Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:5]([CH3:12])=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[OH-].[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+].O>[NH2:3][C:4]1[C:9]([Br:1])=[N:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12]
Reactant: COc1cc(C)c(N)cn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C)c(N)c(Br)n1
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
Bromine (4.8 g) was added in one portion to a mixture of 5-amino-2-methoxy-4-methylpyridine (3.9 g) in acetic acid (25 ml) and sodium acetate (4.0 g). The resulting mixture was stirred for 20 min. and then added to a solution of sodium hydroxide (15 g) in water (200 ml). The product was extracted with chloroform, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride/ethyl acetate, 19:1→4:1) to give 4.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[ClH:16]>CC(O)=O>[ClH:16].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH3:15])/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(N)nc1
Agent: Cl
Solvent: CC(=O)O
Product: C/C(=C\c1ccc(N)nc1)C(=O)O
Temperature: 100 °C

Procedure:
To ethyl (E)-3-(6-aminopyridin-3-yl)-2-methylacrylate (5.0 g, 24.2 mmole) was added HOAc (25 mL) and cone. HCl (25 mL). Hie reaction was stirred and heated at 100° C. for 6 hr, cooled to RT and concentrated to dryness. The remaining residue was triturated with Et2O, filtered and dried under vacuum to give the title compound (53 g, quantitative) as a white solid: LCMS (ES) m/e 179.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (br s, 2H), 8.16 (d, J=1.7 Hz, 1H), 8.08 (dd, 1H), 7.42 (s, 1H), 7.08 (d, J=9.3 Hz, 1H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[O:29][CH3:30])[CH:12]=[CH:13][C:14]=2CCC(OCC)=O)=[C:6]([CH3:31])[CH:5]=1)(=[O:3])[NH2:2].[Li+].[OH-].C[CH2:35][O:36]C(C)=O>CO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:11]2[CH:12]=[CH:13][C:14]([CH2:35][OH:36])=[C:10]2[C:7]2[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[CH:5][C:6]=2[CH3:31])=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CCc1ccn(-c2ccc(Cl)cc2OC)c1-c1ccc(C(N)=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cl)ccc1-n1ccc(CO)c1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.6 %

Procedure:
To a solution of ethyl 3-(2-(4-carbamoyl-2-methylphenyl)-1-(4-chloro-2-methoxyphenyl)-1H-pyrrol-3-yl)propanoate (580 mg, 1.3 mmol) in MeOH (5 mL) was added aqueous LiOH solution (2 mol/L, 5 mL), and the reaction mixture was stirred at room temperature for three hours. TLC (PE: EtOAc=1:2) showed that the starting material was consumed. The aqueous layer was washed with EtOAc (10 mL), and acidified by 0.5 N HCl to pH=2. The aqueous layer was extracted with a mixture of EtOAc and MeOH (v/v=10:1, 20 mL×3), and the combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography and preparative HPLC to afford the titled compound as an off-white solid (68.3 mg, yield: 12.6%).
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44](O)=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 2 h
Yield: 74 %

Procedure:
23 g (0.086 mol) of prolyl-arginine (2) are dissolved in 100 ml of water and to this solution under stirring there is added a solution of 53 g (0.1 mol) of pentafluorophenyl ester of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane. 2 hours thereafter the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide and stirred at room temperature (20° C.) for 48 hours. Then dimethylformamide is evaporated to 1/3 of its volume and the solution is poured into one liter of ether. After 2 hours the resulting residue is filtered-off, washed on the filter with ether and dried in vacuum. After reprecipitation from a mixture ethylacetate-ethanol-ether (3:1:30) there are obtained 47 g (74%) of the product (3) having the following properties: M.p. 90° C., [α]D20 -39.0° (c 1.0; 10% CH3COOH); Rf =0.51 (A, "Eastman"), 0.82 (B, "Eastman"); EHis =0.34 (pH=2.4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([N:27]=[C:28]=[O:29])=[O:26].CCCCCC>C1(C)C=CC=CC=1>[F:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:24]=1[C:25]([NH:27][C:28]([NH:7][C:6]1[CH:8]=[C:2]([Cl:1])[C:3]([S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[Cl:21])=[CH:4][C:5]=1[F:9])=[O:29])=[O:26]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F

Procedure:
0.21 Gram of 5-chloro-2-fluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline was dissolved in 6 ml of toluene, and to this solution was added dropwise a solution of 0.11 g of 2,6-difluorobenzoyl isocyanate in 4 ml of toluene with ice-cooling and stirring. After completion of addition, the reaction solution was stirred overnight at room temperature. Thereafter, 6 ml of n-hexane was added, the precipitated crystals were filtered off and dried to obtain 0.20 g of N-(2,6-difluorobenzoyl)-N'-[5-chloro-2-fluoro-4-{2-chloro-4-(trifluoromethyl)phenylthio}phenyl]urea as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:13]1[S:21][C:20]2[C:19]([C:22]#[N:23])=[CH:18][N:17]=[C:16]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[C:15]=2[CH:14]=1>[Cu]I.O1CCOCC1>[N:1]1([C:13]2[S:21][C:20]3[C:19]([C:22]#[N:23])=[CH:18][N:17]=[C:16]([NH:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:15]=3[CH:14]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(I)cc23)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CNc2ncc(C#N)c3sc(-n4ccnc4)cc23)cc1
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To an oven dried Schlenk tube was added CuI (0.0057 g, 0.030 mmol), imidazole (0.097 g, 1.42 mmol), Cs2CO3 (0.405 g, 1.25 mmol). The tube was evacuated and purged to argon 5 times. Under argon, the tube was supplied with 2-iodo-4-(4-methoxybenzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 27 (0.25 g, 0.59 mmol) trans-1,2-cyclohexanediamine (0.014 mL, 0.12 mmol), and dioxane (1 mL). The reaction contents were briefly evacuated and the vessel purged to argon 3 times, then sealed and brought to 110° C. with stirring. After 24 h, 20 mL of CH2Cl2 were added to the cooled reaction. The mixture was filtered and solvents removed in vacuo. Silica gel column chromatography (eluent: 3% MeOH in CH2Cl2) provided 0.12 g of 37. 1H NMR (400 MHz, d6-DMSO). δ 8.57 (t, J=6 Hz, 1H), 8.47 (s, 1H), 8.23 (bs, 1H), 8.00 (s, 1H), 7.71 (bs, 1H), 7.31 (d, J=8 Hz, 2H), 7.21 (bs, 1H), 6.91 (d, J=8 Hz, 2H), 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:24][O:25][C:26]1(OC)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:26]3([O:25][CH3:24])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Reactant: COC1(OC)CCCCCC1
Product: COC1(OCCOCn2c(C)nc(C(C)C)c2Sc2cc(Cl)cc(Cl)c2)CCCCCC1
Yield: 59.5 %

Procedure:
5-(3,5-Dichlorophenylthio)-4-isopropyl-1-[2-hydroxyethoxymethyl]-2-methyl-1H-imidazole (8) (450 mg, 1.20 mmol) prepared in accordance with the method as described in WO 96/10019 was converted to the acetal with 1,1-dimethoxycycloheptane (1.90 g, 12.0 mmol) in the same manner as the example 1 to give the compound 9 (358 mg, 59%) as oil. Rf 0.57 (Al2O3 60, Type E, 2:1 hexane -EtOAc).
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]>>[CH2:4]([OH:3])[C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reaction time: 0.25 h

Procedure:
The fermentation medium is a pineapple peel hydrolysate pretreated by dilute acid. For pretreatment, the concentration of the dilute acid is 2%, the operation temperature is 130° C., and the reaction time is 15 min at this temperature. In this case, NaOH is added to adjust the pH value of the hydrolysate to be 6.0, the fermentation temperature is controlled at 30° C., the agitation of the incubator is maintained at 100 rpm, and the ratio of the inocula size of the culture and the volume of the fermentation medium is 1:6 (v/v). The content of xylose in the pineapple peel hydrolysate is 19.8 g/L, and after 65 hr of fermentation, the amount of xylitol produced is 7.5 g/L, and the overall utilization of xylose is up to 97.4%, as shown in Table 4.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1)([O-])=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[OH-].[Na+].[H][H]>[C].[Pd].CO>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Solvent: CO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A 500 ml. electromagnetically stirred autoclave was charged with 10 g of 1-nitroanthraquinone having a purity of 91.5% and containing 7.0% of 1,5-dinitroanthraquinone, 0.5% of 1,8-dinitroanthroquinone and 1.0% of anthraquinone as impurities, 120 g of a 3% aqueous solution of sodium hydroxide (0.01 mole as sodium hydroxide), 80 g of methanol, and 200 mg of 5% palladium-carbon (2% based on the 1-nitroanthraquinone). The 1-nitroanthraquinone was hydrogenated at a temperature of 50° C. and a pressure of 40 to 30 Kg/cm2.G. In 60 minutes, 0.16 mole of hydrogen was absorbed, whereupon the reaction was stopped. The inside of the autoclave was purged with nitrogen, and 80 g of a 3% aqueous solution of sodium hydroxide was added. Methanol was distilled off at reduced pressure (60 to 70 mmHg abs.) and 40 to 50° C. Then, the reaction mixture was suction-filtered in a stream of nitrogen to remove the catalyst and the diaminoanthraquinones. The filtrate was oxidized with air at 20 to 30° C. for 2 hours with stirring to afford 7.65 g of 1-aminoanthraquinone having a purity of 98% in a yield of 93% of theory.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:16]=[C:17]([C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:26]([C:24]3[O:25][C:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:30])([F:13])[F:29])[CH:16]=4)=[CH:22][CH:23]=3)=[O:27])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(-c2cccc(C(F)(F)F)c2)o1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-[3-(trifluoromethyl)phenyl]-2-furoic acid (Aldrich) according to methods A and C; yield 44 mg, 0.11 mmol (51%): 1H NMR (300 MHz, methanol-d4) δ 1.99 (d, J=14 Hz, 2H), 2.22 (s, 1H), 2.34 (d, J=14 Hz, 2H), 2.52 (s, 2H), 3.58 (s, 2H), 3.69 (s, 4H), 4.43 (s, 1H), 7.12 (d, J=4 Hz, 1H), 7.34 (d, J=4 Hz, 1H), 7.64-7.69 (m, 2H), 8.11-8.17 (m, 1H), 8.24 (s, 1H); MS (DCI/NH3) m/z 391 (M+H)+; Anal. C21H21F3N2O2.HCl: C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:10]([C:12]2[C:13]3[C:18]([N:19]=[C:20]4[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]4)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])=[CH:5][CH:4]=1.C(OC(C)C)(C)C.[BrH:54]>>[BrH:54].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:10]([C:12]2[C:25]3[C:20]([N:19]=[C:18]4[C:13]=2[CH:14]=[CH:15][CH:16]=[CH:17]4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)OCc3ccccc3)cc2)cc1
Agent: Br
Solvent: CC(C)OC(C)C
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCC(=O)O)cc2)cc1

Procedure:
6.3 g of (3) in 30 ml of 33% HBr/glacial acetic acid are ##STR16## heated at 60° C. for 2 hours and, after cooling, 60 ml of diisopropyl ether are added, and the precipitate is filtered off with suction and dried in vacuo:
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-])(=[O:3])=[O:2].FC(F)(F)C(O)=O.CC[N:21](C(C)C)C(C)C>>[CH3:9][C:8]1[CH:7]=[CH:6][C:5]([S:1]([NH2:21])(=[O:3])=[O:2])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(N)(=O)=O)cc1

Procedure:
The azatetracyclic compounds that are the subject of the invention herein can be prepared in the following reaction Schemes I and II. In reaction Scheme I a method of producing azatetracyclic benzamides is shown and in reaction Scheme II a method for producing azatetracyclic amines is shown. ##STR10## Referring to reaction Scheme I, trans-1,2-di-carbomethoxy-4-methylene-cyclopentane is reacted with sodium hydroxide followed with acid to produce trans-4-methylene-1,2-cyclopentanedicarboxylic acid. The dicarboxylic acid is reacted with acetic anhydride to produce cis-tetrahydro-5-methylene-1H-cyclopenta c!furan-1,3(3aH)-dione. The ammonium salt 4 is prepared by reacting the anhydride 3 in dry methylene chloride with ammonia gas. The imide 5 is prepared from the ammonium salt by reacting the ammonium salt with acetyl chloride. The imide is reacted with lithium aluminum hydride and ditertiarybutyl dicarbonate to produce cis-1,1-dimethylethylhexahydro-5-methylenecyclopenta c!pyrrole-2(1H)carboxylate 6. The term BOC is used herein to refer to t-butyloxy carbonyl. The BOC-amine 6 is reacted with bis(p-toluenesulfonyl) sulfodiimide to produce the p-toluenesulfonamide 7. The term Tos is used herein to represent p-toluenesulfonyl. The p-toluenesulfonamide is reacted with thexyl borane to produce the endo alcohol 8. The endo alcohol is reacted with p-toluenesulfonyl chloride to produce the tosylate 9. The tosylate 9 is reacted with trifluoroacetic acid and treated with Hunig's base to provide the p-toluenesulfonamide tetracycle 10. The sulfonamide tetracycle 10 was reductively cleaved to produce the aminoazatetracycle 11. Coupling of the aminoazatetracycle 11 with benzoic acid derivative 12 under mixed anhydride conditions gave the protected benzamide tetracycle 13. Basic hydrolysis of the acetamide 13 gives the benzamide tetracycle 14 which upon treatment with HCl produces the hydrochloride salt of the benzamide tetracycle 15.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:8][C:7]1[C:2]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([O:13][CH3:12])[CH:19]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Br)c(Br)c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ncc([N+](=O)[O-])cc2Br)c1
Yield: 40 %

Procedure:
Obtained (1.15 g, yield 40%) following the procedure described in Intermediate 27, starting with 2,3-dibromo-5-nitropyridine (9.33 mmol, 2.63 g), 3-methoxyphenylboronic acid (9.33 mmol, 1.42 g).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][CH:3]=1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[C:12]#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:7][C:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[CH3:8])=[CH:3][S:4][CH:5]=1
Reactant: Brc1cscc1Br
Reactant: Cc1cc(C#N)ccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(C#N)ccc1-c1cscc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A mixture of 3,4-dibromothiophene (3 g, 12.5 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2 g, 12.5 mmol), Na2CO3 (2.7 g, 25 mmol), Pd(PPh3)4 (1.4 g, 1.25 mmol) in a mixture of toluene/EtOH/H2O (40 mL, 5:3:2) was stirred at 80° C. under nitrogen overnight. The reaction mixture was diluted with EtOAc (80 mL), and washed with water and brine. The organic phase was dried over Na2SO4, concentrated in vacuo, and purified on silica gel column (PE: EtOAc=30:1) to afford 4-(4-bromothiophen-3-yl)-3-methylbenzonitrile (Scheme III, 13, X1=4-cyano-2-methylphenyl) (2.4 g, yield 68%) as yellow oil. 1H NMR (CD3OD 400 MHz): δ 7.56 (s, 1H), 7.50-7.48 (m, 2H), 7.31 (d, J=3.2 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 2.10 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=C)[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2].[O:26]=[O+][O-].CSC>ClCCl>[C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][CH:17]=[O:26])[C:12]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:11]=2[O:10][C@@H:9]1[CH3:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)Oc2ccc(F)cc21
Solvent: ClCCl
Solvent: CSC
Product: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of 2.20 g (6.28 mmol) ((6R,7S)-9-allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-carbamic acid tert-butyl ester in 120 ml dichloromethane was treated with ozone at −75° C. for 20 minutes. Methyl sulfide, 2.27 g (30.6 mmol), was added and the solution was stirred for 4.5 hours at room temperature. The solvent was distilled off under vacuum and the residue was extracted with ethylacetate/water to yield 2.05 g crude [(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-carbamic acid tert-butyl ester, MS m/e (%): 353.2 (M+H+, 11), 297.3 (60), 253.2 (100).
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.O.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl-].[NH4+]>C(O)C>[N:8]([C@@H:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[OH:6])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CC2OC2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Yield: 47.6 %

Procedure:
Cyclopentene oxide (5 g) was dissolved in ethanol (100 ml) and water (25 ml) and treated with sodium azide (3.9 g) and ammonium chloride (3.2 g) at reflux for 8 h. the mixture was cooled, excess solvent evaporated off at reduced pressure and extracted with ether. The organic solution was washed with water, dried (MgSO4) and evaporated. The residues were taken up in hexane, washed with water to remove any remaining ethanol, dried (MgSO4) and evaporated to give trans-1-azidocyclopentan-2-ol 3.6 g.
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2[CH:11]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH:1]1([N:6]2[CH:10]=[CH:9][CH:8]=[C:7]2/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccn1C1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cccn1C1CCCC1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A solution of 1-cyclopentyl-1H-pyrrole-2-carbaldehyde (10.4 g), malonic acid (20.0 g) and piperidine (1.71 mL) in pyridine (64.0 mL) was refluxed overnight. The obtained reaction mixture was allowed to be cooled to room temperature, and then slowly poured into ice and 6N hydrochloric acid (300 mL). The mixture was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.74 g).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH:17]([CH2:22]O)[C:18]([O:20][CH3:21])=[O:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([S:6]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:17](=[CH2:22])[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C(=O)OC)N(Cc1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 1.0 g (2.54 mmol) of methyl [(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate in 10 ml of pyridine cooled to -5° C. was added 0.432 ml (5.58 mmol) of methanesulfonyl chloride. The mixture was stirred at 0° C. for 48 hours. To the mixture was added ice and H2O and the mixture was extracted with ethyl acetate. The extract was washed with H2O, 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum and the residue triturated with ethyl acetate-hexane to give 0.90 g of a solid, 128-142° C. Anal. for C19H22N2O7S2 : Calc'd: C,50.2; H,4.9; N,6.2; S,14.1; Found: C,49.6; H,5.0; N,6.9; S,14.0; Mass spectrum (ES) 455.5 (M+H).