Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:18]1[CH2:17][CH2:16][CH:15]([N:14]2[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:20][CH2:19]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccccc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of {(S)-1-[1-(tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester (1.80 g, 5.22 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo affording (S)-1-[1-(Tetrahydropyran-4-yl)-1H-benzoimidazol-2-yl]ethylamine as a light yellow solid (415 mg, 32%). LCMS: RT 0.27 min [M+Na]+ 268.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2.Cl.[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[O:20])=[CH:15][CH:14]=1)[CH:6]=[N:5]2
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.5 mmol of 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propionyl chloride in 10 ml of methylene chloride was added dropwise to an ice-cooled solution of 1.53 g (7.2 mmol) of 4-(trifluoromethoxy)aniline hydrochloride and 1.58 g (15.6 mmol) of triethylamine in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual solid was recrystallized from methanol to give 2.00 g (61 percent of theoretical) of the above-named product as colorless crystals which melted at 156.5°-158° C. The structure of the product was confirmed by its IR and NMR spectrum. (Compound 6)
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of cyclopentylamine (0.148 mL, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (622 mg, 4.50 mmol) followed by 1-(bromomethyl)-4-nitrobenzene (648 mg, 3.00 mmol). The resulting mixture was stirred at rt for 16 hours, more 1-(bromomethyl)-4-nitrobenzene was added (324 mg, 1.5 mmol), and stirring was continued for an additional 2 hours. The mixture was diluted with water, extracted with CH2Cl2, and the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by precipitation from methanol to afford the title compound (554 mg, quant.). MS (ESI) m/z 356.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]([NH2:22])=O)[CH:15]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([C:20]#[N:22])[CH:15]=1
Reactant: Cn1nc(C(N)=O)cc1CCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
To a mixture of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxamide (10.5 g, 35.2 mmol) and pyridine (5.69 mL, 70.4 mmol) in dichloromethane (200 mL) at 0° C. was added trifluoroacetic anhydride (5.47 mL, 38.7 mmol) over two minutes. The solution was stirred at 0° C. for about 20 minutes, then was allowed to warm to ambient temperature. After 2 hours, more pyridine (2.8 mL) and trifluoroacetic anhydride (1.5 mL) were added. The reaction was quenched by adding 2 M sodium carbonate (200 mL). The mixture was extracted with chloroform. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of about 50 mL. A white solid was present. Heptane (150 mL) was added, and the mixture was concentrated to a volume of about 25 mL, then hexanes were added and the solid was collected by filtration. The white solid was washed with hexanes and dried to provide 8.50 g of 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile that contained a small amount of an impurity.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[Cl:32][C:33]1[S:37][C:36]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[S:37][C:36]([S:38]([NH:41][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:13]3[C:6]4=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]4[N:4]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:40])=[O:39])=[CH:35][CH:34]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 5-chloro-2-thiophenesulfonamide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH2:18])=[CH:11]2)[CH2:2][CH2:3][CH3:4].[OH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][CH:9]=[C:10]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]([CH2:17][NH:18][C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=1)=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(OC)ccc2cc(CN)c(=O)[nH]c12
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOc1c(OC)ccc2cc(CNC(=O)Cc3ccc(O)cc3)c(=O)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
8-Butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline (77.7 mg, 0.281 mmol) obtained in Example 7-2, 4-hydroxyphenylacetic acid (47.0 mg, 0.309 mmol) and N-hydroxybenzotriazole (41.8 mg, 0.309 mmol) were dissolved in DMF (3 ml), and EDC (59.2 mg, 0.309 mmol) and triethylamine (30 μl) were successively added thereto. The mixture was stirred at 50° C. for 3 hours, and then a saturated aqueous solution of sodium bicarbonate (3 ml) and toluene (5 ml) were added thereto. The precipitated crystals were collected through filtration, and washed successively with water, 1 N hydrochloric acid, water, and ethyl acetate to give the title compound (88 mg, yield 76%) as colorless crystals (Table 32).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([C:12]2[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][N:13]=2)[CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1nc(-c2cc(Br)c(O)c(Br)c2)no1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2cc(Br)c(OCc3ccc(OC)cc3)c(Br)c2)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
Sodium hydride (100 mg of a 60% suspension in oil, 2.5 mmol) was added to a stirred solution of ethyl 3-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-5-carboxylate (980 mg, 2.5 mmol) in dry dimethylformamide (5 mL) under nitrogen and the mixture was stirred at room temperature for 15 minutes. 4-Methoxybenzyl chloride (470 mg, 3.0 mmol) was added and the resulting solution was stirred at 50° C. for 20 h. The cooled mixture was treated with water (10 mL) to give a colourless solid that was filtered, washed with water and dried. Crystallization from di-isopropyl ether gave the title compound (840 mg, 65%) as a colourless powder. 1H NMR δ (ppm) (DMSO-d6): 1.41 (3 H, t), 3.52 (3 H, s), 4.49 (2 H, t), 5.06 (2 H, s), 7.01 (2 H, d), 7.53 (2H, d), 8.30 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([O:19]CC)=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:13]3[NH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:12]=3[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cc2c([nH]1)C(c1ccc(F)c(F)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc2c([nH]1)C(c1ccc(F)c(F)c1)CC2

Procedure:
The title compound was synthesized from ethyl 6-(3,4-difluorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide in water according to General Procedure 7.
Reaction SMILES: C(OC([NH:11][C:12]([CH3:27])([CH3:26])[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][OH:18])=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[NH2:11][C:12]([CH3:27])([CH3:26])[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][OH:18]
Reactant: CC(C)(CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(N)CN(CCCO)C(=O)OC(C)(C)C

Procedure:
0.11 g of palladium-carbon was added to an ethanol (30 mL) solution of 1.1 g of 2-(benzyloxycarbonylamino)-1-(tert-butoxycarbonyl-3-hydroxypropylamino)-2-methylpropane, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. After the completion of reaction, the reaction solution was concentrated to obtain the compound of interest.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)=[N:4][N:3]=1.C([Sn](=O)CCCC)CCC.[N:51]([Si](C)(C)C)=[N+:52]=[N-:53].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]5[NH:53][N:52]=[N:51][N:34]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)=[N:4][N:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](c3nnc(C)o3)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(5-methyl-1,3,4-oxadiazol-2-yl)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g), dibutyltin oxide (0.035 g), azidotrimethylsilane (0.97 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.023 g, 14%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]I)[N:12]=2)=[CH:4][CH:3]=1.S1CCCCS1.[Li]CCCC.[S:28]1[CH2:33][CH2:32][CH2:31][S:30][CH2:29]1.CN1CCCN(C)C1=O>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][CH:29]3[S:30][CH2:31][CH2:32][CH2:33][S:28]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCI
Reactant: C1CSCSC1
Agent: C1CCSSC1
Agent: [Li]CCCC
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCC1SCCCS1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
Add a cold (−78° C.) solution of 2-(4-bromo-phenyl)-4-(2-iodo-ethyl)-5-methyl-oxazole (See Intermediate 30) (1.05 g, 2.67 mmol) in 15 mL THF to a cold (−78° C.) solution of dithiane anion [Preparation: Add n-BuLi (7.5 mL, 12 mmol, 1.6M in hexanes) to a −20° C. solution of 1,3-dithiane (1.92 g, 15.9 mmol) in 25 mL THF. Stir 20 min at −78° C. and add 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 4.03 g, 31.4 mmol).] Stir the reaction mixture at −78° C. for 15 min. Add water and warm to room temperature. Add dichloromethane, and separate the layers. Dry the crude organic extracts over MgSO4, filter and concentrate. Purify on silica gel 0-10% EtOAc/Hexanes to give 2-(4-bromo-phenyl)-4-(2-[1,3]dithian-2-yl-ethyl)-5-methyl-oxazole (0.672 g, 66%). MS (m/e): 384 (M+1).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][Si](C(C)C)(C(C)C)C(C)C)=[CH:20][CH:19]=3)[C:13](=[O:17])[N:14]([CH2:15][CH3:16])[C:7]=12)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[N:12]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:13](=[O:17])[N:14]([CH2:15][CH3:16])[C:7]=12)(=[O:3])[CH3:2]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred solution of [1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (480 mg) in THF (5 ml) was added a solution of tetrabutylammonium fluoride (778 mg) in THF (2 mL) at 0° C. The mixture was stirred at 0° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (AcOEt/Hexane=1/1) to give the title compound (276 mg).
Reaction SMILES: [N:1]([CH:4]([N:15]1[CH:18]([SH:19])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[N+:2]=[N-:3].Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>CN(C)P(N(C)C)(N(C)C)=O.C1C=CC=CC=1.[Ag]>[N:1]([CH:4]([N:15]1[CH:18]([S:19][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[CH:17]([NH:20][C:21](=[O:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]1=[O:31])[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Ag]
Solvent: c1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Reaction time: 22 h

Procedure:
To a cooled solution of silver salt at the mercapto group of benzyl 2-azido-2-(3-phenoxyacetamido-4-mercapto-2-oxo-1-azetidinyl)acetate (3.08 g.) in hexamethylphosphoramide (12 ml.) was added 2,2,2-trichloroethyl chloroformate (1.15 ml.) over a period of 3 minutes, and the resultant mixture was stirred at room temperature. After stirring for 22 hours, the mixture was diluted with benzene (15 ml.) and filtered through a pad of Celite. The filtrate was poured into cold water and extracted with ethyl acetate (100 ml.). The extract was washed with water, a dilute aqueous solution of sodium bicarbonate, water and then an aqueous solution of sodium chloride successevely. Drying and removal of the solvent left an oil (3.40 g.), which was chromatographed on silica gel (60 g.) with a mixed solvent of methylene chloride and ethyl acetate (20:1 by volume) as an eluent to give benzyl 2-azido-2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]acetate (2.20 g.). Further, the same product (160 mg.) was recovered from the other fractions.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCN(CCC)c1c(SC)nc2c(Br)cc(C)cn12
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCCN(CCC)c1c(SC)nc2c(-c3ccc(Cl)cc3Cl)cc(C)cn12
Yield: 72.5 %

Procedure:
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (50 mg) was dissolved in a mixed solvent of 1,2-dimethoxyethane (6 mL) and water (1 mL). 2,4-Dichlorobenzeneboronic acid (53 mg), barium hydroxide octahydrate (88 mg) and tetrakistriphenylphosphine palladium complex (16 mg) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. After being allowed to cool, the reaction mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give N-[8-(2,4-dichlorophenyl)-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylamine (43 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:26])=[C:10]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=3[O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=[O:17])[CH:11]=2)[C:6]([CH3:28])([CH3:27])[CH2:5][C:4]1=[O:29])[CH3:2].[CH3:30][Mg]Br.CCOCC.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.ClCCl>[C:16]([C:15]1[CH:18]=[CH:19][C:20]([O:21][C:22]([F:23])([F:24])[F:25])=[C:13]([C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:28])([CH3:27])[CH2:5][C:4](=[O:29])[N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[CH3:26])[CH:14]=1)(=[O:17])[CH3:30]
Reactant: C[Mg]Br
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C=O)ccc3OC(F)(F)F)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(C(C)=O)ccc3OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of Compound 2A (270 mg, 0.66 mmol) in 3 mL of dry THF was cooled to −78° C. and treated with a 3M solution of methyl magnesium bromide in ether (0.24 mL, 0.73 mmol). The reaction mixture was allowed to slowly warm to room temperature where it was quenched with 10 mL of a saturated ammonium chloride solution. The reaction mixture was then passed through a 10 mL SPE (solid phase extraction) column which was further washed with dichloromethane. The eluant was collected and stripped to give crude alcohol which was then dissolved in dichloromethane and treated with Dess-Martin reagent (336 mg, 0.79 mmol) and stirred at room temperature overnight. The reaction was quenched with 4 mL of saturated sodium thiosulfate solution and 4 mL of saturated sodium bicarbonate solution, the reaction mixture was stirred until clear. The reaction mixture was passed through another SPE and eluted with dichloromethane, removal of solvent yielded crude ketone which was purified with flash chromatography (25% EtOAc/hexane) to yield 207 mg (75%) of the desired product (Compound 19A) and a white solid. MS (electrospray): mass calculated for C23H24F3NO3, 419.17; m/z found 420.2 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:34]([NH:36][C:37]1[S:38][C:39]([Cl:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43](O)=[O:44])[N:41]=1)=[O:35]>C(OCC)(=O)C.CN(C)C=O>[CH:34]([NH:36][C:37]1[S:38][C:39]([Cl:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[S:12][CH:13]=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1)=[O:35]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Cl
Yield: 98.6 %

Procedure:
A solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3cephem-4-carboxylic acid (4.3 g.) and trimethylsilylacetamide (17.1 g.) in dry ethyl acetate (130 ml.) and a solution of dimethylformamide (0.92 ml.), phosphoryl chloride (1.09 ml.) and 2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.6 g.) in dry ethyl acetate (27 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-chlorothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 5.6 g.).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:7]([NH:8]C(=O)OC(C)(C)C)[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3]1.[ClH:31]>C(Cl)Cl.O1CCOCC1>[ClH:31].[ClH:31].[NH2:8][C@H:7]1[CH2:6][CH2:5][N:4]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:30])[CH2:3][C@H:2]1[OH:1]
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C3)c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CC[C@H](N)[C@H](O)C3)c2c1
Reaction time: 2 h

Procedure:
1,1-dimethylethyl ((3R,4S)-3-hydroxy-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1 (2H)-yl]ethyl}-4-piperidinyl)carbamate (258 mg, 0.6165 mmol) was dissolved in DCM (10 mL) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (2 ml). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give the title compound as a pale pink solid (223 mg).