Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O-:25])=[O:24])=[CH:8][CH:7]=1)=[O:3].[Na+].C(N(CC)C(C)C)(C)C.[C:36]([O:42][CH2:43]Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38].C(OCC)(=O)C>CN(C)C=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[NH2:1][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:18][C@H:17]3[N:14]([C:15](=[O:22])[C@@H:16]3[C@H:19]([OH:21])[CH3:20])[C:13]=2[C:23]([O:25][CH2:43][O:42][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:24])=[CH:8][CH:7]=1)=[O:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccc(COC(N)=O)cc3)C[C@H]12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccc(COC(N)=O)cc3)C[C@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A solution of sodium (5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13 mg) in dry dimethylformamide (0.5 ml) was cooled with ice, and thereto were added N,N-diisopropylethylamine (5 mg), benzyltriethylammonium chloride (5 mg) and pivaloyloxymethyl chloride (11 mg). The mixture was gradually warmed to room temperature and stirred for overnight. To the reaction mixture were added ethyl acetate and ice water to separate by a separating funnel. The organic layer was washed with cold water (three times) and a cold saturated aqueous sodium chloride solution (twice), and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel thin-layer chromatography (ethyl acetate) to give [(2,2-dimethylpropanoyl)oxy]methyl (5R,6S)-3-(4-{[(aminocarbonyl)oxy]methyl}phenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (9.2 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CN(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22]>CN(C)C=O.O>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCOC(CBr)OCC
Reactant: Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(CNc1ccncc1)OCC
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 13.5 %

Procedure:
A solution of 4-aminopyridine (23.2 g.) in a mixture of dried hexamethylphosphoric triamide (45 g.) and dried dimethylformamide (80 ml) was dropwise added over 20 minutes with stirring and ice-cooling to a suspension of 65.5% sodium hydride (10 g.) in dried dimethylformamide (20 ml.). After dried dimethylformamide (20 ml.) was further added thereto, the mixture was stirred for 1 hour under ice-cooling, for 20 minutes at ambient temperature and for 40 minutes at 50° C. A solution of bromoacetaldehyde diethyl acetal (54 g.) in dried dimethylformamide (20 ml.) was dropwise added thereto over 5 minutes at 50° C. The resulting mixture was stirred for 15 hours at 80° C and for 3 hours at 100° C. After cooling, water was added to the reaction mixture and the resulting mixture was concentrated under reduced pressure to remove dimethylformamide. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was in turn washed 3 times with water and once with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residual oil was purified by column chromatography on alumina (300 g.) using a mixture of ethyl acetate and hexane (1 : 1) as a developing solvent to give oil of 4-pyridylaminoacetaldehyde diethyl acetal (7.0 g.).
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].O>ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:21]=1[C:22]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:23]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: c1cnc2c(c1)NCCCC2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a mixture of 2.90 g of 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine, 2.37 g of triethylamine in 40 ml of dichloromethane is added 5.16 g of 2-chloro-4-nitrobenzoyl chloride in 50 ml of dichloromethane. The mixture is stirred at room temperature under argon for 3 hours and then poured into water. The organic layer is separated and washed with 1N NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the pad washed with CH2Cl2 and ethyl acetate and the filtrate concentrated to dryness. The residual solid (7.13 g) is triturated with ethyl acetate to give 4.41 g of off-white crystals, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>C(Cl)Cl>[C:4]([CH:3]([N:2]([CH3:1])[C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: O=C1CCC(=O)O1
Reactant: CNC(C#N)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C(=O)CCC(=O)O)C(C#N)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of the compound obtained in Step A (9 mmol), succinic anhydride (7.5 mmol) and pyridine (1 ml) in methylene chloride (30 ml) is stirred overnight. After conventional treatment, the title compound is obtained in pure form.
Reaction SMILES: O=[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[O:3]1.O(Cl)[Cl:20]>N1C=CC=CC=1>[Cl:20][C:2]1[O:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1
Reactant: ClOCl
Reactant: COC(=O)CCC1OC(=O)N=C1c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCc1oc(Cl)nc1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of methyl 3-(2-oxo-4-phenyloxazolin-5-yl)propionate (3.00 g), pyridine (0.98 ml) and phosphoric oxychloride (7.62 g) was stirred at 105° C. for 2 hrs. The reaction mixture was slowly poured into ice water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography, and methyl 3-(2-chloro-4-phenyl-5-oxazolyl)propionate (2.40 g, yield 75%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:7, volume ratio).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[C@H:11]([OH:25])[C@@H:10]1[OH:26].[C:27](Cl)(=[O:30])[CH2:28][CH3:29].FC(F)(F)C(O)=O.NC1N=C(Cl)N=C2C=1N=CN2[C@@H]1C[C@H](NC(=O)CC)[C@@H](O)[C@H]1O>>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([NH:8][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:10]([OH:26])[C@H:11]2[OH:25])=[C:19]([Cl:23])[N:18]=1
Reactant: CCC(=O)Cl
Reactant: N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared from (1S,2R,3S,5R)-3-amino-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol trifluoroacetate and propionyl chloride using a procedure analogous to that used to prepare N-[(1S,2R,3S,4R)-4-(6-amino-2-chloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide trifluoroacetate in Example 2. MS (ES+) m/e 360 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Product: COc1cccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)c1
Yield: 77 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3-methoxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 206b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide (Example 206a) and 3-methoxybenzeneboronic acid resulting in a 77% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21].N1CCCCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:14]1[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:12][C:13]1=[O:21])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1CCc2cc(Br)ccc21
Temperature: 110 °C
Yield: 11.2 %

Procedure:
A reaction mixture of 0.422 g 5-bromoindanone, 1.3 g oxindole and 0.9 ml piperidine in 3 ml of dimethylforamide was heated in a sealed tube at 110° C. overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The black residue was chromatographed on a silica gel column, eluting with ethyl acetate and hexane to give 73.0 mg of 3-(5-bromoindan-1-ylidene)-1,3-dihydroindol-2-one as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.F[C:35]1C=CC(C)=C(S(Cl)(=O)=O)[CH:40]=1>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:40]
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2C)CCO3)cc1

Procedure:
4-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=468.9 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 5-fluoro-2-methyl-benzenesulfonyl chloride and yielded 4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[CH2:10]([Br:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[Br-:17].[CH2:10]([N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2ccccc2)cn1Cc1ccccc1
Product: [Br-]
Yield: 93 %

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 1 equivalent of benzyl bromide (1.26 g, 7.36 mmol) was added to the solution and refluxed for 2.5 h. Solution was filtered hot to remove the KBr precipitate and placed back onto reflux. The second equivalent of benzyl bromide (1.38 g, 8.10 mmol) was added to solution and refluxed for 1.5 h. The solution was cooled and the white precipitate was collected and analyzed. Yield: 93%. 1H NMR (500 MHz, DMSO-d6): δ 5.55 (s, 4H, CH2), 7.43-7.46 (m, 10H, aryl), 9.86 (s, 1H, NCHN); 13C NMR (125 MHz, DMSO-d6): δ 51.50, 119.11, 128.27, 128.84, 128.93, 132.61, 136.68
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]>>[C:16]([NH:15][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([N+:24]([O-:26])=[O:25])[CH:28]=2)(=[O:34])=[O:35])[CH:3]=1)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: CCOC(=O)CC(NC(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Corresponding to Example 3c, 2.60 g of (4b) were reacted with 3-nitrophenylsulphonyl chloride. A solid was obtained (yield: 1.76 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[Li+].[CH3:21]C([N-]C(C)C)C.IC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([CH3:21])=[CH:10][C:3]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.5 %

Procedure:
To a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (D22) (3.37 g, 9.99 mmol) in THF (50 mL) stirred at −35° C. was added 2M THF solution of LDA (9.99 mL, 19.99 mmol) and the mixture was stirred for 45 min at this temperature. Iodomethane (1.250 mL, 19.99 mmol) was added dropwise to the mixture and the mixture was then allowed to warm to RT over 2 hours. The reaction was quenched with addition of saturated NH4Cl aq. solution and the mixture was poured into saturated NH4Cl aq. solution (100 mL). The mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in cyclohexane to give the title compound (2.93 g). LCMS (A): m/z (M+H)+ 351/353, C14H11BrN2O2S requires 350/352 (acidic).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:47])[NH:12][CH:13]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:14]([N:16]1[CH2:20][CH2:19][CH:18]2[N:21]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:22][CH:23]([C:24](=[O:36])[NH:25][CH:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][CH2:28][CH2:27]3)[CH:17]12)=[O:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]1([NH:25][C:24]([CH:23]2[CH2:22][N:21]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:18]3[CH2:19][CH2:20][N:16]([C:14](=[O:15])[CH:13]([CH:41]4[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]4)[NH:12][C:11](=[O:47])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:17]23)=[O:36])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH2:27]1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2S(C)(=O)=O)C1CCCCC1
Reaction time: 1.5 h

Procedure:
A solution of 22 (222 mg, 0.3 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 1.5 h, the solution was concentrated, diluted with EtOAc, washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was diluted with ACN/H2O containing 0.1% HOAc and purified by reverse-phase HPLC (2″ Dynamax® C18, 10-100% ACN/H2O containing 0.1% HOAc). The product-containing fractions were frozen and lyophilized to afford 23 as a white solid.
Reaction SMILES: [SH:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].FC1C([O:22][C:23](=O)[CH2:24][CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29])=C(F)C(F)=C(F)C=1F>CN(C1C=CN=CC=1)C>[N+:28]([O:27][CH2:26][CH2:25][CH2:24][C:23]([S:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])=[O:22])([O-:30])=[O:29]
Reactant: O=C(CCCO[N+](=O)[O-])Oc1c(F)c(F)c(F)c(F)c1F
Reactant: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)c1ccncc1
Product: C[C@H](CSC(=O)CCCO[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Using the same procedure described in Example 1 but starting from 1-[(2S)-3-mercapto-2-methyl-1-oxopropyl]-L-proline (Captopril)(0.41 g, 1.9 mmol), 4-(nitrooxy)butanoic acid pentafluorophenyl ester (0.60 g, 1.9 mmol) TEA (0.26 ml, 1.9 mmol) and DMAP (0.23 g, 1.9 mmol) after purification with Flash chromatography of the residue (CH2Cl2/Acetone 80:20) the title compound (0.140 g, 20%) was obtained as a white foam.
Reaction SMILES: C(N)C=C.[CH2:5]([N:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH3:21])C1=S)[CH:6]=[CH2:7]>ClCCl>[CH2:5]([NH:8][CH2:13][CH2:12][CH2:11][NH:10][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH3:21])[CH:6]=[CH2:7]
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Solvent: C=CCN
Solvent: ClCCl
Product: C=CCNCCCNc1cc(Cl)ccc1C
Yield: 41.2 %

Procedure:
A mixture of allylamine (1.0 mL) and the hydrobromide salt of Step B (1.0 g) was heated at 100° C. under nitrogen for 45 minutes. The reaction was cooled and partitioned between dichloromethane and 1 N sodium hydroxide. The aqueous layer was extracted with dichloromethane, the extracts were dried over sodium sulfate and concentrated in vacuo to give a yellow oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 98:2 dichloromethane-methanol to 90:10 dichloromethane-methanol containing 0.2% ammonium hydroxide) provided the title compound (0.35 g, 50.5%) as a yellow oil which was used as such in the next step.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([O:15]C(OC)=O)=[CH:13][C:12]([N:20]=[C:21]=[O:22])=[C:11]([F:23])[CH:10]=1.CNC(NC)=[S:27].[CH:30]1[N:34]=[CH:33][N:32]([C:35](N2C=NC=C2)=[O:36])[CH:31]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N:20]2[C:21](=[O:22])[N:34]([CH3:30])[C:33](=[S:27])[N:32]([CH3:31])[C:35]2=[O:36])=[C:11]([F:23])[CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=S)NC
Reactant: COC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(=S)n(C)c(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3 ml of triethylamine and then a solution of 22.4 g (91.2 mmol) of 4-chloro-2-fluoro-5-(methoxycarbonyloxy)phenyl isocyanate in 100 ml of toluene were added dropwise at approximately 20° C. to a solution of 9.5 g (91.2 mmol) of N,N′-dimethylthiourea in 20 ml of toluene. After addition of 29.6 g (182.5 mmol) of carbodiimidazole, the mixture was heated for 3 hours at 80° C. The reaction mixture was stirred overnight at approximately 20° C., then washed three times with water and finally concentrated under reduced pressure. The crude product was purified by column chromatography (mobile phase: cyclohexane/ethyl acetate=10:1). Yield: 18.1 g (63%); m.p.: 242-246° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.Cl[C:17]([O:19][CH3:20])=[O:18].O>O1CCCC1>[F:9][C:10]1[C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Fc1ccccn1
Reactant: COC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1F
Temperature: -78 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
2 M lithium diisopropyl amide (11.3 mL, 22.5 mmol) is slowly added over a solution of 2-fluoropyridine (2 g, 20.5 mmol) in tetrahydrofuran (90 mL) under nitrogen atmosphere at −78° C. After 4 h at that temperature methyl chloroformate (1.9 mL, 24.6 mmol) is added and the mixture is stirred for an additional hour at −78° C. and allowed to reach room temperature overnight. Reaction mixture is slowly poured over water and extracted in diethyl ether. Organic layer is washed with brine, dried over sodium sulfate and solvent is evaporated in vacuo. Residue is purified by normal phase Isco chromatography eluting with hexane/diethyl ether (9/1) to give 495.2 mg of the title compound. MS (m/z): 156 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)=[CH:14][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8](C(O)=O)=[CH:7][CH:6]=1.[CH:57]([NH:59][NH2:60])=[O:58].CCN=C=NCCCN(C)C.O.ON1C2C=CC=CC=2N=N1.CN1CC[O:87][CH2:86]C1>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([C@H:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)=[CH:14][C:3]=1[CH2:4][C:5]1[N:10]=[N:9][C:8]([C:57]([NH:59][NH:60][CH:86]=[O:87])=[O:58])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Reactant: CN1CCOCC1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=CNNC(=O)c1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)benzyl)pyridazine-3-carboxylic acid (1.4 mmol) from Step 1, formic hydrazide (107 mg, 1.8 mmol), EDCI (394 mg, 2.1 mmol), and 1-hydroxybenzotriazole hydrate (426 mg, 2.7 mmol) in N,N-dimethylformamide (15 mL) was added 4-methylmorpholine (0.45 mL, 4.1 mmol). The resulting mixture was stirred at ambient temperature overnight. After dilution with ethyl acetate, the organic layer was subsequently washed with water, hydrochloric acid (1.0 M), saturated sodium bicarbonate and brine prior to drying over magnesium sulfate. Filtration and removal of the volatiles under reduced pressure yielded titled compound as a glassy off-white amorphous solid, which was used without further purification.