Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[S:12][CH:11]=2)=[O:9])[CH2:2][CH2:3]1)(=[O:30])=[O:29]
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1CCCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
[1,4]Diazepan-1-yl-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.075 g, 0.27 mmol) was dissolved in DCM (30 mL) and cooled in an ice-bath before addition of triethylamine (0.082 g, 0.82 mmol) and methanesulfonyl chloride (0.038 g, 0.33 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residue taken up in methanol (2.5 mL) and treated with sodium hydroxide (1 M, 0.3 mL). After 1 hour the solvent was removed and the crude material was purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were combined and freeze-dried to give the title compound (0.045 g). LCMS m/z 355.14 [M+H]+ R.T.=5.95 min (Analytical Method 2).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])[OH:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]#[CH:21])[CH:15]=[CH:14][C:13]=2[N+:22]([O-:24])=[O:23])=[O:11])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C#CCOc1ccc([N+](=O)[O-])c(C(O)c2ccc(C(C)C)cc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C#CCOc1ccc([N+](=O)[O-])c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanol in 200 ml acetone are added dropwise 60 ml Jones reagent. After stirring for 2 h at rt the reaction is quenched by the addition of isopropanol and sodium bisulphite solution (40%). Extraction with dichloromethane affords (4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:13]([O:12][C:4]1[CH:5]=[C:6]([CH3:11])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1[N+](=O)[O-]
Yield: 84.5 %

Procedure:
A mixture of 3,5-dimethyl-4-nitrophenol (17.6 g), benzyl chloride (20.0 g) and anhydrous K2CO3 (13.2 g) in acetone (100 ml) is stirred under reflux for 22 hours. The reaction mixture is filtered and the precipitate washed with acetone. The acetone extract is concentrated in vacuo and the residue short path distilled (160°-170° C.; 50μ) to give 22.9 grams of an orange liquid which crystallized on standing.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([CH:13](C3C=CC=CC=3)C3C=CC=CC=3)[CH2:10]2)=[CH:5][CH:4]=1.[NH2:28][CH2:29][C@H:30]([OH:32])[CH3:31].C(C1C=CC(C2CN(C(NCC=C)=[O:48])C2)=CC=1)(C)(C)C>O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][N:11]([C:13]([NH:28][CH2:29][C@H:30]([OH:32])[CH3:31])=[O:48])[CH2:12]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: C=CCNC(=O)N1CC(c2ccc(C(C)(C)C)cc2)C1
Reactant: C[C@@H](O)CN
Solvent: O
Product: C[C@@H](O)CNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
This compound was prepared from compound (32) and (R)-1-amino-2-propanol using the procedure described for compound (12). m.p. 107-108° C. Found: C, 54.78; H, 5.75; N, 9.01. C14H17F3N2O2.0.25 H2O requires C, 54.81; H. 5.71, N, 9.13%.
Reaction SMILES: Cl[CH2:2][CH:3]([O:13][CH:14]([CH3:16])[CH3:15])[CH:4](Cl)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+].[S:23](S([O-])=O)([O-:26])(=[O:25])=[O:24].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:2][CH:3]([O:13][CH:14]([CH2:16][S:23]([O-:26])(=[O:25])=[O:24])[CH2:15][S:17]([O-:20])(=[O:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+:21].[Na+:21]
Reactant: O=S([O-])[O-]
Reactant: CCCCCCCC(Cl)C(CCl)OC(C)C
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCC(C)OC(CS(=O)(=O)[O-])CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
The compounds are made substantially as described in Example 2A above, using appropriate substitutions of starting materials (138.6 g of 1,3-dichloro-2-propan-2-yloxydecane, 112.5 g of sodium sulfite, 39.0 g of sodium meta-bisulfite, 34.52 g of sodium carbonate, 550.43 g of water, 190° C., 20 hours). Following reaction, the reaction mixture is cooled to ambient temperature and unloaded to afford 826.5 g of light brown reaction product.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)[CH2:2][CH3:3].[NH2:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.O=[C:20]([CH2:27][CH2:28][CH3:29])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([CH2:27][CH2:28][CH3:29])[NH:13][C:14]2=[N:15][NH:16][CH:17]=[C:18]12)[CH2:2][CH3:3]
Reactant: Nc1cc[nH]n1
Reactant: CCCOc1ccccc1C=O
Reactant: CCCC(=O)CC(=O)OCC
Product: CCCOc1ccccc1C1C(C(=O)OCC)=C(CCC)Nc2n[nH]cc21

Procedure:
The title compound was prepared from 2-propoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:49]1[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]1>C1COCC1>[O:13]=[C:14]1[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]1[CH:52]1[CH2:53][CH2:54][S:49][CH2:50][CH2:51]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2ccccc21
Reactant: OC1CCSCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 20 h

Procedure:
Diethyl azodicarboxylate (446 mg, 2.56 mmol) was added to a solution of tert-butyl 2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (J. Org. Chem., 1995, 60, 1565-1582) (500 mg, 2.13 mmol), triphenylphosphine (672 mg, 2.56 mmol), and tetrahydro-2H-thiopyran-4-ol (Chem. Comm., 2002, 10, 1070-1071) (303 mg, 2.56 mmol) in THF (10 mL). After 20 h, the reaction was concentrated in vacuo and the crude product purified by silica gel column chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 95:5, to give the title compound. MS: m/z=335 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH2:22])[O:4]1.O=[C:24]1[CH2:27][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:25]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[NH2:22][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[CH:21][N:13]2[C@H:5]1[C@@H:6]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:24]2[CH2:25][CH:26]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27]2)[O:4]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CN)O[C@H]2n1cnc2c(N)ncnc21
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CC(NC[C@H]2O[C@@H](n3cnc4c(N)ncnc43)[C@@H]3OC(C)(C)O[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-amine (2.04 g, 6.66 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (1.2 g, 7.0 mmol) in methanol (41 mL) was treated with acetic acid (0.37 mL, 6.5 mmol) at rt and the flask was evacuated and flushed with nitrogen (×3). The reaction mixture was treated at rt with sodium cyanoborohydride (1.0 g, 16 mmol), which afforded instant gas evolution and a nearly colorless, clear solution in a few minutes. The reaction mixture was stirred for 1 h at rt; HPLC/LC MS indicated starting material remained. At 1 h 20 min additional ethyl 3-(3-oxocyclobutyl)propanoate (0.50 g, 2.93 mmol) in MeOH (3 mL) was added. The reaction mixture was stirred for 30 min and treated with water (12 mL). The mixture was concentrated in vacuo and the residual aqueous layer was diluted with saturated aqueous sodium bicarbonate (40 mL, to pH 9) and extracted with CH2Cl2 (3×60 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford the crude title compound as a white foam/very pale yellow oil, which was carried on without further purification: MS (ESI+) for C22H32N6O5 m/z 461.2 (M+H)+ and 483.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][CH:5]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:6][C:5]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a solution of 100 g (386.5 mmol) 4(3-chloro-propoxy)-5-methoxy -benzoic acid methyl ester in 300 ml acetic acid was added dropwise 100 ml of 70% nitric acid. The mixture was heated to 50° C. for 1 hr and then poured into ice water. The mixture was extracted with chloroform. The organic solution was washed with dilute sodium hydroxide and then dried over magnesium sulfate. The solvent was removed. Ether was added an the mixture was stirred until solid was deposited. The solid was collected by filtration giving 98 g of 4-(3-Chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester as white crystals: mass spectrum (electrospray, m/e,): M+H 303.8; 2M+NH4 623.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]2[C:17]([CH:18]3[CH2:28][CH:19]3[CH2:20][O:21]2)=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2F)ccc2c1OCC1CC21
Reaction time: 2 h
Yield: 96.3 %

Procedure:
2,4-Difluorobenzenesulphonyl chloride (0.468 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylater (Intermediate 42, 0.438 g) in pyridine (2 mL) and DCM (4 mL) and the solution was left at room temperature for 2 hours. The mixture was diluted with DCM, washed with 2M hydrochloric acid, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl (1aRS,7bSR)-5-(2,4-difluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.761 g) as a light coloured gum.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].Cl[C:10]([O:12]C(Cl)(Cl)Cl)=[O:11]>>[CH2:5]1[C:6](=[O:7])[N:2]([O:1][C:10]([O:12][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:11])[C:3](=[O:8])[CH2:4]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1O
Product: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
11.5 g (0.1 mol) of N-hydroxysuccinimide was admixed with 6 ml (0.05 mol) of trichloromethyl chloroformate (TCF), and the resultant admixture was melted by heating. The heating was continued for 10 minutes and then the resultant melt was allowed to cool and to deposit a colorless crystalline material. This crystalline material was filtered off from the liquid phase and recrystallized from acetonitrile, affording 6.5 g of the titled compound in the form of colorless crystals. Yield 50%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C#N)(C)C.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27]([S:31](Cl)(=[O:33])=[O:32])=[C:26]([CH3:35])[C:25]=1[CH3:36].Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([NH:11][S:31]([C:27]1[C:28]([CH3:30])=[CH:29][C:24]([O:23][CH3:22])=[C:25]([CH3:36])[C:26]=1[CH3:35])(=[O:33])=[O:32])[CH:12]([CH3:13])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To a solution of D-valine benzyl ester (4 g, 19.3 mmol) and trimethylsilylcyanide (7.2 mL, 57.9 mmol) in acetonitrile (40 mL) was added 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (4.8 g, 19.3 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate (100 mL) and transferred to a separatory funnel. Aqueous hydrochloric acid (120 mL, 2.5%) was added and the organic layer was separated and washed with 5% sodium bicarbonate and brine and then dried over magnesium sulfate. The organics were removed in vacuo to give 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyric acid benzyl ester (8 g) as a brown oil.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:11]2[CH:12]=[C:13]([O:25]C(=O)C3C=CC=CC=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:34]([N:10]([C:11]1[CH:12]=[C:13]([OH:25])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(=O)(=O)c2ccccc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccccc1)N(Cc1ccccc1)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.1 %

Procedure:
To a stirred solution of benzoic acid 3-(benzenesulfonyl-benzyl-amino)-4-benzyloxy-phenyl ester (which was obtained in Example 18) (1.80 g, 3.28 mmol) in THF (10 mL) and methanol (10 mL) was added 10% of sodium hydroxide (10 mL). The mixture was stirred at room temperature for 1.5 hours, acidified with concentrated hydrochloric acid and diluted with water (200 mL). The aqueous solution was extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (1.20 g, 82%); 1H NMR (300 MHz, CDCl3) δ 4.71 (brs, 4H), 6.49 (d, J=3.0 Hz, 1H), 6.62(dd, J=9.0, 3.0 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 7.10-7.70 (m, 15H), 9.07 (brs, 1H); MS (ES) m/z: 444.0 ((M−H)−, 100%); HRMS Calcd. for C26H22NO4S(M−H)−: 444.1275. Found: 444.1270.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[N:3]1[C@@H:14]1[C:28](=[O:29])[N:16]2[C:17]([C:22]([O:24]COC)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12>CO>[CH3:1][C:2]1([CH3:30])[NH:6][CH:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4](=[O:13])[N:3]1[C@@H:14]1[C:28](=[O:29])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12
Reactant: COCOC(=O)C1=C(Cl)CS[C@@H]2[C@H](N3C(=O)C(c4ccccc4)NC3(C)C)C(=O)N12
Solvent: CO
Product: CC1(C)NC(c2ccccc2)C(=O)N1[C@@H]1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 0.5 h
Yield: 88.6 %

Procedure:
A solution of 0.5 g of methoxymethyl 7β-(2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl)-3-chloro-3-cephem-4-carboxylate in 10 ml of methanol is refluxed for 1 hour, and the reaction mixture is concentrated to a third volume and stirred for 30 minutes under ice-cooling. The resulting precipitate is collected by filtration and dried under reduced pressure to yield 0.4 g of 7β-(2,2-dimethyl-5-oxo-4-phenylimidazolidin-1-yl)-3-chloro-3-cephem-4-carboxylic acid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=[O:21].C([NH:27][C@:28]1([C:45](NC(C)(C)C)=[O:46])[C@@H:32]([CH2:33][CH2:34][CH2:35][B:36]2[O:40]C(C)(C)C(C)(C)[O:37]2)[CH2:31][NH:30][CH2:29]1)(=O)C>C(#N)C>[NH2:27][C@:28]1([C:45]([OH:46])=[O:21])[C@@H:32]([CH2:33][CH2:34][CH2:35][B:36]([OH:37])[OH:40])[CH2:31][N:30]([CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:29]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: OCCN1CCCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N[C@@]1(C(=O)O)CN(CCN2CCCCC2)C[C@@H]1CCCB(O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
A cooled (0° C.) solution of N-(2-hydroxyethyl)piperidine (90.5 mg, 0.70 mmol) and diisopropylethylamine (0.30 mL, 1.7 mmol) in anhydrous acetonitrile (12 mL) under nitrogen was treated with methanesulfonyl chloride (80.2 mg, 0.70 mmol), stirred 2 h, and treated with (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and heated to 60° C. for 15 h. The reaction mixture was concentrated, deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-(2-(piperidin-1-yl)ethyl)pyrrolidine-3-carboxylic acid (140 mg, 64%) as a glassy colorless solid. NMR (D2O) δ 3.85-4.05 (m, 2 H), 3.65-3.80 (m, 3 H), 3.35-3.55 (m, 5 H), 2.85-3.00 (m, 2 H), 2.60 (m, 1 H), 1.80-1.95 (m, 2 H), 1.55-1.75 (m, 4 H), 1.10-1.50 (m, 4 H), 0.63-0.73 (m, 2 H). MS (m+1): 328.3; MS (m−H2O+1): 310.0.
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=O)C.[NH3:16].[CH3:17][OH:18]>>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:6]1[CH2:4][C:17]([NH2:16])=[O:18]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: N
Reactant: CO
Product: NC(=O)Cc1cc2ccccc2[nH]1

Procedure:
Treat 5-bromo-1H-indole-2-carboxylic acid ethyl ester 1 (X═Br, 4.67 mmol) with 7 N NH3/MeOH as described in General Synthetic Procedure III to afford 5-bromo-1H-indole-2-carboxylic acid amide 4 (X═Br, R2═R3═H) as an ivory-colored solid. Treat 5-bromo-1H-indole-2-carboxylic acid amide (100 mg, 0.41 mmol) with diphenyldisulfide (1.50 equiv., 141 mg, 0.65 mmol) as described in General Synthetic Procedure VIIb to give the title compound Id (85 mg) as an ivory-colored solid. 1H NMR (DMSO-d6) δ 12.5 (brs, 1H), 8.0 (brs, 1H), 7.72 (brs, 1H), 7.59-7.08 (m, 8H); LC/MS: m/z obs=347 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:14])[CH2:4][CH2:3]1.[C:15]([O:19][C:20]([NH:22][C@@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.[Na]>CO>[C:15]([O:19][C:20]([NH:22][CH:23]1[CH2:27][CH2:26][N:25]([C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH2:4][CH2:3]2)[CH2:24]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C1CCC(c2cccc[n+]2[O-])CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN([C@H]2CC[C@H](c3cccc[n+]3[O-])CC2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 17.8 mL of methanol containing 2-(4-oxocyclohexyl)pyridine N-oxide (1.8 g, 9.41 mmol) and 1.75 g (9.41 mmol) of (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine was added 3.23 mL (56.4 mmol) of glacial acetic acid under an inert atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes, cooled to 0° C., and treated with four equal portions of solid sodium cyanoborohyride (total: 296 mg, 4.71 mmol). The reaction mixture was stirred at 0° C. for 20 minutes more. All volatiles were removed under reduced pressure and the residue was taken up in 200 mL of ethyl acetate. The organic layer was washed with 10% sodium carbonate solution and brine, then dried (sodium sulfate) and concentrated to yield 2.86 g of the crude product as an oil. The desired trans-2-[4-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-cyclohexyl]-pyridine N-oxide was obtained via preparative centrifugal chromatography on silica gel (chloroform-methanol gradient elution). A portion of this material (544 mg, 1.505 mmol) was dissolved in 300 mL ethyl acetate at 0° C., and HCl gas was bubbled through the solution for 10 min. The reaction mixture was allowed to come to room temperature over a 1 hour period. All volatiles were rotoevaporated under reduced pressure to give a white solid. This material was resuspended in 200 mL of ethyl acetate and treated with 10 ml of 10% sodium carbonate solution. After 10 minutes the phases were separated and the organic layer was dried (sodium sulfate). The aqueous layer was concentrated to dryness and the residue was stirred with a chloroform-methanol mixture (4:1, v/v). The suspension was filtered and the filtrate was combined with the ethyl acetate extracts. The combined organic extracts were then concentrated and azeotropically dried with toluene to give 400 mg of the title compound as a tan powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:24][OH:25])=[CH:4][CH:3]=1.[CH3:26][C:27](OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([Mg]Br)C.C(OCC)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: OCc1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Agent: CC[Mg]Br
Solvent: CC#N
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ncc(Cl)cc1Cl
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a stirred suspension of [10-chloro-1-(3,5-dichloropyridin-2-yl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-yl]methanol (376 mg, 0.946 mmol) in acetonitrile (10 mL) was added Dess-Martin reagent (481 mg, 1.14 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and a solution of ethyl magnesium bromide in diethyl ether (3.0 M, 568 μL, 1.70 mmol) was added at −78° C. After 30 min, the reaction mixture was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (301 mg, 0.707 mmol, 75%).