Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=4[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1.[N:38]([O-])=O.[Na+]>CC(O)=O>[CH3:1][C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[N:25]=[C:24]5[N:26]=[N:38][NH:27][C:23]5=[CH:22][C:21]=4[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[C:5]2[CH:34]=[CH:35][CH:36]=[CH:37][C:4]=2[N:3]=1
Reactant: O=N[O-]
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc(N)c(N)cc3-c3ccccc3)cc2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1C1CCN(Cc2ccc(-c3nc4nn[nH]c4cc3-c3ccccc3)cc2)CC1

Procedure:
6-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylpyridine-2,3-diamine (4-4, 0.052 g, 0.106 mmol) was dissolved in 1 ml HOAc. NaNO2 (0.008 g, 0.117 mmol) was added. After 1 h the reaction was concentrated in vacuo and diluted with saturated aqueous NaHCO3. The mixture was extracted 3× with DCM. The combined extracts were dried over Na2SO4, filtered and concentrated to afford pure 5-(4-{[4-(2-methyl-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-6-phenyl-1H-[1,2,3]triazolo[4,5-b]pyridine (5-1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 7.73 (m, 1H), 7.59 (m, 1H), 7.38 (d, 2H, J=8.0 Hz), 7.31 (m, 4H), 7.22 (m, 4H), 4.19 (m, 1H), 3.64 (s, 2H), 3.10 (d, 2H, J=12.0 Hz), 2.67 (s, 3H), 2.59 (m, 2H), 2.20 (t, 2H, J=11.6 Hz), 1.86 (d, 2H, J=10.0 Hz). MS m/z (M+H)=500.22.
Reaction SMILES: S([O:5][CH2:6][CH2:7][N:8]1[C:12]([NH2:13])=[C:11]([NH2:14])[CH:10]=[N:9]1)(O)(=O)=O.[OH-].[Na+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O.O1CCOCC1>[NH2:13][C:12]1[N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]=1[NH:14][C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnn(CCOS(=O)(=O)O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(NC(=O)Oc2ccccc2)cnn1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4,5-diamino-1H-pyrazol-1-yl)ethanol sulfate (5 g) in water (30 ml) and dioxane (15 ml) was added aqueous sodium hydroxide solution under ice-cooling to adjust the mixture to pH 7. Phenyl chloroformate (3.42 g) was added to the mixture with controlling pH at 7, and the whole mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate-tetrahydrofuran (1:1) and the extract was dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude product of phenyl [5-amino-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]carbamate as an oil, which was used for Preparation 44 without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:29]([O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:23][CH:24]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCc3ccccc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(COc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.7 %

Procedure:
Trifluoroacetic acid (6 mL) was added to a solution of N-tert-butoxycarbonyl-4-(4-benzyloxyphenoxy)piperidine (B, 473 mg) in dichloromethane (12 mL) at room temperature. After stirring at room temperature for 20 hr, the reaction was quenched with saturated sodium hydrogen carbonate. The resulting mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the titled compound (345 mg) as a yellow brown solid, which was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:37])C(=O)C1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:37])[NH:12][C:11]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][N:25]=2)=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Solvent: ClCCl
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 72.8 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.44 g, 0.89 mmol) was reacted with NBS (0.17 g, 0.94 mmol) in DCM (30 mL) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.37 g, 72%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O>[C:20]([O:19][C:17]([N:5]1[CH2:6][C@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:8][C@H:4]1[CH2:3][OH:2])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reaction time: 0.83 h

Procedure:
A solution of N-t-butoxycarbonyl-4-(R)-t-butyldimethylsilyloxy proline methyl ester (86.65 g, 241 mmol), in THF (150 ml), was added over 90 minutes to a solution of lithium aluminum hydride (247 ml of a 1 M solution in THF, 247 mmol), under argon, so that the temperature did not exceed 12° C. Stirring was continued for 50 mins and then EtOAc (500 ml) was added cautiously, followed by sodium sulphate decahydrate (34 g), and the resulting mixture stirred for 16 hrs at room temperature. Anhydrous sodium sulphate (34 g) was added and the mixture stirred an additional 30 min and then filtered. The solids were washed with EtOAc (800 ml), the filtrates combined and the solvent evaporated in vacuo. The title compound was obtained as a colourless oil and used in the next step without further purification.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:47][C:48]1[CH:49]=[CH:50][C:51]([C:54]2([C:57]([OH:59])=O)[CH2:56][CH2:55]2)=[N:52][CH:53]=1.C(N(C(C)C)C(C)C)C.CN>CN(C)C=O>[CH3:10][NH:6][C:57]([C:54]1([C:51]2[CH:50]=[CH:49][C:48]([Br:47])=[CH:53][N:52]=2)[CH2:56][CH2:55]1)=[O:59]
Reactant: O=C(O)C1(c2ccc(Br)cn2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1(c2ccc(Br)cn2)CC1
Reaction time: 0.33 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.13 g; alternatively, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate may be used) was added to a solution of 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid (0.10 g) and ethyl-diisopropyl-amine (70 μL) in N,N-dimethylformamide (1 mL) at room temperature. The solution was stirred for 20 min prior to the addition of methylamine (2 mol/L in tetrahydrofuran, 0.62 mL). The resulting solution was stirred at room temperature for 1 h and then concentrated. The residue was purified by HPLC on reversed phase (0.125% aqueous ammonia/methanol) to afford the title compound. Yield: 0.10 g (95% of theory); LC (method 1): tR=1.44 min; Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19]Cl)[C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH2:30]([C:33]1([O:39][CH2:40][CH2:41][OH:42])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH2:31][CH3:32]>C(C(C)=O)C.[I-].[Na+]>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:17][CH2:18][CH2:19][N:36]3[CH2:37][CH2:38][C:33]([O:39][CH2:40][CH2:41][OH:42])([CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]3)[C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2c(c1)N(CCCCl)c1ccccc1S2
Reactant: CCCC1(OCCO)CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: CCCC1(OCCO)CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)CC1
Yield: 99.6 %

Procedure:
10 g of 2-trifluoromethyl-10-(3-chloropropyl)-phenothiazine were dissolved in 50 ml of methyl ethyl ketone and 4.36 g of sodium iodide, 2.9 g of triethylamine, then dropwise a solution of 5.4 g of 2-(4-propyl-4-piperidyloxy)-ethanol in 50 ml of methyl ethyl ketone were added successively thereto. The mixture was refluxed for 24 hours and after cooling, the precipitate formed was removed by vacuum filtration. The precipitate formed was removed by filtration and the filtrate was evaporated in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with an aqueous solution of sodium bicarbonate, then with water and the solution was dried and concentrated in vacuo to obtain 14.2 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine as a beige product which was dissolved in 50 ml of ethanol. The resulting solution was reacted with an ether solution of hydrogen chloride and the hydrochloride was precipitated by the addition of ether. The said precipitate was recovered by vacuum filtration and was washed with ether and crystallized from acetonitrile to obtain 7 g of 2-trifluoromethyl-10-[3-(4-β-hydroxyethoxy-4-propylpiperidino)-propyl]-phenothiazine hydrochloride as white crystals melting at 192° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([OH:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([OH:12])[CH2:11][NH:8][CH2:9]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CNC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (620 mg, 1.16 mmol) in DCM (5 mL) was added TFA (2 mL) and the resulting mixture allowed to stir for 1.5 h at r.t. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]azetidine-3-ol as a yellow oil (450 mg, 89%). LCMS: (method A): RT 1.84 min [M+H]+ 435.2
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].CCN(CC)CC.Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C(Cl)Cl>[CH:25]([S:26]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][CH:4]2[CH2:8]1)(=[O:28])=[O:27])=[CH2:24]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CS(=O)(=O)N1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a stirred mixture of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.0 g, 4.71 mmol) in DCM (20 mL) at 0° C., Et3N (1.43 g, 14.1 mmol) was added. The mixture was stirred at 0° C. for 5 min, and then a solution of 2-chloroethanesulfonyl chloride (0.77 g, 4.71 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL×3). The combined organic layer was washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/petroleum ether) to afford the desired product (0.5 g, 35% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].C(=O)([O-])[O-].[Na+].[Na+].[C:27]([NH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:29])[CH3:28].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:4]([CH:5]=[C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:30][C:27](=[O:29])[CH3:28])[CH:36]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C=C2C(=O)Nc3ccccc32)cc1-c1cccc(NC(C)=O)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added to a solution of 3-(3-Bromo-4-methoxy-benzylidene)-1,3-dihydroindol-2-one (0.2 g, 0.61 mmol) in toluene (1 ml) and ethanol (2 ml), followed by addition of 2M aqueous sodium carbonate (1.2 ml, 2.4 mmol). To this mixture was added 3-acetamidophenylboronic acid (0.12 g, 0.67 mmol), and the mixture was heated to 100° C. in a sealed tube and held there for 12 hours. The reaction was then poured into water (50 ml) and extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and concentrated. Chromatography (silica, 30-40% ethyl acetate/hexanes),afforded a waxy solid that was triturated with diethyl ether/hexanes and then dried to afford 0.05 g (22%) of N-[2′-methoxy-5′-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-biphenyl-3-yl]-acetamide as a reddish orange solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[O:35][CH:36]([C:52]([OH:54])=[O:53])[S:37][C:38]2[CH:43]=[CH:42][C:41]([O:44]C(=O)C)=[C:40]([O:48]C(=O)C)[CH:39]=2)/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[C:22]([OH:25])[C:21]=4[C:26]([OH:28])=[O:27])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])O.[Na+:59]>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[O:35][CH:36]([C:52]([OH:54])=[O:53])[S:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:48])[CH:39]=2)/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O-:31])=[O:30])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[C:22]([OH:25])[C:21]=4[C:26]([OH:28])=[O:27])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:59].[Na+:59].[Na+:59].[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[O:35][CH:36]([S:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:48])[CH:39]=2)[C:52]([OH:54])=[O:53])/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O-:31])=[O:30])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[C:22]([OH:25])[C:21]=4[C:26]([OH:28])=[O:27])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:34]/[O:35][CH:36]([S:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([OH:48])[CH:39]=2)[C:52]([OH:54])=[O:53])/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:29]([O-:31])=[O:30])=[C:15]([CH2:18][S:19][C:20]4[S:24][N:23]=[C:22]([OH:25])[C:21]=4[C:26]([OH:28])=[O:27])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)Oc1ccc(SC(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4snc(O)c4C(=O)O)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(/C(=N/OC(Sc2ccc(O)c(O)c2)C(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CSc4snc(O)c4C(=O)O)CS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
After 600 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(carboxy)(3,4-diacetoxyphenylthio)methoxy]imino]acetamido]-3-[[(4-carboxy-3-hydroxy-5-isothiazolyl)thio]methyl]-3-cephem-4-carboxylic acid obtained in Example 4 (10) was suspended in 20 ml of water, saturated sodium hydrogencarbonate aqueous solution was added to the suspension at room temperature to adjust pH to 8. After stirring at room temperature for 2.5 hours, the aqueous solution was adsorbed to DIAION HP20 followed by elution with water. The fractions containing the desired product were collected. After concentration, the concentrate was freeze dried to give 150 mg of trisodium 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(carboxy)(3,4-dihydroxyphenylthio)methoxy]imino]acetamido]-3-[[(4-carboxy-3-hydroxy-5-isothiazolyl)thio]methyl]-3-cephem-4-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@H:18]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20].I[CH2:30][CH2:31][CH2:32][N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[NH:35][C:34]1=[O:42].C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O.ClCCl.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:30][CH2:31][CH2:32][N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[NH:35][C:34]3=[O:42])[CH2:10][CH2:11]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[C@H:18]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reactant: O=c1[nH]c2ccccc2n1CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 65 °C
Yield: 29.6 %

Procedure:
A mixture of (R)-methyl 2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (355 mg, 0.854 mmol, 1 equiv), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (258.06 mg, 0.854 mmol, 1 equiv) and potassium carbonate (354.1 mg, 2.562 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was cooled to ambient temperature and worked up using 5% methanol in dichloromethane and water. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude mixture was purified by preparatory thin layer chromatography using 7% methanol in dichloromethane. The purified extract was lyophilized to afford the title compound as a white solid (140 mg, ˜30%); 1H NMR (400 MHz, DMSO-d6): δ 1.59 (t, 2H, J=15.2 Hz, J=14.8 Hz), 1.81 (bs, 2H), 2.33 (bs, 4H); 2.54-2.64 (m, 2H); 2.69-2.73 (m, 2H); 3.74 (s, 3H); 3.84 (t, 2H, J=6.8 Hz); 4.14 (d, 1H, J=4.4 Hz); 4.79 (d, 1H, J=4.8 Hz); 5.89 (s, 1H)); 6.78-6.84 (m, 3H); 6.97 (d, 3H, J=2.4 Hz); 7.16-7.18 (m, 1H); 7.23 (t, 2H, J=7.2 and 8.8 Hz); 7.39-7.46 (m, 5H); 10.82 (s, 1H; MS for C32H35N5O4 m/z 554.07 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][C@@H:43]([CH2:47][OH:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:33])[F:32])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH:43]([CH2:47][OH:48])[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C(CO)C1

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([C:11]#N)[C:5]2=[C:4]([NH2:13])[N:3]=1.C(O)=[O:15]>[Ni]>[NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[C:10]([CH:11]=[O:15])[C:5]2=[C:4]([NH2:13])[N:3]=1
Reactant: O=CO
Reactant: N#Cc1cnc2[nH]c(N)nc(N)c1-2
Agent: [Ni]
Product: Nc1nc(N)c2c(C=O)cnc-2[nH]1
Temperature: 80 °C

Procedure:
About 6.0 g of Raney Ni was added to a stirred solution of about 2.0 g of Compound 12 and about 50 ml of HCOOH. The mixture was heated to about 80° C. for about 2 hours, until no starting material could be detected by TLC. The mixture was cooled to room temperature and filtered through Celite®. The filtrate was evaporated under reduced pressure, azeotroping with methanol to remove traces of HCOOH. The residue was dissolved in about 25 ml of hot water, treated with Norit®, an activated adsorption carbon commercially available from American Norit Company, Inc., and filtered through Celite®. The filtrate was neutralized with NH4OH. The light brown precipitate which resulted was filtered and dried to yield about 1.40 g of Compound 13, which was immediately used in subsequent reactions without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:21])[CH2:18][CH2:19][CH3:20]>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: CCCC(=O)N(C)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(=O)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Approximately 5 ml of a solution of 4-bromobenzo[b]thiophene (2.87 g; prepared in a manner similar to that described in Example 9 Method A) in tetrahydrofuran (30 ml) was added under nitrogen to magnesium turnings (0.45 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes, then the mixture was heated under reflux for a further 15 minutes. A solution of N-methoxy-N,3-dimethylpropionamide (2.12 g) in tetrahydrofuran (15 ml) was added, the mixture was heated under reflux for 30 minutes, then it was cooled to ambient temperature and quenched by the addition of 2M hydrochloric acid (30 ml). The mixture was stirred at ambient temperature for 1.5 hours, then the product was extracted into ethyl acetate (150 ml). The combined extracts were washed with water (2×100 ml) and saturated aqueous sodium chloride solution (200 ml), dried (MgSO4), and the solvents were removed in vacuo. The residue was purified by Biotage flash chromatography over silica using a 97:3 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)-3-methylpropan-1-one (1.7 g) as a colourless oil which was used without further purification.