Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]2)=[O:10])=[C:4]([F:28])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:35]1(C(Cl)=O)[CH2:37][CH2:36]1>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:35]4[CH2:37][CH2:36]4)=[O:22])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([F:28])[CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)NNC(=O)Nc2ccc(Br)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-[2-(2-{[(4-bromo-2-fluorophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-pyrrolidinecarboxylate (3.59 mmol) in water (150 mL) was treated with potassium carbonate (17.96 mmol). The reaction was heated to reflux and was stirred overnight. A white solid had formed on the top of the aqueous solution. The reaction was allowed to cool to room temperature. Analysis by LCMS indicated complete consumption of the starting material and the mixture was concentrated to dryness in vacuo. The crude material was dissolved in dichloromethane (100 mL) and was treated with a solution of cyclopropanecarbonyl chloride (3.59 mmol) in dichloromethane (5 mL). After 30 min of stirring, LCMS analysis indicated that the intermediate amine had converted to a mixture of the desired product and a product that corresponded to bis-acylated product. The reaction solution was concentrated to dryness in vacuo and was dissolved in methanol (50 mL). The suspension was stirred at room temperature for 30 min. Analysis by LCMS indicated that the majority of the material now existed as a mixture of the desired product and the intermediate amine. Additional portions of cyclopropanecarbonyl chloride (3.59 mmol) were added to the reaction mixture twice (30 min apart). Analysis by LCMS indicated the complete conversion of the intermediate amine. The reaction mixture was diluted with water (100 mL) and acidified to pH˜4 using 1N aq HCl. The methanol was removed in vacuo, and the resulting aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aq sodium bicarbonate, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to dryness. The resulting solid was purified by flash chromatography (0-10% methanol/dichloromethane) to give the title compound as a white amorphous solid (850 mg, 58% yield). MS(ES)+ m/e 409/411 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:7]([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:33]=[C:32]3[O:34][CH2:35][C:29]4[C:30]5[C:31]3=[C:22]([CH2:23][O:24][C:25]=5[CH:26]=[C:27]([C:36]3[NH:40][C:39]([C@@H:41]5[CH2:45][C@H:44]([CH2:46][O:47][CH3:48])[CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][CH:37]=3)[CH:28]=4)[CH:21]=2)=[CH:18][N:19]=1)=[O:8])=[O:4].Cl>C(O)C>[CH3:48][O:47][CH2:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:39]2[NH:40][C:36]([C:27]3[CH:26]=[C:25]4[O:24][CH2:23][C:22]5[C:31]6[C:30]4=[C:29]([CH2:35][O:34][C:32]=6[CH:33]=[C:20]([C:17]4[NH:16][C:15]([C@@H:10]6[CH2:11][C@H:12]([CH3:14])[CH2:13][N:9]6[C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[N:19][CH:18]=4)[CH:21]=5)[CH:28]=3)=[CH:37][N:38]=2)[CH2:45]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: COC[C@@H]1CN[C@H](c2ncc(-c3cc4c5c(c3)OCc3cc(-c6cnc([C@@H]7C[C@H](C)CN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)cc(c3-5)OC4)[nH]2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4S)-tert-butyl 2-(5-(7-(2-((2S,4S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (245 mg) and 5 mL 1.25N HCl in ethanol was stirred at room temperature overnight, then at 60° C. for 1 hour, then concentrated to an orange solid as an HCl salt (180 mg) that was used without further purification.
Reaction SMILES: I[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[NH3:16]>C(Cl)(Cl)Cl>[NH2:16][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[C:10]([S:13][CH3:14])[CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:15]
Reactant: N
Reactant: CSc1ccc2c(c1)CCC(I)C(=O)N2
Solvent: ClC(Cl)Cl
Product: CSc1ccc2c(c1)CCC(N)C(=O)N2
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g of 3-iodo-7-methylthio-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one and 15 g of ammonia in 20 mL of chloroform was shaken in a bomb at 100° C. for 3 hours. The bomb was cooled, vented and the contents transferred to a separatory funnel. The mixture was washed with water, dried over magnesium sulfate, filtered and solvents removed under vacuum to give the product. 1H NMR (200 MHz,CDCl3): 1.90 (m,1H), 2.3-2.7 (m,2H), 2.45 (s,3H), 2.85 (m,1H), 3.39 (dd;8,11Hz;1H), 6.89 (d,8Hz,1H), 7.10 (m,2H), 8.3 (br s,1H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4](=O)[CH2:5][C:6]([O:8]CC)=[O:7].[N:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[N+:14]=[N-:15].[O-]CC.[Na+]>C(O)C>[CH2:23]([NH:22][C:20]([C:19]1[CH:25]=[CH:26][C:16]([N:13]2[C:4]([CH:3]=[C:2]([CH3:1])[CH3:12])=[C:5]([C:6]([OH:8])=[O:7])[N:15]=[N:14]2)=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)C=C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2C=C(C)C)cc1
Temperature: 50 °C
Reaction time: 10.5 h
Yield: 78.2 %

Procedure:
Ethyl 5-methyl-3-oxo-4-hexenoate (1.10 g, 6.56 mmol, 1.1 eq.) obtained in Example 95a) and 4-azido-N-ethylbenzamide (purity 90%, 1.23 g, 5.82 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (550 mg, 7.82 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min and at 50° C. for 10.5 hr. Ethanol was evaporated from the reaction mixture, and the residue was diluted with 2% aqueous sodium carbonate solution (40 ml) and washed with ethyl acetate (40 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (15 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (2:1, 50 ml), acidified (pH<3) with 6N hydrochloric acid and extracted three times with ethyl acetate (50 ml) and ethyl acetate-THF (3:1, 40 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with ethyl acetate and diethyl ether and dried to give the title compound as a grayish white powder (1.43 g, 4.55 mmol, 78.2%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[CH:11]=[N:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccncc1NCc1ccc(F)cc1
Temperature: 116 °C
Yield: 85.9 %

Procedure:
Methyl 3-bromoisonicotinate (220 mg, 1.02 mmol), 4-fluorobenzylamine (132 μL, 1.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.051 mmol), Xantphos (89 mg, 0.153 mmol), and cesium carbonate (500 mg, 1.53 mmol) were combined in dioxane (4 mL) under N2 in a sealed microwave tube. The reaction mixture was heated at 116° C. in a microwave for 1 h. The mixture was then filtered, washing with DCM, to remove solids. The solution was concentrated in vacuo and purified by silica gel chromatography (20-50% EtOAc/hexanes) to give 228 mg (88%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.93 (d, 1H, J=5.0 Hz), 7.79 (br s, 1H), 7.63 (d, 1H, J=5.0 Hz), 7.27-7.34 (m, 2H), 7.03 (t, 2H, J=8.6 Hz), 4.47 (d, 2H, J=5.6 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13FN2O2, 261. found 261.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Br:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C.CC(C)([O-])C.[K+].C(OC(C1N(C(OC(C)(C)C)=O)CC2N(C3C=CC=CC=3)C(Br)=CC=2C1=O)=O)C.FC(F)(F)C(O)=O>O1CCCC1.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[C:4]([OH:3])=[C:6]2[CH:10]=[C:9]([Br:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]2=[CH:18][N:19]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)cc(Br)n1-c1ccccc1)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CCOC(=O)C1C(=O)c2cc(Br)n(-c3ccccc3)c2CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncc2c(cc(Br)n2-c2ccccc2)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-bromo-2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (390 mg, 0.767 mmol) was dissolved in tetrahydrofuran (5 mL) and then cooled with an acetone-dry ice bath. Potassium tert-butoxide in tetrahydrofuran (0.92 mL, 0.92 mmol, 1 M solution) was added; after addition, the reaction was stirred for 10 min at −78° C. The cold bath was removed and the reaction was stirred for another 30 min at room temperature (RT) before quenching with saturated ammonium chloride aqueous solution and extracting with ethyl acetate. The organic phase was subsequently washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and filtered, concentrated to give an oil containing crude intermediate 2-bromo-4-oxo-1-phenyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridine-5,6-dicarboxylic acid 6-tert-butyl ester 5-ethyl ester, which was then dissolved in dichloromethane (20 mL) at room temperature. Trifluoroacetic acid (5 mL) was added; the resulting reaction mixture was stirred overnight at room temperature before all solvents were removed. The residue was dissolved in dichloromethane and basified with triethylamine, then air was bubbled through the solution for 5 hours. The solvent was then removed, and the residue was purified with column to give the title compound. 1H NMR (200 MHz, CDCl3): δ (ppm)=11.52 (s, 1H), 8.06 (s, 1H), 7.65-7.28 (m, 5H), 7.02 (s, 1H), 4.52 (q, 2H, J=7.4 Hz), 1.48 (t, 3H, J=7.4 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:32]1[C:40]2[C:35](=[CH:36][C:37](B(O)O)=[CH:38][CH:39]=2)[CH:34]=[CH:33]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:32]1[C:40]2[C:35](=[CH:36][C:37]([C:2]3[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:3]=3)=[CH:38][CH:39]=2)[CH:34]=[CH:33]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2[nH]ccc2c1
Yield: 80.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (0.058 mg; 0.05 mmol), N,N-diisopropylethylamine (0.345 mL; 2 mmol) and 1H-indol-5-ylboronic acid (0.201 g; 1.25 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.161 g (81%) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:29][CH:28]=[N:27][CH:26]=1)CCC>>[S:29]1[C:25]([C:2]2[S:6][C:5]([N:7]3[CH2:11][C@:10]4([CH:16]5[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]5)[CH2:12]4)[O:9][C:8]3=[O:19])=[CH:4][CH:3]=2)=[CH:26][N:27]=[CH:28]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)s1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2cncs2)s1

Procedure:
The title compound was prepared by a method analogous to that described in Example 5 from (R)-3′-(5-bromothiophen-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 5-(tri-n-butylstannyl)thiazole. The title compound (31 mg) was obtained as a pale solid, m/z 348 (MH+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[CH2:6][C:7](=[O:27])[C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1.O.CO>COC(C)(C)C>[CH3:3][O:4][C:5](=[O:28])[CH2:6][C@@H:7]([OH:27])[C@H:8]([N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH3:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1
Reactant: COC(=O)CC(=O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CO
Product: COC(=O)C[C@@H](O)[C@@H](Cc1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Sodium borohydride (0.227 g, 6 mmol) is added to the stirred solution of (R)-4-(tert-butoxy-carbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-oxo-pentanoic acid methyl ester (4) in tert-butyl methyl ether at 18-22° C. Water (3 ml) is added over a period of approx. 20 minutes at 18-22° C., then stirring is continued for approx. 15 minutes. Methanol (3 ml) is added over a period of approx. 30 minutes at 18-22° C., then stirring is continued for approx. 30 minutes to give a solution of (3R,4R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-3-hydroxy-pentanoic acid methyl ester (5), which is used as such in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:32]=[CH:33][CH:34]=1)[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]2([CH3:31])[S:21][C:20]([NH:22][C@H:23]3[CH2:28][CH:27]4[CH2:29][CH:24]3[CH2:25][CH2:26]4)=[N:19][C:18]2=[O:30])[CH2:12][CH2:11]1)=[O:9].C([O-])([O-])=O.[K+].[K+].Cl[CH2:42][CH2:43][O:44][CH2:45][CH2:46]Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:24]12[CH2:29][CH:27]([CH2:26][CH2:25]1)[CH2:28][C@@H:23]2[NH:22][C:20]1[S:21][C:17]([CH3:31])([CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8](=[O:9])[C:7]3[CH:32]=[CH:33][CH:34]=[C:5]([O:4][CH2:3][CH2:2][N:1]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[CH:6]=3)[CH2:11][CH2:12]2)[C:18](=[O:30])[N:19]=1
Reactant: CC1(CC2CCN(C(=O)c3cccc(OCCN)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O
Reactant: ClCCOCCCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(CC2CCN(C(=O)c3cccc(OCCN4CCOCC4)c3)CC2)SC(N[C@H]2CC3CCC2C3)=NC1=O

Procedure:
A mixture of 5-((1-(3-(2-aminoethoxy)benzoyl)piperidin-4-yl)methyl)-2-((2S)-bicyclo[2.2.1]heptan-2-ylamino)-5-methylthiazol-4(5H)-one (100 mg, 0.207 mmol), K2CO3 (114 mg, 0.83 mmol), KI (Aldrich, 6.9 mg, 0.041 mmol), 1-chloro-2-(2-chloroethoxy)ethane (Aldrich, 38 mg, 0.27 mmol) in CH2Cl2 (3 mL) was heated at reflux for 10 d. Saturated NaHCO3 (50 mL) was added, and the crude product was extracted with CH2Cl2 (4×60 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, CH2Cl2 with 0-4% MeOH) afforded the title compound as a colorless thin film (10 mg). MS (ESI, pos. ion) m/z: 555 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.2 %

Procedure:
tert-Butyl 3-(4-nitrophenoxy)pyrrolidine-1-carboxylate (9.73 mmol, 3 g) was dissolved in dichloromethane (2.5 mL). Trifluoroacetic acid (1 mL) was added and the reaction mixture stirred at room temperature for 30 minutes. The reaction was purified by SCX chromatography to give the title compound (2.11 g). MS (ESI) m/z 209.0 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=4[CH3:12])=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: Cc1nccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c1C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
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: C1COCCO1
Product: Cc1nccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)c1C

Procedure:
To a solution of intermediate 24 (1.769 mmol) in 1,4-dioxane (7 ml) and a saturated solution of NaHCO3 (7 ml) was added intermediate 5 (0.38 g, 1.504 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.2 mg, 0.176 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was diluted with EtOAc, and then it was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 5% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 11 precipitated from diisopropylether (0.190 g, 32%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:20]([O-])=O)[C:10]([F:19])=[C:11]([F:18])[C:12]=3[O:14][CH:15]([F:17])[F:16])[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.[Pd]>[NH2:20][C:9]1[C:10]([F:19])=[C:11]([F:18])[C:12]([O:14][CH:15]([F:16])[F:17])=[C:13]2[C:8]=1[C:7](=[O:23])[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c(N)c2c1=O
Yield: 64.3 %

Procedure:
3.0 g (0.0074 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-5-nitro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=F] [prepared as described in step (e) above] were dissolved in 800 ml of acetic acid by heating. 0.75 g of 5% w/w palladium-on-carbon was then added to the solution, and the mixture was stirred at 70°-80° C. for 3 hours under a current of hydrogen. At the end of this time, the reaction mixture was filtered, and the filtrate was concentrated by evaporation under reduced pressure. The residue was washed with diethyl ether to give 1.78 g of ethyl 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate as a colorless powder, melting at 295°-296° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C[O-].[Na+].Br[CH2:16][C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18].Cl>CO>[C:19]1([C:17]([C:16]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1]=2[OH:10])=[O:18])[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CBr)c1cccs1
Reactant: COC(=O)c1ccccc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(c1cccs1)c1sc2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl thiosalicylate (2.0 g) was added dropwise to a stirred solution of sodium methoxide (1.28 g) in methanol (50 ml) at ambient temperature. The mixture was stirred at ambient temperature for 15 minutes and then a solution of 2-(bromoacetyl)thiophene (2.26 g) in methanol (50 ml) was added dropwise. After the addition was complete the mixture was boiled under reflux for 3 hours, then cooled, and 10% aqueous hydrochloric acid (100 ml) was added. A solid was collected by filtration, dried and then recrystallized from ethanol to give 2-thenoylbenzo[b]thiophene-3-ol.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:11](=[O:26])[C:10]=2[C:9]=1[CH3:27])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C>>[CH3:27][C:9]1[C:10]2[C:11](=[O:26])[N:12]([CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[CH2:13][CH2:14][CH2:15][C:16]=2[NH:17][C:8]=1[CH:6]=[O:5]
Reactant: Cc1c(C(=O)OC(C)(C)C)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 40.9 %

Procedure:
3-Methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 10b (725 mg, 1.92 mmol) was dissolved in trifluoroacetic acid (2.6 ml, 34.2 mmol) in an ice-water bath under stirring. The reaction mixture was stirred at 40° C. in a water bath for 5 minutes, added with triethoxy methane (0.42 ml, 2.5 mmol) in one portion at −5° C. in an ice-water bath, and stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm up to room temperature, became brown and stirred for another 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with a little water, adjusted to pH 8 with dilute sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (50 ml×3). The combined organic extracts were concentrated under reduced pressure to obtain henna solid. The solid was purified by silica gel column chromatography to obtain the title compound 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c (240 mg, yield 40%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH+:8]([O-:35])[C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:24][CH3:25])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccccc12
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH+]([O-])c2c(Cl)cncc2Cl)c2c1oc1ccccc12
Yield: 71.8 %

Procedure:
A suspension of N-(3,5-dichloropyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (200 mg, 0.518 mmol) (example 1) and m-chloroperbenzoic acid (50-55%) (880 mg, 2.5 mmol) in chloroform (10 ml) was refluxed for 2 h. The reaction was cooled and washed with saturated sodium bicarbonate and water. The organic solvent was distilled of in vacuo and the residue was purified by column chromatography using 20% acetone-chloroform as the eluent to give 150 mg of N-(3,5-dichloropyrid-4-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 265-270° C.