Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].O=S(Cl)Cl.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[Cl:33])[NH2:29]>C1(C)C=CC=CC=1.CC(C)=O.O>[Br:1][C:2]1[C:3]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([NH:29][C:28]1[CH:30]=[CH:31][C:32]([Cl:33])=[C:26]([Cl:25])[CH:27]=1)=[O:6]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1cc(C(F)(F)F)cc(Br)c1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 3-bromo-2-piperid-1-yl-5-trifluoromethylbenzoic acid (680 mg; 1 eq.) in toluene (15 ml) is added SOCl2 (0.55 ml). After refluxing for 2 hours, the reaction medium is evaporated to dryness and the oil obtained is taken up in acetone (5 ml). This solution is added dropwise, while maintaining the temperature between 15 and 20° C., to a solution of 3,4-dichloroaniline (625 mg; 2 eq.) in water (7 ml) and acetone (10 ml). After stirring for 1 hour at room temperature, the precipitate is filtered off by suction, washed with water and dried. 820 mg of 3-bromo-N-(3,4-dichlorophenyl)-2-piperid-1-yl-5-trifluoromethylbenzamide are obtained in the form of a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH3:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].C(OCC)(=O)C.C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:24].[CH:20]1([C:19]2[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[CH2:21][CH2:22]1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1-Boc-piperazine (7.2 g), 2,3-dichloro-5-methylpyridine (5 g), palladium (II) acetate (179 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (499 mg) and sodium tert-butoxide (4.1 g) was added toluene (30 mL), and the mixture was refluxed for 5 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). To a mixture of 4-(3-chloro-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1 g), tripotassium phosphate (30 g) and cyclopropylboronic acid (5.5 g) were added toluene (80 mL) and water (4 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g). 4-(3-Cyclopropyl-5-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added and the mixture was filtered to give the title compound (4.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:4][O:3][C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:7][CH:6]=1)=[O:2]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Combine 4-carbomethoxyphenylboronic acid (1.021 g, 5.67 mmol), 1-bromo-2,4-difluorobenzene (1.000 g, 5.181 mmol.), Pd(OAc)2 (0.113 g, 0.50 mmol), triphenylphosphine (0.149 g, 0.505 mmol), and sodium carbonate (1.664 g, 0.568 mmol). Purge the reaction vessel with argon. Add dimethylformamide (20 mL) and water (2.0 mL) with stirring. Place sealed reaction in an 80° C. oil bath and allow to stir for 24 hours. Cool reaction to room temperature, dilute with ethyl acetate, and filter through a short plug of celite with additional ethyl acetate. Wash organics with water, dry over magnesium sulfate, filter, and evaporate. Purification by flash column chromatography yields 2′,4′-difluorobiphenyl-4-carboxylic acid methyl ester as a yellow solid. Dissolve the purified ester in dioxane (5 mL) and add 5M sodium hydroxide (1 mL). Stir vigorously at 50° C. for 15 hours. Upon completion, acidify the reaction with conc. HCl and extract with ethyl acetate. Evaporation of the solvent yields 300 mg (24.7%) of the title compound. MS (m/e): 233.0 (M−).
Reaction SMILES: Cl.[CH2:2]([N:4]=[C:5]=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CNC.[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([CH:36]=1)[C:33](O)=[O:34].[Cl-].[NH4+]>ClCCl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:37]([F:40])([F:39])[F:38])=[C:32]([CH:36]=1)[C:33]([N:4]([CH3:5])[CH3:2])=[O:34]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (hereinafter, referred to as EDC, 2.67 g, 13.93 mmol), 1-hydroxybenzotriazole monohydrate (140 mg, 0.91 mmol), and dimethylamine (2.0 M solution in THF, 10.0 mL, 20.0 mmol) were added at room temperature to a solution of 5-fluoro-2-(trifluoromethyl)benzoic acid (1.93 g, 9.27 mmol) in dichloromethane (50 mL), and the mixture was stirred at room temperature for 5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with dichloromethane. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-60/40 (gradient)] to obtain the title compound (1.32 g, yield: 61%).
Reaction SMILES: [CH2:1]([C:4]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH:2]=[CH2:3].[OH-].[Na+].Cl>C(O)C>[CH2:1]([C:4]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C(F)(F)F)cc1OCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCc1ccc(C(F)(F)F)cc1OCC(=O)O
Yield: 93.6 %

Procedure:
Using the procedure of Step D of Example 16, 6.25 g of the product of Step A, 10.9 ml of 2N sodium hydroxide in 40 ml of ethanol were reacted and then 10.9 ml of 2N hydrochloric acid were added to obtain 5.28 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:7][C:6]=12.CNN>CO>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][NH2:14])=[N:7][C:6]=12
Reactant: CC(C)[C@@H](CN1C(=O)c2ccccc2C1=O)Nc1ccn2ncc(Br)c2n1
Agent: CNN
Solvent: CO
Product: CC(C)[C@@H](CN)Nc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of (S)-2-(2-(3-bromopyrazolo[1,5-a]pyrimidin-5-ylamino)-3-methylbutyl)isoindoline-1,3-dione (3.8 g, 8.9 mmol) in methanol was added methylhydrazine (4.1 g, 89 mmol) and the reaction stirred overnight at ambient temperature. The reaction was concentrated and the residue was purified by chromatography, eluting with 10% MeOH/dichloromethane to 5% MeOH solution containing 7M ammonia/dichloromethane to yield (S)—N2-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-3-methylbutane-1,2-diamine (2.2 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14](S(C)=O)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:20]=[CH:19][C:12]3[N:13]=[C:14]([NH:21][C@H:22]4[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]4)[S:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)c1nc2ccc(Oc3ccnc(Cl)c3)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 95 °C
Reaction time: 120 h
Yield: 112 %

Procedure:
To the solution of 6-(2-chloropyridin-4-yloxy)-2-(methylsulfinyl)benzo[d]thiazole (100 mg, 0.31 mmol) in 1.6 ml of NMP was added (S)-tert-butyl 3-aminopiperidine-1-carboxylate (200 mg, 1 mmol) and DIPEA (70 μL, 0.4 mmol). The reaction solution was stirred at 95° C. for 5 days. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give (S)-tert-butyl 3-(6-(2-chloropyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (160 mg) as TFA salt. ES/MS m/z 461.1 (MH+).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CN(C)C=O.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:21][CH:22]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:9][CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([OH:10])[CH2:4]3)[N:19]=2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Reactant: OC1CCCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC1CCCC(OCc2coc(-c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With ice-cooling, initially 2.25 g of an 80 percent suspension of sodium hydride and then 5.8 g of 1,3-cyclohexanediol were added to a mixture of 50 ml of dimethylformamide and 50 ml of tetrahydrofuran. The mixture was stirred at about 25° C. for 3 hours. 10.5 g of 4-chloromethyl-2-(4-fluorophenyl)oxazole (1) was then added, the mixture was heated at 70° C. and the reaction was monitored by thin-layer chromatography. After the reaction ended, the mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was separated off, dried and concentrated and the residue was purified on silica gel by flash chromatography (ethyl acetate/n-heptane=1:1). This gave the alcohol 3 as an oil. C16H18FNO3 (291.33) MS(ESI): 292 (M+H+). Methyl 2-{3-[2-(4-fluorophenyl)oxazol-4-ylmethoxy]cyclohexyloxy}-6-methylbenzoate 5
Reaction SMILES: [OH:1][C:2]12[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]1([OH:15])[C:5]1[CH:16]=[CH:17][C:18]([CH:20]([CH3:22])[CH3:21])=[CH:19][C:4]=1[O:3]2.O.NN.[OH-].[K+]>C(O)COCCO>[OH:15][C:6]1([C:5]2[CH:16]=[CH:17][C:18]([CH:20]([CH3:21])[CH3:22])=[CH:19][C:4]=2[OH:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]1=[O:1]
Reactant: CC(C)c1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)c1ccc(C2(O)Cc3ccccc3C2=O)c(O)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 6439.8 %

Procedure:
To a solution of 4b,9b-dihydroxy-7-isopropyl-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (1.0 g, 3.3 mmol) in diethylene glycol (10 ml) were added with hydrazine hydrate (80%, 0.36 g, 9.6 mmol), followed by stirring at 150° C. for 15 min. The reaction mixture was added potassium hydroxide (360 mg, 6.4 mmol), and stirred at 165-170° C. for 1 hrs. The reaction mixture was extracted with ethylacetate, and purified using column chromatography (20% ethylacetate in hexane) to afford the title compound (60 g, 6.5%).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:8](=[O:19])[N:7]1[CH2:20][CH:21]1[CH2:23][CH2:22]1)C.[OH-].[Na+]>C(O)C>[CH:21]1([CH2:20][N:7]2[C:8](=[O:19])[C:9]3[C:14](=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=3)[CH:6]2[CH2:5][C:4]([OH:24])=[O:3])[CH2:23][CH2:22]1
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.1 %

Procedure:
1.0 g of (2-cyclopropylmethyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)acetic acid ethyl ester were dissolved using 10 ml of ethanol and 3.5 ml of a 1 N aqueous solution of NaOH added. The mixture was stirred for 3 h at ambient temperature and then the solvent removed in vacuo. Afterwards, 30 ml of water were added and the pH of the solution adjusted to pH=2 using aqueous HCl-solution. The solution was then extracted three times using 50 ml of EA each. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 0.35 g of an amorphous solid (Rf(EA/MeOH 5:1)=0.43; MS (ES+): 314 (M+1)+).
Reaction SMILES: C(S)[CH2:2][S:3]([O-])(=O)=O.[Na+].[Br:9][C:10]1[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1.O>C(#N)C>[Br:9][C:10]1[C:11]([S:3][CH3:2])=[N:12][C:13]([Cl:16])=[N:14][CH:15]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1nc(Cl)ncc1Br
Yield: 58.6 %

Procedure:
2 g of MeSNa (28.5 mmol; 1 eq.) and 6.5 g of 5-bromo-2,4-dichloropyrimidine (28.5 mmol, 1 eq.) were stirred in 50 mL dry acetonitrile at rt for 24 h. Then the mixture was poured into water, extracted with DCM, dried (Na2SO4) and evaporated to dryness. The product was recrystallized from hexane to yield 4 g of Intermediate 12 (70% yield).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:27]2[CH2:29][CH2:28]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:30][NH:31][C:32](=N)[CH2:33][CH3:34]>>[CH:27]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:30][N:31]=[C:32]([CH2:33][CH3:34])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:19]=[N:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=3)=[N:16][CH:17]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: CCC(=N)NO
Reactant: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(C#N)CC3)cn2)cn1
Product: CCOc1ccc(-c2ncc(C(=O)N(C3CC3)C3CCN(c4nc(CC)no4)CC3)cn2)cn1

Procedure:
The title compound is prepared from 2-(6-ethoxy-pyridin-3-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 6. LC (method 3): tR=1.96 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: FC1C([O:8][C:9](=O)[C@H:10]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)=[CH:14][CH:13]=2)=C(F)C(F)=C(F)C=1F.O[NH:40][C:41](=[NH:43])[CH3:42]>>[C:30]([O:29][C:27](=[O:28])[NH:26][C@@H:10]([C:9]1[O:8][N:43]=[C:41]([CH3:42])[N:40]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:16][CH:17]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(=N)NO
Product: Cc1noc([C@@H](Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)NC(=O)OC(C)(C)C)n1
Yield: 88.9 %

Procedure:
[2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (96 mg,) was prepared from 2-(R)-tert-butoxycarbonylamino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid pentafluorophenyl ester (140 mg, 0.25 mmol) and N-hydroxy-acetamidine (37 mg, 0.5 mmol) following the general procedure O.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([NH2:27])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:26][CH:25]([NH:27][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CC(C)(C)OC(=O)N1CC(NCc2cccc(-c3ccnc(Cl)n3)c2)C1

Procedure:
Intermediate 1 was coupled with 3-Amino-azetidine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 375.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25]1([C:28](=O)[CH3:29])[CH2:27][CH2:26]1>CN(C)C(=O)C>[CH:25]1([C:28](=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH3:29])[CH2:27][CH2:26]1
Reactant: CC(=O)C1CC1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CC(=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)C1CC1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.065 g, 0.18 mmol) was reacted with 1-cyclopropylethanone (0.54 g, 6.4 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 120 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with ethyl acetate/hexane (2:1) and filtered to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>CC#N>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(Nc2cc(F)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
A mixture of 2,4-difluoro-1-nitrobenzene (3.69 g, 23.2 mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (4.0 g, 23.2 mmol) and DIPEA (3.97 mL, 23.2 mmol) in CH3CN (37 mL) was stirred at RT for 18 h under an argon atmosphere. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as a yellow solid (4.84 g, 67%). LCMS (Method B): RT 3.80 min [M+H]+ 312.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH2:10][C:9](=[O:11])[C:8]([OH:12])=[CH:7][N:6]=1)[CH3:3].C(C(CCCC)C([O-])=O)C.[Na+].[CH:24]([NH:26][C@@H:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([OH:38])=[O:37])=[C:31]([CH2:34]Cl)[CH2:32][S:33][C@H:28]12)=[O:25].C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:24]([NH:26][C@@H:27]1[C:39](=[O:40])[N:29]2[C:30]([C:36]([O-:38])=[O:37])=[C:31]([CH2:34][N+:2]([CH3:3])([CH3:1])[CH2:4][C:5]3[NH:6][CH:7]=[C:8]([OH:12])[C:9](=[O:11])[CH:10]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: O=CN[C@@H]1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12
Reactant: CN(C)CC1=NC=C(O)C(=O)C1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Reaction time: 2 h
Yield: 43.2 %

Procedure:
2-(N,N-Dimethylamino) methyl-5-hydroxy-4-pyridone (15.85 g) was dissolved in N,N-dimethylformamide (238 ml) by addition of sodium 2-ethylhexanoate (10.44 g). To the resulting solution was added dropwise a cooled solution of 7β-formamido-3-chloromethyl-3-cephem-4-carboxylic acid (13.04 g) at 50C and the mixture was stirred for 2 hours at the same temperature. The mixture was added dropwise to a mixture of ethyl acetate (2.5 l) and diisopropyl ether (2.5 l) and the resulting precipitates were collected by filtration,washed three times with a mixture of ethyl acetate and diisopropyl ether (1:1) and dried in vacuo. The powder was poured into cold water (300 ml) and the mixture was adjusted to pH 3.0 with 1N hydrochloric acid. After the insoluble materials were filtered off, the filtrate was chromatographed on Diaion HP-20 (1300 ml) at 50° C. and the elution was carried out with 10% aqueous isopropyl alcohol. The eluate was lyophilized to give 7β-formamido- 3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (8.31 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([C:31]2[CH:39]=[CH:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28](O)=[O:29])[CH:23]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([C:31]2[CH:39]=[CH:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C(=O)O)c2)c2ccc3sccc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(CO)c2)c2ccc3sccc3c2)CC1
Reaction time: 1 h
Yield: 36.8 %

Procedure:
A solution of lithium aluminum hydride (1.0 M, 0.24 mL, 0.24 mmol) was added at 0° C. to a solution of 4-[benzo[b]thiophen-5-yl-(3-carboxy-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (55 mg, 0.12 mmol) in THF (2 mL). The reaction mixture was stirred for 1 hour and it was then quenched by addition of water, MeOH (1 drop) and an aqueous solution of KOH (15%, 2 drops). The resulting mixture was stirred for 15 minutes and it was filtered over a celite pad. The filtrate was evaporated under reduced pressure and the crude residue was purified by preparative TLC (6/4, hexane/EtOAc) to give 20 mg of 4-[benzo[b]thiophen-5-yl-(3-hydroxymethyl-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil. This material was dissolved in DCM (2 mL) and trifluoroacetic acid (100 μL) was added, the resulting mixture was stirred overnight. The solvent was evaporated under reduced pressure and the residue was triturated with Et2O to give 3 mg of 3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-phenyl)-methanol trifluoroacetate as a gray powder.