Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[CH:16][N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:6]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@H:5]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:3])[CH3:2].C1C(=O)N([Br:43])C(=O)C1>C(O)C>[C:1]([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:17])=[C:16]([Br:43])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:6]([O:25][CH2:26][CH2:27][O:28][CH3:29])[C@H:5]1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3cc(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Solvent: CCO
Product: COCCO[C@H]1[C@H](OC(=O)C(C)(C)C)c2ccn3c(Br)c(C)nc3c2N(C(C)=O)[C@@H]1c1ccccc1
Reaction time: 1 h

Procedure:
To a of 0° C. cooled solution of 0.40 g (0.83 mmol) (7R,8R,9R)-10-acetyl-8-(2-methoxyethoxy)-2-methyl-9-phenyl-7-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in ethanol (5 ml) is added 0.15 g (0.83 mmol) NBS and the mixture is stirred for 1 h. Afterwards the reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution and it is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (ether/triethylamine: 95/5) to provide 0.30 g (0.53 mmol/65%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=0.96 (s, 9H), 2.09(s, 3H), 2.42(s, 3H), 3.23(s, 3H), 3.40–3.53 (m, 2H), 3.69–3.98 (m, 2H), 4.23(t, 1H), 5.75 (d, 1H), 6.02 (s, 1H), 6.80(d, 1H), 7.16(s, 5H), 8.18(d, 1H).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]([F:35])([F:34])[C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>CCOCC.O>[CH:1]([N:31]1[CH2:32][CH2:33][CH:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12]([F:35])([F:34])[F:11])=[CH:14][CH:15]=3)[N:20]=2)[CH2:29][CH2:30]1)=[O:3]
Reactant: FC(F)(F)c1ccc(-n2nc(C3CCNCC3)c3ccccc32)cc1
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=CN1CCC(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Temperature: 55 °C
Reaction time: 3.5 h
Yield: 69.2 %

Procedure:
A stirred mixture of 4-[1-(4-trifluoromethylphenyl)-1H-indazol-3-yl]piperidine-1-carbonitrile of Example 101 (15 g, 0.041 moles) and 25% H2SO4 (100 ml) was refluxed for 20 hours. The mixture was cooled, poured into H2O, and basified with a 25% NaOH solution. The product was extracted (dichloromethane), dried (MgSO4), and concentrated which yielded 13 g (93%) of 1-[4(trifluoromethyl)phenyl]-3-(4-piperidinyl)-1H-indazole as an oil. A mixture of formic acid (1 ml, 0.027 moles) and acetic anhydride (2.4 ml, 0.025 moles) was warmed at 55° C. for 1.5 hours. The solution was cooled to 30° C. and a suspension of the indazole (4.0 g, 0.012 moles) in ether (10 ml) was added. The mixture was stirred at ambient temperature for 3.5 hours and then poured into H2O and basified with a 5% NaOH solution. The product was of an oil. The oil was purified on the high pressure liquid chromatograph (silica gel, 100% ethyl acetate) to yield 3.1 g (72%) of 1-formyl-4-[1-[4-(trifluoromethyl)phenyl]-1H-indazol-3-yl]piperidine, m.p. 109°-111° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[N:25][CH:26]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (74 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate, and recrystallized from ethanol-hexane to give the title compound (51 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([C:19]([NH:21][NH2:22])=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:22][NH:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:14][CH:15]=1)=[O:20]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added (1,1′-biphenyl)-4-carbohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 201 mg of the title compound (86%) as a yellow solid in 99.8% purity by HPLC (Rt: 6.49, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[OH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>CN(C=O)C.O>[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)#[N:7]
Reactant: N#CCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCCOc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
21.0 g (130 mmol) of 5-bromopentanenitrile, 15.2 g (100 mmol) of methyl 4-hydroxybenzoate and 28 g (200 mmol) of potassium carbonate are dissolved in 100 mL of DMF. The mixture is heated to 80° C. overnight. 100 mL (100 mmol) of a 1N NaOH solution is added to the above mixture. The suspension is heated at reflux for 30 min until the reaction is completed. The reaction mixture is allowed to cool down to room temperature and thrown onto cold water. The solution is carefully acidified with a 25% HCl solution and is stirred for 15 min. The product is filtrated off, washed with water and dried overnight under vacuum to give 19.3 g of 4-(4-cyanobutoxy)benzoic acid as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(O)c(F)c1F
Yield: 91.4 %

Procedure:
A solution of 1-benzyloxy-2,3-difluoro-4-nitrobenzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 g, 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s, 2H); MS (ESI) m/z: 146.1 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16]I.O>CN(C=O)C>[CH3:16][O:14][C:13](=[O:15])[C@H:9]([C@H:10]([CH3:12])[OH:11])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-L-allo-threonine (500 mg, 2.28 mmol) in DMF (5 mL), KHCO3 (637 mg, 4.56 mmol) and MeI (227 μl, 3.65 mmol) were added and the reaction was stirred 5 h at rt. Water (20 mL) was added and the mixture was extracted with ether (3×20 mL), dried (Na2SO4) and evaporated to afford the methyl ester 106 (494 mg, 93%) that was used without purification in the next step. 1H-NMR (500 MHz, CDCl3): 1.19-1.25 (m, 3H), 1.48 (s, 9H), 3.78 (s, 3H), 4.05-4.10 (m, 1H), 4.32-4.40 (m, 1H), 4.45-4.54 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCOCC1>[CH3:12][N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2ncccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ncccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 2.5 g of 2-hydroxymethyl -1-methylimidazo[4,5-b]pyridine (prepared as described in Preparation 30), 6.5 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 3.47 ml of tributylphosphine, 3.52 g of 1,1'-(azodicarbonyl) dipiperidine and 250 ml of 1,4-dioxane were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 1:1 to 0:1 by volume and subsequently mixtures of ethyl acetate and methanol in ratios ranging from 20:1 to 10:1 by volume as the eluent, to give 4.1 g of the title compound.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]2[C:33]([NH:34][C:35]3[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=3[F:42])=[CH:32][C:31]([F:43])=[CH:30][C:9]=2[O:10][C:11]2[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=2)[CH2:14][NH:15][S:16]([NH:19]C(=O)OC(C)(C)C)(=[O:18])=[O:17])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:43][C:31]1[CH:30]=[C:9]([O:10][C:11]2[CH:29]=[CH:28][CH:27]=[C:13]([CH2:14][NH:15][S:16](=[O:18])(=[O:17])[NH2:19])[CH:12]=2)[C:8]([NH:7][S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:5])=[O:6])=[C:33]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=2[F:42])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
814 mg of tert-butyl [(3-{2-[(cyclopropylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}benzyl)sulfamoyl]carbamate (Intermediate 18A; 1.08 mmol, 1 eq.) were dissolved in 30 mL DCM and 1.67 mL TFA were added. The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between saturated aq. sodium bicarbonate solution and dichloromethane. The pH was adjusted to pH=8 with aq. 2N sodium hydroxide solution. The layers were separated and the aqueouse layer reextracted twice with dichloromethane. The combined organic layers were washed once with brine, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC providing 322 mg of the desired product (46% yield).
Reaction SMILES: [F:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[C:5]([N+:16]([O-])=O)[C:3]=1[NH2:4].[Sn](Cl)Cl>CO>[F:1][C:2]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[C:5]([NH2:16])[C:3]=1[NH2:4]
Reactant: Nc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1F
Agent: Cl[Sn]Cl
Solvent: CO
Product: Nc1ccc(Oc2ccccc2)c(F)c1N
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of 2-fluoro-6-nitro-3-phenoxyaniline (260 mg, 1.05 mmol) in methanol (20 ml) was added tin(II)chloride (1.18 g, 5.24 mmol). The reaction was heated to reflux overnight and then cooled to rt. The mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). The solution was poured into an aqueous saturated sodium bicarbonate solution (150 mL), causing a precipitate to crash out. The mixture was filtered using ethyl acetate to rinse. The filtrate was washed with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-70% ethyl acetate/hexane to yield the desired product (195 mg, 85%) 1H NMR (300 MHz, DMSO-d6) 7.22-7.31 (m, 2H), 6.94-7.01 (m, 1H), 6.82 (d, J=7.8 Hz, 2H), 6.31 (dd, J=8.5, 1.5 Hz, 1H), 6.20 (dd, J=8.5, 8.5 Hz, 1H); ES-MS m/z 219.3 (MH)+; HPLC RT (Method A) 2.40 min.
Reaction SMILES: C([O:5][C:6]([C:8]1([C:14]2[CH:25]=[CH:24][C:17]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]([O:20][C:18]([C:17]1[CH:16]=[CH:15][C:14]([C:8]2([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:25][CH:24]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)c1ccc(C2(C(=O)OC(C)(C)C)CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)c1ccc(C2(C(=O)O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a solution of isopropyl 4-[1-(tert-butoxycarbonyl)cyclohexyl]benzoate (13) (0.136 g, 0.39 mmol) in dichloromethane (1.5 ml) was added trifluoroacetic acid (0.5 ml) and the mixture was stirred at ambient temperature under argon atmosphere for 2.5 hours. The volatiles were evaporated and the residue was chromatographed on silica gel with toluene-dioxane-acetic acid (95:5:1) as eluent to give the title compound (0.105 g, 92%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:38])[C:35]2[CH:34]=[C:33]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]5[CH2:23][CH2:22][CH:21]([NH:24]C(=O)C(F)(F)F)[C:20]=4[C:19]=35)[C:8](=[O:36])[C:7]=2[CH2:6][O:5][C:4]1=[O:37])[CH3:2].[ClH:39].CO>O>[ClH:39].[NH2:24][CH:21]1[C:20]2=[C:11]3[CH2:10][N:9]4[C:33](=[CH:34][C:35]5[C@:3]([CH2:1][CH3:2])([OH:38])[C:4](=[O:37])[O:5][CH2:6][C:7]=5[C:8]4=[O:36])[C:12]3=[N:13][C:14]3[CH:15]=[C:16]([F:32])[C:17]([CH3:31])=[C:18]([C:19]=32)[CH2:23][CH2:22]1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(=O)C(F)(F)F)CC3
Agent: Cl
Solvent: CO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(N)CC3
Temperature: 80 °C
Reaction time: 7 h

Procedure:
625 mg of the compound prepared in (10) above was added to a mixed solution of 7.5 ml of concentrated hydrochloric acid, 18 ml of methanol and 12 ml of water, and stirred at 80° C. for 7 hours. Insoluble substances were removed by filtration and the filtrate was purified with HPLC (CAPCELL PAK C18) using a mixture of acetonitrile-water-1N hydrochloric acid (20:80:1) to obtain 138 mg of Isomer A and 143 mg Isomer B of the title compound.
Reaction SMILES: S(O)([O-])(=O)=O.[NH2:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:40][O:41][CH3:42])[C:13]([NH:15][CH:16]2[C:38](=[O:39])[N:18]3[C:19]([C:35]([OH:37])=[O:36])=[C:20]([CH2:23][N+:24]45[CH2:31][CH2:30][C:27]([C:32](=[O:34])[NH2:33])([CH2:28][CH2:29]4)[CH2:26][CH2:25]5)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1.[C:43](=O)([O-:45])[OH:44].[Na+:47]>CC(C)=O>[C:43]([NH:6][C:7]1[S:11][N:10]=[C:9]([C:12](=[N:40][O:41][CH3:42])[C:13]([NH:15][CH:16]2[C:38](=[O:39])[N:18]3[C:19]([C:35]([O-:37])=[O:36])=[C:20]([CH2:23][N+:24]45[CH2:31][CH2:30][C:27]([C:32](=[O:34])[NH2:33])([CH2:26][CH2:25]4)[CH2:28][CH2:29]5)[CH2:21][S:22][C@H:17]23)=[O:14])[N:8]=1)([O-:45])=[O:44].[Na+:47]
Reactant: O=C([O-])O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@H]12)c1nsc(N)n1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[N+]34CCC(C(N)=O)(CC3)CC4)CS[C@H]12)c1nsc(NC(=O)[O-])n1
Yield: 50.4 %

Procedure:
To a suspension of crystals of 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate sulfate (syn isomer) (500 mg) in 50% aqueous acetone (4 ml) was added sodium hydrogencarbonate (323 mg) at ambient temperature. Carbonic acid gas was bubbled into the mixture for four hours and diluted with water. The resulting mixture was chromatographed on non-ionic adsorption resin "Diaion HP-20" (50 ml) eluting with water. The desired fractions were collected and lyophilized to give sodium 7-[2-(5-carboxylatoamino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4-carbamoyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate (syn isomer) (239.6 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.[NH2:28][C:29]1[NH:33][N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[NH:28][C:29]3[N:33]([N:32]=[C:31]([C:34]([NH2:36])=[O:35])[CH:30]=3)[C:3](=[O:2])[C:4]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:12][CH:11]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(C(=O)c1ccc(OCc2ccccc2)cc1)C1CCCCC1
Reactant: NC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Yield: 1.8 %

Procedure:
A mixture of 1.0 g (2.7 mmol) of 3-(4-benzyloxy-phenyl)-2-cyclohexyl-3-oxo-propionic acid methyl ester, 340 mg (2.7 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid amide, 51 mg (10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 15 mL of toluene was heated at reflux for 72 h. The reaction mixture was then concentrated to a residue which chromatographed on silica gel (Biotage; gradient elution 15% ethyl acetate in dichloromethane to 6% methanol in dichloromethane) to give a residue which was further purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) 22 mg (2% yield) of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid amide as indicated by 1H-NMR; LC-MS calcd for C26H26N4O3 [M++H]+: 443.2, found: 443.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[NH:20][CH:21]=[CH:22]2)=[O:30]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 1H-indole-5-carboxylic acid. MS: 403.3 (M+H).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1.[CH:27](=[O:29])[CH3:28].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:19][C:20]1[C:25]([CH:27]([OH:29])[CH3:28])=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1
Reactant: CC=O
Reactant: Fc1cccc(F)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(O)c1ccc(F)nc1F
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
In nitrogen atmosphere, diisopropylamine (134 mL) was dropwise added to a solution mixture of an n-butyl lithium hexane solution (2.62 M, 368 mL) and tetrahydrofuran (800 mL) at −60° C. or below. The resulting reaction solution was stirred at −60° C. for 30 min, and then a tetrahydrofuran solution (100 mL) of 2,6-difluoropyridine (100 g) was dropwise added thereto at −60° C. or below. The resulting reaction solution was stirred at the same temperature for 1 hr, and then acetoaldehyde (97.6 mL) was dropwise added thereto. Then, a 2 N hydrochloric acid aqueous solution (1000 mL) was dropwise added to the reaction solution, and further ethyl acetate (1000 mL) and toluene (1000 mL) were added thereto. The organic layer was separated and concentrated under reduced pressure to give 129 g of the title compound. The physical property values of this compound were as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N+:8]1([O-])[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C[Si]([C:24]#[N:25])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O.C(Cl)(Cl)Cl>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][C:2]1[N:1]=[C:6]([C:24]#[N:25])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1c2ccccc2C(=O)[N+]1([O-])Cc1ccccn1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
2-(2-Pyridylmethyl)-1H-isoindole-1,3(2H)-dione N-oxide (8.0 g, 31 mmol) was dissolved in mixed solvent of nitroethane (80 ml) and chloroform (150 ml), and trimethylsilyl cyanide (9.3 g, 94 mmol) and N,N-dimethylcarbamoyl chloride (6.8 g, 63 mmol) were added thereto. The mixture was stirred at room temperature for 4 hrs and at 60° C. for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.8 g, 22%) as white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C.C(OCC)C.CCCCCC>[CH2:19]([N:12]1[C:8]([CH3:7])=[CH:9][CH:10]=[C:11]1[C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(C)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)C(=O)c1ccc(C)n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of potassium tert-butoxide (1.34 g, 12 mmol) in DMF (30 ml) was added dropwise a solution of methyl (5-methylpyrrol-2-yl)oxoacetate (2.0g, 12 mmol) in DMF (5 ml). The reaction mixture was stirred for 2 hours, cooled to 0° C., and then treated dropwise with a solution of benzyl chloride (1.4 ml, 12 mmol) in DMF (5 ml). The mixture was stirred for 6 hours, poured into water (150 ml) and then extracted with ether (2 × 100 ml). The organic layers were washed with brine (2 × 50 ml), dried and then evaporated under reduced pressure to give an orange oil. Chromatography (eluent diethyl ether-hexane 1:1) gave methyl (1-benzyl-5-methylpyrrol-2-yl)oxoacetate (2.0 g]as a yellow oil, 1H nmr delta 2.22 (3H,s), 3.87 (3H,s), 5.65 (2H,s), 6.1 (1H,d), 7.9 (2H,d), 7.2-7.4 (4H,m) ppm.