Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:9]2=[N:8][C:7]=1[CH3:16])([O:3][CH2:4][CH3:5])=[O:2].[CH3:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([CH3:27])[C:19]=1[CH2:20]Br.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:20][C:19]3[C:18]([CH3:17])=[CH:25][C:24]([F:26])=[CH:23][C:22]=3[CH3:27])[C:9]2=[N:8][C:7]=1[CH3:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: Cc1cc(F)cc(C)c1CBr
Reactant: CCOC(=O)c1c(C)nc2c(O)cccn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2c(OCc3c(C)cc(F)cc3C)cccn12
Yield: 82.5 %

Procedure:
A mixture of 3-carboethoxy-8-hydroxy-2-methylimidazo[1,2-a]pyridine (1.5 g, 6.8 mmol), 2,6-dimethyl-4-fluorobenzylbromide (1.6 g, 7.5 mmol), sodium iodide (0.1 g), potassium carbonate (1.9 g, 13.6 mmol) and acetonitrile (50 ml) was refluxed for over night. The solvent was removed in vacuo. The residue was dissolved in CH2Cl2, washed with water, dried over Na2SO4 and evaporated. The residue was chromatographed on silica, eluting with heptane:isopropyl ether(1:2) to give 2.0 g (83%) of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9].[OH:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[CH2:9]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C=CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCOc1ccc(C(=O)OC)cc1
Yield: 68.6 %

Procedure:
5.2 g of 8-bromooctene, 5.0 g of methyl 4-hydroxybenzoate and 14 g of potassium carbonate were added to 70 ml of 2-butanone, and the mixture was refluxed for 7 hours in an atmosphere of argon. After the solid matters formed therein were filtered off, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography, to obtain 4.9 g of compound (8) (Yield: 68%)
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:7]([O:10][N:11]=[C:12]([C:16]1[N:20]=[C:19]([NH2:21])[S:18][N:17]=1)[C:13]([OH:15])=[O:14])[CH:8]=[CH2:9].[CH3:22]O.[OH-].[Na+]>C(Cl)Cl.N1C=CC=CC=1.O>[CH2:7]([O:10][N:11]=[C:12]([C:16]1[N:20]=[C:19]([NH2:21])[S:18][N:17]=1)[C:13]([O:15][CH3:22])=[O:14])[CH:8]=[CH2:9]
Reactant: CO
Reactant: C=CCON=C(C(=O)O)c1nsc(N)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CCON=C(C(=O)OC)c1nsc(N)n1
Temperature: -20 °C
Reaction time: 0.83 h
Yield: 69.4 %

Procedure:
To solution of phosphorus pentachloride (10.92 g) in methylene chloride (110 ml) was added 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (11.4 g) under cooling at -20° C. and stirring, which was continued for 50 minutes at -15° to -5°. To the mixture was dropped a solution of methanol (2.4 g) in pyridine (15.82 g) at -30° to -10° under stirring, which was continued for 20 minutes at -10° C. To the reaction mixture was dropped water (110 ml) and the mixture was adjusted to pH 2 with 1N aqueous sodium hydroxide and then stirred for 30 minutes at 0° C. The resulting precipitate was filtered, washed with water and dried to give methyl 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetate (syn isomer) (8.40 g).
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.N#N.[Cl:15][C:16]1[N:17]=[C:18]([Cl:35])[C:19]2[CH:24]=[CH:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:20]=2[N:21]=1>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([Cl:35])[C:19]2[CH:24]=[C:23]([CH3:1])[N:22]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:26])=[O:27])[C:20]=2[N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: CC(C)NC(C)C
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(C)cc3c(Cl)nc(Cl)nc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of diisopropylamine(2.2 g, 21.9 mmol, 1.5 eq) in THF (50 mL) was added nBuLi (2.5 mol/L, 6.4 mL, 16.07 mmol, 1.1 eq) dropwise under N2 at −78° C., then the mixture was stirred for 30 min at −78° C. And followed by 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (5 g, 14.6 mmol, 1 eq) in THF (50 mL) was added to the mixture, then the mixture was stirred for another 30 min at −78° C. Mel (2.28 g, 16 mmol, 1.1 eq) was added to the mixture for 30min at −78° C. The mixture was stirred at room temperature overnight and quenched with sat NH4Cl, then extracted with EtOAc. The organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure to give the crude product which was purified by reverse phase preparative HPLC to afford 2.5 g of 2,4-dichloro-6-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine as a white solid. ESIMS (M+H)+=358.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[S:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[OH-].[K+].[CH3:20]C(C)=O>>[CH3:20][S:13][C:9]1[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][C:2]([F:1])([F:16])[F:17])[CH:15]=[CH:14][C:7]=2[N:8]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)Oc1ccc2c(c1)CCCC(=S)N2
Agent: [K+]
Agent: [OH-]
Product: CSC1=Nc2ccc(OC(F)(F)F)cc2CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(trifluoromethoxy)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-thione (22 g, 84.3 mmol) in acetone (1500 ml) was added KOH (7.1 g, 127 mmol) and Mel (18.1 g, 127 mmol) and the mixture was stirred at RT for 1 h. The resulting mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (1000 mL). The mixture was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by flash column chromatography on neutral aluminium oxide eluting with hexane to give the title compound.
Reaction SMILES: ClC1C=CC2N3C(=O)C(C(OCC)=O)=CN=C3SC=2C=1.[SH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]1[C:34](=O)[C:33]([C:36]([OH:38])=[O:37])=[CH:32][NH:31][C:30]1=[O:39]>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[N:29]3[C:30](=[O:39])[N:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[C:34]3[S:21][C:22]=2[CH:27]=1
Reactant: O=C(O)c1c[nH]c(=O)n(-c2ccc(Cl)cc2S)c1=O
Agent: CCOC(=O)c1cnc2sc3cc(Cl)ccc3n2c1=O
Product: O=C(O)c1cnc(=O)n2c1sc1cc(Cl)ccc12
Yield: 60 %

Procedure:
from ethyl 8-chloro-4-oxo-4H-pyrimido[2,1-b]benzthiazole-3-carboxylate, via 1-(2-mercapto-4-chlorophenyl)-5-carboxypyrimidine-2,6-dione, 7-chloro-1-oxo-1H-pyrimido-[6,1-b]benzthiazole-4-carboxylic acid (yield 60% of theory; m.p. 264°-265° C.).
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:11][CH2:12][CH3:13])[C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH3:3].[C:14](Cl)(=[O:23])[C:15]1[C:16]([O:21][CH3:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH2:12]([O:11][CH:5]([O:4][CH2:2][CH3:3])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH3:13]
Reactant: CCOC(OCC)[C@@H]1CCCN1
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(OCC)[C@@H]1CCCN1C(=O)c1ccccc1OC
Reaction time: 0.5 h
Yield: 75 %

Procedure:
L-prolinal diethyl acetal hydrochloride is dissolved, together with the o-anisoyl chloride (853 mg, 4.01 mmol), in methylene chloride (12 ml), and triethylamine (1.7 ml, 12.2 mmol) is added dropwise thereto under ice-cooling and agitation. After the dropwise addition, stirring is further continued for 30 minutes under cooling and then for one hour and a half at room temperature. Ether (40 ml) is added to the reaction mixture, and the ethereal layer is separated, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of edible salt, dried over sodium sulfate and filtrated. The filtrate is concentrated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel (n-hexane-ethyl acetate, 2:1) to give 952 mg (75%) of the title compound as a pale yellow syrup.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[NH2:11])=[O:5])C.[Br:18][C:19]1[CH:34]=[CH:33][C:22]([C:23](Cl)=[N:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>ClC(Cl)C.Cl[Ti](Cl)(Cl)Cl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:4](=[O:5])[C:6]3[N:7]=[N:8][N:9]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[N:11]=2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1nnn(-c2ccccc2)c1N
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=c1c2nnn(-c3ccccc3)c2nc(-c2ccc(Br)cc2)n1-c1ccc(Cl)cc1
Temperature: 170 °C
Reaction time: 48 h

Procedure:
A mixture of 5-amino-1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (30 mg, 0.33 mmol), 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride (51 mg, 0.16 mmol) and TiCl4 (20 μL) in anhydrous dichloroethane (1 mL) is heated in microwave reactor at 170° C. for 1 h and then at 115° C. for 48 h in an oil bath. After cooling down to room temperature, the mixture is worked up as in example 2 and purified by flash column chromatography (silica gel, 0˜30% EtOAc/hexane) to provide the title compound 5-(4-Bromo-phenyl)-6-(4-chloro-phenyl)-3-phenyl-3,6-dihydro-[1,2,3]triazolo[4,5-d]pyrimidin-7-one as white solid. (45 mg, 73%). 1H NMR (CDCl3) δ (ppm) 8.15(d, 2H), 7.59(t, 2H), 7.49(t, 1H), 7.43 (d, 2H), 7.37(d, 2H), 7.21(d, 2H), 7.10(d, 2H), 2.87(m, 1H). HPLC-MS calculated C22H13BrClN5O (M+1+): 478.0. Found: 478.0.
Reaction SMILES: [H-].[Na+].C1OCCOCCOCCOCCOC1.[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:21][NH:22][C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1.O>[F:18][C:19]1[C:20]([CH2:31][N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:21][N:22]([S:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)(=[O:49])=[O:48])[C:23]=1[C:24]1[C:25]([F:30])=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccccn2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26 mg) in tetrahydrofuran (4 mL) were added dropwise 15-crown-5 (0.13 mL), a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (162 mg) in tetrahydrofuran (1 mL) and pyridine-2-sulfonyl chloride (133 mg) under ice-cooling, and the mixture was stirred for 0.5 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate) to give the title compound as a pale-yellow oil (yield 221 mg, 95%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:9]([Cl:27])=[CH:10][C:11]([F:26])=[C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])[CH:13]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:27][C:9]1[C:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:13][C:12]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[NH:16][C:15]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chloroformate (2.58 g) was dropwise added into a solution of 3-(5-amino-4-chloro-2-fluorophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (XLVI) in pyridine (25 ml) at 0° C., and stirred at room temperature for one hr. The reaction mixture was diluted with ethyl acetate, washed with 1N hydrochloric acid followed by water, and dried over sodium sulfate. After concentration, the crystals (5.46 g) were collected by filtration. 1H NMR (CDCl3, 300 MHz) 1.31 (3H, t, J=7.1 Hz), 4.22 (2H, q, J=7.1 Hz), 6.20 (1H, s), 7.14 (1H, br), 7.29 (1H, d, J=8.8 Hz), 7.36 (1H, d, J=6.0 Hz), 8.26 (1H, bd, J=6.4 Hz) ppm.
Reaction SMILES: [CH2:1]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:15]1([S:21]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)(Cl)Cl.[Fe]>[CH2:1]([C:10]1[S:11][C:12]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2cccs2)cc1
Reactant: ClSc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Cc2ccc(Sc3ccccc3)s2)cc1
Reaction time: 192 h
Yield: 27.5 %

Procedure:
A solution of 34 g (0.179 mole) of 2-p-anisylthiophene in 500 ml of carbon tetrachloride was treated with 23 ml (28.5 g, 0.197 mole) of benzenesulfenyl chloride and 0.1 g of iron powder. The mixture was allowed to stand at room temperature for eight days. The mixture was filtered to remove a small amount of solid. The filtrate was evaporated to give 67 g of crude solid product. Recrystallization from 220 ml of ethyl acetate gave 15.4 g (29%) of 2-p-anisyl-5-(phenylthio)thiophene, m.p. 92°-93° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]2[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[C:13]([C:14]4[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=4)[C:17]#[N:18])[N:8]3[N:7]=2)[CH2:5][CH2:4]1.CCN(CC)CC.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>CC#N>[C:17]([C:16]1[CH:15]=[C:14]([C:13]2[N:8]3[N:7]=[C:6]([C:3]4([CH2:2][O:1][C:36](=[O:37])[NH:35][CH:32]([CH3:34])[CH3:33])[CH2:5][CH2:4]4)[N:24]=[C:9]3[C:10]([O:22][CH3:23])=[CH:11][CH:12]=2)[CH:21]=[CH:20][CH:19]=1)#[N:18]
Reactant: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(CO)CC3)nc12
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(-c2cccc(C#N)c2)n2nc(C3(COC(=O)NC(C)C)CC3)nc12
Temperature: 65 °C

Procedure:
Under an argon atmosphere 3-[2-(1-Hydroxymethyl-cyclopropyl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzonitrile (compound 150) (0.03 g, 0.08 mmol) was dissolved in CH3CN (1 mL). Et3N (0.005 mL) and isopropyl isocyanate (0.04 mL) were added and the reaction mixture was shaken at 65° C. for 20 H. Et3N (0.005 mL) and isopropyl isocyanate (0.04 mL) were added again and the reaction mixture was shaken at 65° C. for another 24 H. The solvent was evaporated and the crude product was purified by flash chromatography on silica using DCM:MeOH 99:1 as eluent to afford the title compound as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
4-Nitro-1H-indazole (1.00 g; 6.13 mmol), benzyl bromide (1.15 g; 6.74 mmol) and potassium carbonate (1.69 g; 12.3 mmol) were mixed with DMF (15 mL) and stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was added to water (50 mL) and extracted into ethyl acetate. The combined extracted were dried (sodium sulfate), filtered and evaporated under reduced pressure to give a brown solid. The material was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1 to 10:1 to 5:1). The first component to elute was the desired regioisomer, which was obtained as a yellow solid (730 mg). The other regioisomer was the second component to elute (650 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[C:16]4[C:17](=[CH:21][N:22](CC5C=CC(OC)=CC=5)[N:23]=4)[N:18]=[CH:19][CH:20]=3)[CH:11]=[C:10]([CH3:33])[N:9]=2)[CH:7]=1.ClC1C=CC(F)=C(C2C=C(NC3C=CN=C4C=NN(CC5C=CC(OC)=CC=5)C=34)C=C(C)N=2)C=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C:8]2[CH:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[N:22][NH:23][C:16]=34)[CH:11]=[C:10]([CH3:33])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cn2cc3nccc(Nc4cc(C)nc(-c5cc(Cl)ccc5F)c4)c3n2)cc1
Agent: COc1ccc(Cn2ncc3nccc(Nc4cc(C)nc(-c5cc(Cl)ccc5F)c4)c32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2ccnc3cn[nH]c23)cc(-c2cc(Cl)ccc2F)n1
Temperature: 70 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
(R)-BINAP (0.632 g, 1.015 mmol), diacetoxypalladium (0.053 g, 0.236 mmol) and toluene (10 mL) were combined and heated at 40° C. for 10 minutes. The reaction was removed from heat and 7-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine and 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine as a 6:4 mixture of isomers (0.86 g, 2.355 mmol) suspended in toluene (15 mL), 2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-amine (0.557 g, 2.355 mmol), and sodium 2-methylpropan-2-olate (0.339 g, 3.53 mmol) were added. The reaction was sparged with nitrogen and heated at 100° C. over night. The reaction was cooled to room temperature and methanol (5 mL) was added. This solution was absorbed onto silica gel and chromatographed on silica gel eluting with a step gradient of ethyl acetate:hexanes (35-100%) to afford N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine as an orange foam (0.89 g, 79%). MS [M+H] found 474.4. To N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine (0.89 g, 1.88 mmole) was added TFA (9.38 mL) and the mixture was stirred at 70° C. for 4 hours. The reaction was cooled to room temperature and concentrated to a dark amber residue. The residue was combined with dichloromethane (25 mL) followed by a saturated solution of Na2CO3 (25 mL) to give a solid. The solid was filtered, rinsed with dichloromethane and then water and then dissolved in ethyl acetate (600 mL), extracted with water and then saturated Na2CO3. The organic layer was separated, dried over sodium sulfate, and concentrated to give the title compound as a light yellow solid (0.46 g, 69%). A portion of this material (0.04 g) was purified with preparative using a Sunfire Prep 5 μm C18, 75×30 mm column HPLC eluting with a gradient of 15-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H) 7.45-7.53 (m, 2H) 7.64 (br. s., 2H) 8.00 (d, J=4.04 Hz, 2H) 8.56 (d, J=6.06 Hz, 2H). MS [M+H] found 354.2.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[C:4](=[O:19])[NH:3]1.[OH-].[Li+].Cl>CO>[CH3:1][N:2]1[C:6](=[O:7])[N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[C:4](=[O:19])[NH:3]1
Reactant: COC(=O)c1ccc(Cn2c(=O)[nH]n(C)c2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1[nH]c(=O)n(Cc2ccc(C(=O)O)cc2)c1=O
Yield: 63.4 %

Procedure:
A solution of Example Z (1.0 g, 0.0038 mol) and lithium hydroxide (0.950 g) in MeOH (10 mL) was stirred at RT for overnight. The mixture was acidified by 2N HCl to pH=5-6 and extracted by CH2Cl2 (3×50 mL). The combined organic layers were washed with H2O, dried (MgSO4) and concentrated in vacuo to yield 4-((1-methyl-3,5-dioxo-1,2,4-triazolidin-4-yl)methyl)benzoic acid (0.6 g, 64%). 1H NMR (CDCl3): 7.71 (d, J=8.4 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 2.90 (s, 3H), 2.6 (s, 3H); MS (ESI) m/e: 249 (M+1).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][OH:10])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([O:10][CH2:9][CH2:8][O:7][C:4]1[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]([NH2:1])[O:6][N:5]=1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)c1c(OCCO)noc1N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCOc1noc(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirring solution of tert-butyl 5-amino-3-(2-hydroxyethoxy)-4-isoxazolecarboxylate (R. Neidlein, J.Heterocyclic Chem., 1989, 26,1335) (5.60 g) and triethylamine (3.36 ml) in tetrahydrofuran (50 ml) at room temperature was added dimethylaminopyridine (280 mg) followed by acetic anhydride (2.81 g). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo to yield the crude material (6.0 g). The crude material was purified using the Biotage™ Flash 40i System (silica, 90 g), eluting with ethyl acetate:hexane (1:1) to yield the product as an off white solid (5.0 g)
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:37][O:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:15]([NH:17][CH:18]2[C:35](=[O:36])[N:20]3[C:21]([C:28]([O:30]C(C)(C)C)=[O:29])=[C:22]([CH2:25][O:26][CH3:27])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:37][O:38][CH2:39][C:40]([OH:42])=[O:41])[C:15]([NH:17][CH:18]2[C:35](=[O:36])[N:20]3[C:21]([C:28]([OH:30])=[O:29])=[C:22]([CH2:25][O:26][CH3:27])[CH2:23][S:24][C@H:19]23)=[O:16])[N:13]=1
Reactant: COCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.2 %

Procedure:
Trifluoroacetic acid (8.4 ml) was added to a solution of tert-butyl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate (syn isomer) (2.1 g) in methylene chloride (4.2 ml) and anisole (2.1 ml) under ice-cooling, and the mixture was stirred at ambient temperature for 1.5 hours. The resultant solution was added dropwise to diisopropyl ether (100 ml) and the precipitated substance was collected by filtration. This substance was added to a mixture of water and ethyl acetate, followed by adjusting to pH 7.5 with 10% aqueous sodium hydroxide. The separated aqueous layer was saturated with sodium chloride and then adjusted to pH 1.5 with 10% hydrochloric acid. After extraction with a mixture of ethyl acetate and tetrahydrofuran (1:1 by volume), the extract was washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and then evaporated. The residue was washed with diethyl ether and collected by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (syn isomer) (1.14 g).