Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CO>[CH3:21][O:22][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 60 °C
Yield: 71.9 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of methanol was stirred while heating at 60° C. for two hours. The reaction mixture was concentrated under reduced pressure. Water was added thereto, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.21 g of 2-(3-methoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 37”).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][OH:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[C:1]([N:8]1[CH2:11][CH2:10][C@@H:9]1[CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Yield: 37.5 %

Procedure:
A mixture of (2R)-1-Boc-2-(hydroxymethyl)azetidine (1.5 g, 8.0 mmol; see Tetrahedron Asym. 1998, 9, 2791) and triethylamine (3.5 g, 35 mmol; Spectrum) in dry THF (20 mL) was cooled to 0° C., and methanesulfonyl chloride (0.75 mL, 9.7 mmol; Aldrich) was added slowly with stirring. The reaction mixture was allowed to warm to room temperature and stir for 1 hour, then the solid was removed by filtration and the organic phase was concentrated. The residue was dissolved in dichloromethane (40 mL), washed with water (20 mL), and then concentrated to afford the title compound (800 mg. 3.0 mmol; 38% yield). MS (DCI/NH3): 266 (M+1)+, 283 (M+18)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:17][OH:18])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:17][OH:18])[CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Nc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)ccc1Nc1ccccc1

Procedure:
((3-Nitro-4-(phenylamino)phenyl)methanol (2.141 g, 0.008766 mol) was dissolved in methanol (40 mL) under a nitrogen atmosphere and 10% palladium on carbon (1:9, palladium:carbon black, 0.500 g) was added. The mixture was stirred under one atmosphere of hydrogen for 3 hours. The reaction was filtered, concentrated and the residue dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried over magnesium sulfate and concentrated to give a crude product that was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22]Cl>C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[Br:1]
Reactant: ClCCCCOCCl
Reactant: Clc1nc(Br)[nH]c1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClCCCCOCn1c(Br)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.6 %

Procedure:
To a mixture of 1.08 g of 2-bromo-4,5-dichloroimidazole, 0.51 g of triethylamine and about 30 ml of toluene was added dropwise 0.79 g of 4-chlorobutoxymethyl chloride at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. The deposited crystal was filtered off and washed with about 10 ml of toluene. The filtrate thus obtained was concentrated under reduced pressure, and the residual oily product was purified by column chromatography on silica gel to obtain 0.60 g of 1-(4-chlorobutoxymethyl)-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:21][NH:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:28]3[CH:29]=[CH:30][C:25]([C:23]([NH:22][CH3:21])=[O:24])=[CH:26][CH:27]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Temperature: 90 °C
Yield: 68 %

Procedure:
2,4-Dichloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (4-(methylcarbamoyl)phenyl)boronic acid (1.2 equiv), sodium carbonate (3 equiv) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane (0.1 equiv) were combined in a 5:1 mixture of 1,4-dioxane and water (0.27 M). The mixture was heated to 90° C. for 3 h. The crude product was purified on silica gel (0-100% ethyl acetate in hexane) to give the title compound (68% yield) an orange solid. MS (ESI) m/z 451.2 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.CN(C=O)C.[H-].[Na+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:27]=1[CH3:42].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.C(=O)(O)[O-].[Na+]>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]=[C:28]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:27]=2[CH3:42])[CH2:3]1
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.2 h

Procedure:
Under a N2 atmosphere, 3,3-dimethyl-6-morpholinoindoline (0.100 g, 0.430 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol). Sodium hydride (0.0227 g, 0.947 mmol) was added and the reaction was stirred at rt for 12 minutes. The reaction was treated with 4-chloro-3-methyl-2-phenylquinoline (0.218 g, 0.861 mmol) and placed in a preheated oil bath at 140° C. for 2 h. LCMS showed no starting quinoline remained. The reaction was diluted with EtOAc and 2% sodium bicarbonate. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 20% to 50% EtOAc in hexane, and then purified again by preparative reverse phase chromatography to give 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-3-methyl-2-phenylquinoline. Mass Spectrum (ESI) m/e=450.2 (M+1)
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>O.CC(O)C>[CH:12]1([NH:20][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(NC2CCCCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 3.12 g (0.020 mol) of 4-fluoro-3-nitroaniline, 2.57 g (0.022 mol) of cyclooctylamine and 1.7 g (0.020 mol) of sodium hydrogen carbonate was refluxed for 3 hours in 5 ml of water and 5 ml of 2-propanol. After cooling to room temperature, the residues were filtered off and the filtrate was extracted with chloroform. The solvent was removed in vacuo and the residue was recrystallized from 20% hydrochloric acid. A yellow-green solid melting at 161° C. was obtained.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)C>[C:25]1([S:31]([N:13]2[CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][CH2:11][C:12]2=[O:14])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1CCC(OCc2ccccc2)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: O=C1CCC(OCc2ccccc2)N1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
At ambient temperature and under an inert atmosphere, 4.40 g of 5-benzyloxypyrrolidin-2-one is added to a solution of 4.64 g of sodium bis(trimethylsilyl) amide in 350 cm3 of anhydrous ethyl ether. The mixture is agitated for 30 minutes, then cooled to 0° C., and a solution of 4.06 g of benzenesulphonyl chloride in 30 cm3 of anhydrous ether is added, while maintaining the temperature at 0° C. The temperature is allowed to return to the ambient, then, after filtering and evaporating the solvent under reduced pressure, the residue is chromatographed on silica, eluting with a mixture of ethyl acetate and n-hexane (1-2). After re-crystallizing from a mixture of benzene and n-hexane (1-3), 2.25 g of the expected product is obtained, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([C:15](=[O:18])[NH:16][CH3:17])[C:13]=1[I:14])[C:8](N)=[O:9])=[O:4].N([O-])=[O:22].[Na+].O>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([C:15](=[O:18])[NH:16][CH3:17])[C:13]=1[I:14])[C:8]([OH:22])=[O:9])=[O:4]
Reactant: O=N[O-]
Reactant: CNC(=O)c1c(I)c(C(N)=O)c(I)c(C(=O)NC)c1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CNC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)NC)c1I
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
12.3 g of 3,5-bis(N-methylcarbamoyl)-2,4,6-triiodobenzoic acid amide is suspended in 80 ml of glacial acetic acid. Under agitation, a mixture of 1.66 g of sodium nitrite in 12 ml of concentrated sulfuric acid (prepared under ice cooling) is added in small portions at room temperature; during this step the temperature rises from 24° C. to 42° C. The mixture is then stirred for 3 hours at room temperature, 30 minutes at 50° C., and 90 minutes at 70° C. After agitating overnight at room temperature, the reaction mixture is stirred into 400 ml of water. The precipitate is vacuum-filtered after 4 hours, washed with water, and dried at 50° C. under vacuum. The crude product (11.9 g) is dissolved in 110 ml of water and 12 ml of 2 N sodium hydroxide solution, adjusted to pH 6.5 with 2 N acetic acid, and stirred for 30 minutes with 1 g of carbon. After the carbon has been removed by vacuum-filtering, the solution is precipitated with 16 ml of 2 N hydrochloric acid. After vacuum-filtering and drying at 50° C. under vacuum, 10.7 g (87% of theory) of 3,5-bis(N-methylcarbamoyl)-2,4,6-triiodobenzoic acid is obtained, mp>300° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]1.O.NN>>[NH2:3][O:12][C@H:13]1[CH2:17][CH2:16][C@H:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A mixture of tert-butyl {trans-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]cyclopentyl}methylcarbamate 115 (0.19 g, 0.53 mmol) was treated with hydrazine hydrate (0.03 g, 0.60 mmol). The mixture was stirred at room temperature for 2 hours. The solid was filtered off and the filtrate was concentrated in vacuo. The residue was diluted with DCM, and the insoluble solid was filtered off. The filtrate was concentrated in vacuo to give an oil which was purified by chromatography to give 116 (0.09 g, 44% over 2 steps) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[C:16]([NH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.F[C:34](F)(F)[C:35]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:34]([O:24][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[CH:29][CH:30]=[C:13]([NH:12][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:4]=3)(=[O:10])=[O:11])[CH:14]=2)=[CH:20][CH:21]=1)[CH3:35]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1

Procedure:
4-[3-(3-Trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=463.3 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 3-trifluoromethyl-benzenesulfonyl chloride and yielded 4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.Cl.[CH3:38][NH:39][O:40][CH3:41]>CN(C)C=O>[Cl:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:31]3[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=3)([C:21]3[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=[C:2]([N:39]([O:40][CH3:41])[CH3:38])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CNOC
Agent: Cl
Solvent: CN(C)C=O
Product: CON(C)c1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 100 °C

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl) [6-(trifluoromethyl)pyridin-3-yl]methanol (200 mg, 0.378 mmol, Example 66), N,O-dimethylhydroxylamine hydrochloride (376 mg, 3.78 mmol), and dimethylformamide (2 mL) were combined in a reaction tube which was then sealed and heated to 100° C. for 48 hours. Analysis shows desired product, but also the presence of starting material. Additional N,O-dimethylhydroxylamine hydrochloride (190 mg, 0.195 mmol) was added and the contents were heated for an additional 24 hours. The contents were then cooled, transferred to a separatory funnel, diluted with EtOAc and extracted with a saturated, aqueous NH4Cl solution, followed by deionized water (4×). The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C28H23ClF3N5O2, 553.1; m/z found, 554.2 [M+H]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.79 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.02 (dd, J=8.2, 1.9 Hz, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.75-7.68 (m, 2H), 7.48 (t, J=7.4 Hz, 2H), 7.40 (ddd, J=7.4, 3.9, 1.3 Hz, 1H), 7.32-7.24 (m, 2H), 6.35 (s, 1H), 3.48 (s, 3H), 3.07 (s, 3H), 2.77 (s, 3H).
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[O:8][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[N:14]2)=[CH:10][CH:11]=1)=O.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[N+:18]([C:15]1[CH:16]=[CH:17][N:13]([CH2:12][C:9]2[O:8][C:7]([CH2:5][OH:4])=[CH:11][CH:10]=2)[N:14]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccn(Cc2ccc(CO)o2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-carboxylic acid methyl ester (25.40 g, 61.31 mmol) in THF (154.0 mL) was treated dropwise, at −78° C. with DiBAL (165.0 mL of a 1.7M solution in toluene, 245.22 mmol). The reaction mixture was stirred at −78° C. for 1 h and then allowed to warm up to rt. Sat. aq. Rochelle's salt (600 mL) was added and the reaction mixture was stirred at rt for 2 h. The aq. layer was extracted with EA (2×500 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (40:60 hept-EA) gave the title compound. TLC: rf (40:60 hept-EA)=0.28. LC-MS-conditions 02: tR=0.75 min. 1H NMR (400 MHz, CDCl3) δ 2.05 (s, 1H), 4.60 (s, 2H), 5.36 (s, 2H), 6.31 (d, J=3.0 Hz, 1H), 6.46 (d, J=3.0 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 7.51 (d, J=2.5 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[C:12]([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[C:11]([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[C:12]2([CH:17]=[CH:18][C:19](=[O:21])[CH3:20])[O:31][C:11]2([CH3:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)C=CC1=C(C)CC(O[Si](C)(C)C(C)(C)C)CC1(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)C=CC12OC1(C)CC(O[Si](C)(C)C(C)(C)C)CC2(C)C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To 20 ml of an anhydrous chloroform solution containing 1.0 g of 4-[4-(t-butyldimethylsilyl)oxy-2,6,6-trimethylcyclohex-1-enyl]but-3-en-2-one was added 616 mg of m-chloroperbenzoic acid under ice-cooling, followed by stirring at the same temperature for 8 hours. After completion of the reaction, the reaction mixture was washed several times with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and then, with water, and dried over anhydrous magnesium sulfate. The solvent, etc. were removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 644 mg (yield: 70%) of 4-[4-(t-butyldimethylsilyl)oxy-1,2-epoxy-2,6,6-trimethylcyclohexyl]but-3-en-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][S:11]([O:13][Na])=[O:12]>C(O)C>[CH3:10][S:11]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:13])=[O:12]
Reactant: BrCc1ccc(Br)cc1
Reactant: CS(=O)O[Na]
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(Br)cc1

Procedure:
p-Bromobenzyl bromide (500 mg, 2 mmol) was refluxed with MeSO2Na (306 mg, 3 mmol) in Ethanol for 1 hour. The reaction was cooled, concentrated and purified by flash column (50% acetone/hexanes) to give the desired product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[C:14](Br)(Br)[C:13]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(n1)C(Br)(Br)C(=O)N2CCCOCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc2c(n1)CC(=O)N2CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under argon and at room temperature, 1.10 g (16.8 mmol) of powdered zinc are added in portions to 789 mg (1.68 mmol) of the compound obtained in Step B dissolved in 15 ml of acetic acid. After 5 hours' stirring at room temperature, the reaction mixture is filtered using a Büchner funnel, evaporated to dryness and then coevaporated in the presence of toluene. The residue, which is taken up in ethyl acetate, is washed several times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated and then purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 1:1) to yield the title compound in the form of an orange oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N#N.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1F>CN(C=O)C.O>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: -6 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled slurry of NaH (475 mg, 11.8 mmol, 60%) in dry DMF (10 mL) was added CH2(COOEt)2 dropwise under an N2 atmosphere. After 20 minutes, 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.6 mmol) was added dropwise over 10 minutes and the mixture was stirred at −6° C. overnight. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified chromatography to give diethyl (2,5-difluoro-4-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.87˜7.84 (m, 1H), 7.54˜7.58 (m, 1H), 4.98 (s, 1H), 4.23˜4.27 (m, 4H), 1.28 (t, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[N:24]=[CH:23][C:22]3[C:17](=[C:18]([F:29])[CH:19]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=3)[C:16]2=[O:30])=[N:8][CH:9]=[CH:10][C:11]=1B(O)O)(=[O:3])[CH3:2].Cl.[NH2:32][CH2:33][CH2:34][O:35][C:36]1[N:41]=[C:40]([NH:42][C:43]2[C:44](=[O:51])[N:45]([CH3:50])[CH:46]=[C:47](Br)[CH:48]=2)[CH:39]=[CH:38][CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:15]2[N:24]=[CH:23][C:22]3[C:17](=[C:18]([F:29])[CH:19]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=3)[C:16]2=[O:30])=[N:8][CH:9]=[CH:10][C:11]=1[C:47]1[CH:48]=[C:43]([NH:42][C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([O:35][CH2:34][CH2:33][NH:32][C:5](=[O:4])[CH:6]=[CH2:11])[N:41]=2)[C:44](=[O:51])[N:45]([CH3:50])[CH:46]=1)(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: CC#N
Product: C=CC(=O)NCCOc1cccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
A mixture of 104c (256 mg, 0.62 mmol), 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103b (120 mg, 0.31 mmol), Pd(dppf)Cl2 (47 mg, 0.062 mmol) and K3PO4 (131 mg, 0.62 mmol) in acetonitrile (2 mL) and water (0.2 mL) was stirred at 90° C. for 3 h under N2. The mixture was filtered and the filtrate was concentrated. The residue was washed with petroleum ether, PE to give 104d (160 mg) as brown solid. This material was used for the next step directly.