 %

Procedure:
To a flask with a stir bar and attached to a condenser, was added 1-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-ethanone from Step A (244 mg, 622 μmol), rhodanine (133 ng, 1.0 mmol), NH4OAc (77 mg, 1.0 mmol) and toluene (5 mL). The reaction mixture was heated to reflux and stirred for 8 h at reflux. Additional NH4OAc (50 mg) and toluene (2 mL) was added to the mixture and allowed to reflux for an additional 24 hours. The reaction solution was then diluted with EtOAc (75 mL), washed with NH4Cl (50 mL×3), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed (TLC, DCM/EtOAc 100:0 to 85:15) to provide the intermediate compound. (195 mg, 62% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:33]1C=CC2N(O)N=NC=2C=1.CO[C@H](C)C(O)=O.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C@H:3]([CH3:33])[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CO[C@H](C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CO[C@H](C)C(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (3.58 mL, 0.394 mmol) (See step 3, Example 282), HOBT (0.015 g, 0.099 mmol), (R)-2-methoxypropanoic acid (0.049 g, 0.473 mmol), diisopropylethylamine (0.364 mL, 2.090 mmol), and EDC (0.091 g, 0.473 mmol) in DCM (5 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo, then taken up in H2O. The solid was collected by filtration, air-dried and purified by ISCO column (75% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 448.2 (M+1). IC50 (uM) 0.000452.