Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH2:6][CH2:5][CH2:4][N:3]5[S:2]3(=[O:13])=[O:14])[CH2:26][CH2:25]2)=[CH:32][CH:31]=1
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)N(CCCN2CCN(c3ccc(F)cc3)CC2)c2cccc3c2N1CCC3
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
A solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (5.34 g) in dry N,N-dimethylformamide (50 cc) is added dropwise to a suspension of sodium hydride (0.72 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 15 minutes' stirring, 1-(3-chloropropyl)-4-(4-fluoro-phenyl)piperazine (7.68 g) is added. The reaction mixture is heated to 100° C. for 1 hour and 30 minutes and is then cooled and poured into a mixture of water (300 cc) and ethyl acetate (500 cm). The organic phase is washed with water (3×200 cc), is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 6-cm diameter, 50-cm height) and eluted at a pressure of 0.7 bars of nitrogen with a mixture of cyclohexane and ethyl acetate (80-20 by volume), 125-cc fractions being collected. Fractions 10 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is recrystallized from ethanol (80 cc). 1-[3-(4-(4-Fluorophenyl)piperazinyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (7.2 g) is obtained, melting at 98° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][CH2:32][CH:31]2[C:35]2[CH:36]=[C:37]([C:53]([OH:55])=O)[CH:38]=[C:39]3[C:44]=2[O:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][C@H:47]([CH3:51])[CH2:46]2)=[CH:41][C:40]3=[O:52])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>CN(C=O)C>[F:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][CH2:32][CH:31]2[C:35]2[CH:36]=[C:37]([C:53]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[O:55])[CH:38]=[C:39]3[C:44]=2[O:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][C@H:47]([CH3:51])[CH2:46]2)=[CH:41][C:40]3=[O:52])[CH:27]=[CH:28][CH:29]=1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.5 %

Procedure:
TBTU (138 mg, 0.43 mmol) was added to a stirred solution of 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (97 mg, 0.21 mmol), DIPEA (0.075 mL, 0.43 mmol) dissolved in DMF (1.5 mL) under nitrogen. The resulting solution was stirred at room temperature for 1.5 h. Morpholine (0.028 mL, 0.32 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and evaporated to dryness to afford 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one (63 mg, 56%) as a yellow foam.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C@@H:15]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:13]4)=[CH:10][CH2:9][C:8]1=[CH:7][C:6](=[O:28])[CH2:5][CH2:4]2.C(Cl)(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:42])C=1.[OH-].[K+]>C(OCC)(=O)C.C(O)(=O)C>[OH:42][C@:11]12[CH:10]=[CH:9][C:8]3[C@:3]([CH2:2][OH:1])([CH2:4][CH2:5][C:6](=[O:28])[CH:7]=3)[C@H:20]1[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]2[CH2:13][CH2:14][C@@H:15]1[O:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@H]2C3=CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)O[C@H]1CC[C@H]2[C@@]3(O)C=CC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
A solution of 2 g. of 19-hydroxy-17β-pivaloxyandrosta-4,7-dien-3-one in 2000 ml. of carbon tetrachloride was left to stand with 1.5 g. of meta-chloroperbenzoic acid for two and a half days, whereupon an additional 0.5 g. of meta-chloroperbenzoic acid was added. After five days the solution was repeatedly extracted with 2% aqueous potassium hydroxide until the extracts were alkaline. The solution was then extracted with water and evaporated. The residue obtained was treated with 9 ml. of 0.2 N methanolic potassium hydroxide for 30 minutes. Then 9 ml. of 0.2 N acetic acid in ethyl acetate was added and the mixture was concentrated at reduced pressure. Recrystallization of the residue combined with thick layer chromatography yielded 7-hydroxy-8,19-oxido-17β-pivaloxyandrost-4-en-3-one, mp. 211°-212° C. λ max 246 mμ, 8α,19-dihydroxy-17β-pivaloxyandrost-4,6-dien-3-one, mp 202°-203° C., λ max 280 mμ, as well as 8β,19-dihydroxy-17β-pivaloxyandrost-4,6-dien-3-one, mp. 218°-220° C., λ max 282 mμ. The structure of these compounds was confirmed by ir and nmr spectroscopy.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:19][C:20]([CH3:22])=[O:21]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:19][C:20](=[O:21])[CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 50 g (0.2 mol) of 4-benzyloxybenzaldehyde in 500 mL of acetone was diluted with 500 mL of water. To the cloudy emulsion which formed was added 20 mL of 1N sodium hydroxide and the mixture stirred at room temperature for 20 hours. The solids which precipitated were recovered by filtration. Recrystallization from methanol gave the above named product, as a tan flaky solid, in a yield of 51 g (87 percent of theoretical). The product melted at 102°-109° C.; 1H NMR (CDCl3) δ2.29 (s, 3H, CH3 --), 5.04 (s, 2H, --CH2 --), 6.48-7.52 (m, 11H, ArH's and --CH=CH--).
Reaction SMILES: F[C:2]1[C:7](F)=CC=C[C:3]=1[CH2:9][S:10]([C:13]1[N:22]=[C:21]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=1)(=O)=O.[O:29]1C(CS)=CC=[N:30]1>>[OH:26][CH2:25][C@H:24]([NH:23][C:21]1[C:20]2[N:19]=[CH:18][C:17](=[O:28])[NH:16][C:15]=2[N:14]=[C:13]([S:10][CH2:9][C:3]2[O:29][N:30]=[CH:7][CH:2]=2)[N:22]=1)[CH3:27]
Reactant: C[C@H](CO)Nc1nc(S(=O)(=O)Cc2cccc(F)c2F)nc2[nH]c(=O)cnc12
Reactant: SCc1ccno1
Product: C[C@H](CO)Nc1nc(SCc2ccno2)nc2[nH]c(=O)cnc12

Procedure:
The titled compound (0.038 g) was prepared by the method of Example 13, step (c) using the product from Example 13, step (a) (00.10 g) and 5-isoxazolylmethylmercaptan (0.057 g).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=3)[C:16]2=[N:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:6]=1)C.O[Li].O>C1COCC1.CO.O>[Br:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:40])=[O:3])[C:16]1=[N:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34]
Reactant: CCOC(=O)c1cccc(OCCCn2c(=NC(=O)OC(C)(C)C)n(Cc3cccc(Br)c3)c3ccccc32)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1cccc(Br)c1
Temperature: 40 °C
Yield: 103.4 %

Procedure:
To a solution of 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester (155 mg, 0.25 mmol) in THF (2 ml), MeOH (2 ml) and H2O (1 ml) was added LiOH.H2O (53 mg, 1.27 mmol). The reaction was warmed to 40° C. where it was maintained for 20 h. After this time, the reaction was cooled to rt concentrated under reduced pressure and then partitioned between EtOAc and 1M HCl. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 3-(3-{3-(3-bromo-benzyl)-2-[tert-butoxycarbonylimino]-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (150 mg, 100%). HPLC-MS 580, 582 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH:18]=O)[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:13][C:12]2[CH:14]=[C:15]([CH:18]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])[CH:16]=[CH:17][C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: O=Cc1ccc2c(c1)CN(c1ccccn1)CCO2
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc3c(c2)CN(c2ccccn2)CCO3)S1

Procedure:
4-Pyridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine-7-carbaldehyde [compound of Example 1-Step III] (0.868 g, 3.4 mmol) was dissolved in 100 mL dry toluene and to this solution, was added 2,4-thiazolidinedione (0.402 g, 3.4 mmol) and piperidinium acetate (46 mg, 0.32 mmol). The reaction mixture was refluxed in a Dean Stark apparatus for 4 hours. The reaction mixture was cooled and filtered. The residue was washed with petroleum ether (500 mL) and dried in air to give crude material A (0.6 g). The filtrate and petroleum ether wash were combined, cooled overnight and filtered. The filtrate was washed with petroleum ether (500 mL). The residue was dried in air to give crude material B (0.24 g). Both crude materials, A and B were combined and purified by silica chromatography using 1% CH2Cl2 in MeOH to give 5-(4-pridin-2-yl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-7-ylmethylene)-thiazolidine-2,4-dione.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Na].[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 30 ml of 2-cyclohexen-1-one in 35 ml anhydrous ethanol is added dropwise at a temperature below -10° to a reagent prepared from 0.1 g sodium, 100 ml of absolute ethanol and 50 ml of diethyl malonate. The reaction mixture is allowed to warm slowly and is stirred at room temperature overnight. The mixture is evaporated to dryness, the residue is dissolved in ether, the ether solution is washed with brine, dried, filtered and evaporated to dryness. The residue is distilled under reduced pressure to yield diethyl 3-oxocyclohexylmalonate, b.p. 147°/0.5 mm.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C1(C)C(C)=CC=CC=1.C(N(CC)CC)C>O>[C:13]1(=[O:18])[N:1]([CH:2]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: NC(CCC(=O)O)c1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CCC(c1cccs1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture containing one gram of 4-amino-4-(2-thienyl)butyric acid and 0.8 g. of phthalic anhydride in 25 ml. of xylene containing 0.55 g. of triethylamine is heated to reflux the water is removed by azeotroping. After 1.5 hours the mixture is cooled and stirred overnight at room temperature. It is then evaporated to dryness to afford the title compound as a glassy material.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1>[OH-].[K+].O>[SH:3][C:4]1[CH:10]=[C:9]([CH:8]=[CH:7][C:5]=1[NH2:6])[C:11]([OH:13])=[O:12]
Reactant: Nc1nc2ccc(C(=O)O)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(C(=O)O)cc1S

Procedure:
Reflux 59 gm of 2-aminobenzothiazole-6-carboxylic acid (prepared by the procedure of Ann., 558, pg. 29, 1947) in a mixture of 300 gm of potassium hydroxide and 300 gm of water for 31/2 hours. Cool and use in the next step as the dipotassium salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[F:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ncc(F)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(F)cnc1=O)c1ccccc1
Yield: 21.1 %

Procedure:
A solution of 5-fluoropyrimidin-2-one (480 mg) and α-bromoacetophenone (843 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 31/2 hours. The resulting suspension was chilled in ice. The solid was collected by filtration, then crystallised twice from ethanol to give the title pyrimidinone (206 mg yield); m.p. 167°-175°, λmaxEtOH 243 nm (ε 15110), 331 nm (ε 3590), λinf 283 nm (ε 1870), 290 nm (ε 1890), 344 nm (ε 2740).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42]1.[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:46]([C:43]3[CH:44]=[CH:45][O:41][CH:42]=3)(=[O:48])=[O:47])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccoc2)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and furan-3-sulfonyl chloride (125 mg) were added dropwise and the mixture was further stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:2) to give the title compound as a colorless oil (yield 175 mg, 82%).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([O:23]CC)=[O:22])=[O:17])=[CH:14][C:13]=1[CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Li+]>CC(C)=O.O>[CH2:1]([O:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=2)[C:21]([OH:23])=[O:22])=[O:17])=[CH:14][C:13]=1[CH2:31][C:32]1[NH:36][N:35]=[N:34][N:33]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)OCC)c2)cc1Cc1nnn[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)cc1Cc1nnn[nH]1
Reaction time: 6 h
Yield: 8.6 %

Procedure:
A mixture of 580 mg of the product from Example 2 and 280 mg of lithium hydroxide in 10 ml of acetone and 1 ml of water were stirred for 6 hours. The mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether and water. The layers were separated and the aqueous layer was extracted with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and concentrated to dryness. The residue was crystallized from hexane/ethyl acetate to provide 47 mg of the title product, m.p. 147°-150° C.
Reaction SMILES: C(OC(=O)CCN[C:10](=[O:33])[C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:29])[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:14]=[CH:13][C:12]=1[N+:30]([O-:32])=[O:31])(C)(C)C.C([O:39]C(NCCC(O)=O)=O)(C)(C)C.NC1C=CC([N+]([O-])=O)=C(C=1)C(O)=O>>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][C:18]([NH:17][C:15]1[CH:14]=[CH:13][C:12]([N+:30]([O-:32])=[O:31])=[C:11]([CH:16]=1)[C:10]([OH:33])=[O:39])=[O:29])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1cc(NC(=O)CCNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccc([N+](=O)[O-])c(C(=O)O)c1

Procedure:
For the preparation of the ester starting material, N-(t-butoxycarbonyl)-β-alanine and 5-amino-2-nitrobenzoic acid are coupled to give 5-[3-(1-t-butoxyformamido)propionamido]-2-nitrobenzoic acid, MS: 354 (17, M+H), and the latter is reacted with β-alanine t-butyl ester.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)C(C)C)C.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
To a stirred solution of 1H-benzoimidazole-5-carboxylic acid (10 g, 61.7 mmol), morpholine (7.55 mL, 86.3 mmol), ethyldiisopropylamine (16.1 mL, 92.5 mmol) and 4-dimethylaminopyridine (380 mg, 3.08 mmol) in DMF (60 mL) at room temperature was added EDC (12.4 g, 64.8 mmol) in a single portion. The mixture was stirred at room temperature for 3 days then concentrated in vacuo. The product was purified by recrystallisation from acetonitrile (70 mL), providing (1H-benzoimidazol-5-yl)-morpholin-4-yl-methanone (8.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]3([CH3:15])[O:25][CH:9]3[C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: CC1=Cc2cc([N+](=O)[O-])ccc2OC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21C
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran (10.0 g, 0.0457 mol) in dichloromethane (200 ml) at 0° C. was added m-chloroperbenzoic acid (13.5 g, 70%, 0.0548 mol). After stirring for eighteen hours at room temperature the mixture was washed successively with water, aqueous sodium hydrogen carbonate, water and then aqueous sodium hydroxide solution. The organic phase was separated and evaporated under reduced pressure to give 9.96 g (93%) of 6-nitro-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, 1H NMR (CDCl3): δ1.3 (s,3H), 1.55 (s,3H), 1.60 (s,3H), 3.8 (s,1H), 6.9 (d,1H), 8.15 (d,1H), 8.30 (s,1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16]C[O:14]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(#N)C>[O:18]1[CH2:17][CH2:16][O:14][CH:13]1[CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCCC1OCCCO1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1ccc(OCCC2OCCO2)cc1
Yield: 104.5 %

Procedure:
In a 500 ml flask, 120 ml of acetonitrile, 13.8 g of 4-hydroxybenzaldehyde, 19.9 g of 2-(2-bromoethyl)-1,3-dioxane, 1.8 g of potassium iodide, and 35.8 g of potassium carbonate were placed and then, reacted at 80° C. for 5 hr. Thereafter, to the reaction mixture was added 200 ml of ethyl acetate and washed once with a saturated aqueous potassium carbonate solution, distilled water and saturated saline. The washed organic phase was dried over anhydrous magnesium sulfate and the solvent was removed, to give 23.7 g of 4-(2-[1,3]-dioxolan-2-yl-ethoxy)benzaldehyde.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].CN1CCOCC1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(C)=O>[Cl:23][CH2:24][C:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a suspension of 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (1A) (22.7 g, 0.1 mol) in acetone (200 mL) was added 4-methyl morpholine (42.4 mL, 0.3 mol). The solution was cooled to −20° C. and chloroacetyl chloride (12 mL, 0.15 mol) was added dropwise. The reaction mixture was stirred at −10° C. for 10 min before being quenched with H2O (200 mL). The precipitate formed was collected by vacuum filtration and dried to provide 25.3 g (95% yield) of 3-(2-chloro-acetylamino)-N-cyclopropyl-4-methylbenzamide, mp: 150° C. (dec.); 1H NMR (500 MHz, DMSO-D6) δ 9.83 (s, 1H), 8.39 (d, J=3.8 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=6.6 Hz, 1H), 7.28 (d, J=8.3, 1H), 4.32 (s, 2H), 2.82 (m, 1H), 2.22 (s, 3H), 0.66 (m, 2H), 0.56 (m, 2H); 13C NMR (100 MHz, DMSO-D6) δ: 167.2, 165.4, 136.0, 135.8, 132.8, 130.5, 124.8, 124.7, 43.4, 23.4, 18.1, 6.0; Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.66; N, 10.50; Cl, 13.29. Found: C, 53.72; H, 5.95; N, 9.65; Cl, 13.52.