Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5])([OH:3])=O.C(Cl)CCl.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:40]=1[NH2:41]>CN(C=O)C.Cl>[Cl:17][C:10]1[CH:11]=[N+:12]([O-:16])[CH:13]=[C:14]([Cl:15])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:26])[F:27])=[C:20]([O:28][CH2:29][CH:30]2[CH2:31][CH2:32]2)[CH:19]=1)[O:6][C:4](=[O:5])[C:1]([NH:41][C:40]1[CH:42]=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:39]=1[O:38][CH3:37])=[O:3]
Reactant: O=C(O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1NC(=O)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
(S)-4-(2-(carboxycarbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (50 mg, 0.10 mmol) was dissolved in DMF (5 ml), then EDC (29.2 mg, 0.15 mmol) was added. 2-methoxy-4-nitroaniline (34.2 mg, 0.2 mmol) was added at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction was diluted with HCl 1M and extracted with EtOAc. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude product was purified by Preparative reverse-phase HPLC to give 21 mg of the title product. (Yield: 32%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,4-dichloro-1,5-dinitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5]1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[C:32]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH:13]=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(2-aminoethyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 484.2 (M+H)+.
Reaction SMILES: O[CH:2](O)[CH2:3][N:4]1[CH:9]=[CH:8][C:7]2[O:10][C:11]([CH3:13])=[CH:12][C:6]=2[C:5]1=[O:14].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:45]=[CH:44][C:31]2[N:32]([CH2:42][CH3:43])[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]=2[CH:29]=1.S([O-])(O)=O.[Na+].C(OC(=O)C)C.[ClH:57]>C(OCC)(=O)C.CN(C=O)C>[ClH:57].[ClH:57].[CH2:42]([N:32]1[C:33](=[O:41])[C:34]([CH3:40])([CH3:39])[C:35](=[O:38])[N:36]([CH3:37])[C:30]2[CH:29]=[C:28]([O:27][CH2:26][CH2:25][CH2:24][N:23]3[C:22]4[CH:21]=[CH:20][N:19]=[CH:18][C:17]=4[N:16]=[C:2]3[CH2:3][N:4]3[CH:9]=[CH:8][C:7]4[O:10][C:11]([CH3:13])=[CH:12][C:6]=4[C:5]3=[O:14])[CH:45]=[CH:44][C:31]1=2)[CH3:43]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNc3ccncc3N)ccc21
Reactant: Cc1cc2c(=O)n(CC(O)O)ccc2o1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(Cn4ccc5oc(C)cc5c4=O)nc4cnccc43)ccc21
Temperature: 25 °C

Procedure:
A DMF solution (4 ml) of 5-(2,2-dihydroxyethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.20 g), 7-[3-(3-aminopyridin-4-ylamino)propoxy]-1-ethyl-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.37 g), and sodium hydrogensulfite (0.47 g) were heated at 180° C. for 10 minutes (microwave reactor). After the reaction liquid was condensed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:methanol=95:5→60:40). The purified product was condensed under reduced pressure. A 4N-hydrogen chloride ethyl acetate solution was added to an ethyl acetate solution of the residue, which was stirred at room temperature. The generated insoluble matter was separated by filtration, and dried to give the title compound (0.47 g) as a white amorphous solid.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[N:9]=1)=O)C.O>CCO>[CH2:15]([O:14][C:10]1[N:9]=[C:8]([CH2:6][OH:5])[CH:13]=[CH:12][CH:11]=1)[CH3:16]
Reactant: CCOC(=O)c1cccc(OCC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
NaBH4 (5.7 g, 151 mmol) was added in portions during 35 minutes to 6-ethoxy-pyridine-2-carboxylic acid ethyl ester (1.5 g, 7.5 mmol) in EtOH (75 mL). The resulting mixture was stirred at ambient temperature for two days. Water was added and the mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and then concentrated to give the title product (0.85 g) in 74% yield as an oil. This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][CH3:5].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.S([O-])([O-])(=O)=O.[Mg+2]>>[CH2:1]([N:6]=[CH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccccn1
Reactant: CCCCCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCCCCN=Cc1ccccn1

Procedure:
n-Pentylamine (20.3 g, 0.23 mol) was added dropwise to pyridine-2-carboxaldehyde (25.0 g, 0.23 mol) with stirring in an ice bath. After complete addition of the amine, anhydrous magnesium sulfate (6 g) was added and the slurry stirred for 2 hours at 25° C. The solution was filtered, solvent removed, and the product purified by distillation under reduced pressure (0.5 mm Hg at 80° C.) to give a yellow oil. Yield: 29.6 g (73%). 1H NMR (CDCl3, 500 MHz): δ8.64 (m, 1H), 8.38 (s, 1H), 7.99 (m, 1H), 7.72 (m, 1H), 7.28 (m, 1H), 3.67 (t, 2H), 1.73 (sextet, 2H), 1.36 (overlapping quintets, 2H each), 0.90 (t, 3H), GCMS m/e 176.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]>O1CCCC1>[N+:29]([C:20]1[CH:21]=[C:22]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:23]=[CH:24][C:19]=1[O:1][CH2:2][CH:3]1[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1)([O-:31])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2CCNCC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.223 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.276 g) was added and reaction stirred at room temperature. After 1 hour the reaction was partitioned between water (25 mL) and dichloromethane (50 mL) and the reaction quenched with 1N aqueous HCl (5.57 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. Treatment with HCl (4.0M in dioxane, 2 mL) and methanol (2 mL) for 1 hour, followed by concentration, trituration with dichloromethane and filtration gave the title compound.
Reaction SMILES: [O-]CC.[Na+].[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[O:15][CH2:16][CH:17]=[CH2:18])=[CH:9][CH:8]=1)=O.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][N:25]=[N+:26]=[N-:27])[CH3:21].O1CCCC1>C(O)C>[CH2:16]([O:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7](/[CH:5]=[C:24](/[N:25]=[N+:26]=[N-:27])\[C:23]([O:22][CH2:20][CH3:21])=[O:28])=[CH:8][CH:9]=1)=[O:19])[CH:17]=[CH2:18]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: C=CCOC(=O)Nc1ccc(C=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOC(=O)Nc1ccc(/C=C(/N=[N+]=[N-])C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.9 %

Procedure:
To a solution of 689 mg (10.13 mmol) sodium ethoxide in 5 mL absolute ethanol at 0° C. was added a solution of 500 mg (2.44 mmol) of allyl 4-formylphenylcarbamate and 1.25 g (9.75 mmol) ethylazidoacetate dissolved in 5 mL absolute ethanol and 1 mL tetrahydrofuran dropwise over 5 minutes. The mixture was stirred at 0° C. for 1.5 h, then partitioned between ethyl acetate and 1 N HCl until neutral. The organic phase was dried over magnesium sulfate, concentrated and purified by column chromatography, eluting with 25% ethyl acetate/hexane to provide 385 mg of ethyl (2E)-3-(4-{[(allyloxy)carbonyl]amino}phenyl)-2-azidoprop-2-enoate as a yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[N:7]=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[Cl:22][C:5]1[C:6]([C:18]([F:20])([F:21])[F:19])=[N:7][N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)cc2C2CC2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2nc(C(F)(F)F)c(Cl)c2C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Intermediate 13 (1 g, 3.36 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.54 g, 4.0 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) afforded the title compound (0.802 mg). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.39 (d, J 9, 2H), 7.82 (d, J 9, 2H), 1.91-1.80 (m, 1H), 1.10-1.00 (m, 2H), 0.80-0.72 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH:12]1[NH:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4].Cl.Cl[C:20]([O:22][CH2:23][Cl:24])=[O:21]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:4])[CH:5]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:20]([O:22][CH2:23][Cl:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1
Reactant: O=C(Cl)OCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCCl
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
Methylphenidate hydrochloride (1) (2.70 g, 10 mmol) was suspended in DCM (75 mL) and cooled in an ice bath. 4-Dimethylaminopyridine (DMAP) (4.887 g, 40 mmol) was added and the resulting mixture was stirred for 10 min. Chloromethyl chloroformate (3.224 g, 25 mmol) in DCM (10 mL) was added slowly. The ice bath was removed and the reaction was stirred for 5 h at room temperature. Ethyl acetate (250 mL) was added, followed by water (20 mL) to quench the reaction. The ethyl acetate layer was separated and washed with 1N HCl (40 mL) and brine (2×40 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexanes:EtOAc, 3:1) to give 37 as a colorless oil (2.60 g) (yield, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([CH2:16]OC)[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[C:28]1[N:29]=[CH:30][C:31]([C:34]([NH2:36])=[O:35])=[N:32][CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:19][C:28]3[CH:33]=[N:32][C:31]([C:34](=[O:35])[NH2:36])=[CH:30][N:29]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(COC)c21
Reactant: NC(=O)c1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(N)=O)cn3)cc(C)c21
Temperature: 80 °C
Yield: 49.4 %

Procedure:
A suspension of (1,6-dihydroxy-4-methoxymethyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (150 mg, 0.600 mmol) and Cs2CO3 (430 mg, 1.32 mmol) in DMF (4 mL) was treated with 5-bromo-pyrazine-2-carboxylic acid amide (158 mg, 0.780 mmol) at room temperature and the reaction was heated to 80° C. for 2 h. The reaction mixture was concentrated to dryness. The residue was diluted with water and adjusted to pH 2 with 1N HCl. The aqueous phase was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=1:2 to DCM/MeOH=10:1) to afford the title compound as a white solid (110 mg). 1H NMR (300 MHz, CD3OD) δ 8.90 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 7.35 (s, 1H), 7.08 (s, 1H), 5.70 (s, 1H), 5.69-5.66 (m, 1H), 4.21 (q, 2H), 3.14-3.12 (m, 1H), 2.49-2.41 (m, 1H), 2.37 (s, 3H), 1.26 (t, 1H). MS found: (M+H)+: 372.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:59]=[CH:58][C:57]([CH2:60][NH2:61])=[CH:56][CH:55]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35].CN1CCOCC1>CN(C)C=O>[CH2:34]([O:36][C:37](=[O:63])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][C:45]2[C:50]([C:51](=[O:62])[NH:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([CH2:60][NH:61][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=4)=[CH:58][CH:59]=3)=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:39]=1)[CH3:35]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CN)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1cccc(Oc2ncccc2C(=O)NCc2ccc(CNC(=O)c3cccc(O)c3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
3-Hydroxy-benzoic acid (27 mg, 0.19 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (45 mg, 0.23 mmol) were added to a solution of 3-[3-(4-aminomethyl-benzylcarbamoyl)-pyridin-2-yloxy]-benzoic acid ethyl ester hydrochloride (100 mg, 0.19 mmol) (see Preparation 9) and N-methyl morpholine (0.11 ml, 0.97 mmol) in N,N-dimethylformamide (15 ml). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours, concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and water (20 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (99:1 changing to 98:1, by volume) giving 3-(3-{4-[(3-hydroxy-benzoylamino)-methyl]-benzylcarbamoyl}-pyridin-2-yloxy)-benzoic acid ethyl ester (45 mg) as an off-white foam.
Reaction SMILES: [N:1]1([CH2:9][C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:22]([CH3:23])[C@H:21]4[N:18]([C:19](=[O:27])[C@@H:20]4[C@H:24]([OH:26])[CH3:25])[C:17]=3[C:28]([O:30]CC3C=CC([N+]([O-])=O)=CC=3)=[O:29])[CH2:12][N:11]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.P(=O)(O)(O)O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[N:1]1([CH2:9][C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:22]([CH3:23])[C@H:21]4[N:18]([C:19](=[O:27])[C@@H:20]4[C@H:24]([OH:26])[CH3:25])[C:17]=3[C:28]([OH:30])=[O:29])[CH2:12][NH:11]2)[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CN4CCn5nccc54)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: [Pd+2]
Agent: O=P(O)(O)O
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CN4CCn5nccc54)C3)[C@H](C)[C@H]12
Yield: 71.5 %

Procedure:
A solution of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.70 g), 20% palladium hydroxide on carbon (0.4 g), 01 M phosphoric acid buffer (pH=6.0, 35 ml) and tetrahydrofuran (35 ml) was stirred for 5 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo to remove the organic solvent. The aqueous layer was washed twice with ethyl acetate (30 ml) and evaporated in vacuo to remove the organic solvent. The residue was chromatographed on a nonionic adsorption resin "Diaion HP-20" (20 ml) eluting in turn with water (60 ml) and 5% aqueous acetone [120 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-3-[(2S,4S)-2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methylpyrrolidin-4-yl ]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (0.29 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1.[BrH:19]>C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][C:6]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:5]([CH:16]([CH3:18])[CH3:17])[CH:4]=1
Reactant: Br
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CO
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CBr

Procedure:
To 26 parts 4-hydroxymethyl-2,5-diisopropylbenzenesulfonamide dissolved in 100 parts chloroform heated just below reflux is added hydrogen bromide in a slow stream for an hour. The organic phase is washed with aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give 4-bromomethyl-2,5-diisopropylbenzenesulfonamide.
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[CH:12]([C:11]1[C:5]2[O:4][C:3]([CH3:18])([CH2:2][N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH2:7][C:6]=2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]=1[CH3:15])([CH3:14])[CH3:13]
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(c3ccccc3)CC1)O2
Yield: 45.8 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), 4-phenylpiperidine (0.87 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=30:1 to 10:1) and recrystallized from hexane/ethyl acetate to afford 0.55 g of the title compound. Yield 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([N:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7](=[O:21])[C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH3:24])[S:15]([N:18]([CH3:20])[CH3:19])(=[O:16])=[O:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CN(C)S(=O)(=O)N(C)c1ccc(C(=O)Nc2ccc(Cl)cc2)cc1
Yield: 96.2 %

Procedure:
A mixture of 300 mg of 4'-chloro-4-[(dimethylaminosulfonyl)amino]benzanilide 7, 140 mg of potassium carbonate, 130 mg of dimethyl sulfate 8, and 10 ml of dried acetone is refluxed for 30 minutes. Acetone is distilled off from the reaction mixture, the residue is basified with 10% sodium hydroxide solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is crystallized from ethyl acetate-isopropyl ether to give 300 mg of 4'-chloro-4-[methyl(dimethylaminosulfonyl)amino]benzanilide 9 as crystals, m.p. 155°-156° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1.C(N(CC)CC)C>ClCCl>[C:9](/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)([OH:11])=[O:10]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)/C=C\C(=O)Nc1ccc(/C=C/C(=O)O)cc1

Procedure:
The method of Example 1 was employed using 4-aminocinnamic acid hydrochloride (10.0 g, 0.0501 mol) and maleic anhydride (5.00 g, 0.0509 mol). Triethylamine (7.00 ml, 0.0502 mol) in dichloromethane (100 ml) was added to generate the free amine. The yellow maleamic acid was obtained. H.p.l.c. 100%. 1H-n.m.r. (DMSO): δ 10.51 (1H, s, NH); 7.65 (4H, bs, ar H's); 7.55 (1H, d, pH-CH); 6.44 (2H, t, HO2C CH=CH; CO, PhCH=CH); 6.30 (1H, d, HO2C CH=CH CO).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:19])[C:12](=[CH2:18])[CH2:13][C:14](OC)=[O:15]>CCOC(C)=O>[CH3:9][O:10][C:11]([CH:12]1[CH2:13][C:14](=[O:15])[N:1]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH2:18]1)=[O:19]
Reactant: Nc1ccc(O)cc1
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Temperature: 110 °C

Procedure:
A mixture of 4-amino-phenol (3 g, 0.027 mol) and 2-methylene-succinic acid dimethyl ester (4.35 g, 0.027 mol) was heated to 110° C. for 16 h. The dark brown glass was dissolved in EtOAc and purified by silica gel chromatography (20% EtOAc/hexane to EtOAc) to give an orange oil. MS (ESI pos. ion) m/z: 236.2 (M+H). Calc'd Exact Mass for C12H13NO4: 235.24.