Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@:11]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:29][C:28]=3[CH2:27]2)=[O:25])[CH2:15][C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:8][CH2:9][CH2:10][C@@:11]1([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[CH:31][C:30]([C:36]([F:39])([F:38])[F:37])=[CH:29][C:28]=3[CH2:27]2)=[O:25])[CH2:15][C@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO[Si](C)(C)C(C)(C)C)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CCO)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reaction time: 1 h

Procedure:
To a solution of the product of Step C (3.52 g, 6.18 mmol, 1 eq) in THF (50 mL) at rt was added TBAF in THF (12.36 mL of a 1 M solution, 12.36 mmol, 2 eq). After 1 hr, water was added, the solution extracted with DCM, the organics combined, dried over MgSO4, and concentrated. Purification by chromatography (80 g column) eluting with 2 to 6% methanol/DCM with ammonia afforded the title compound of Step D. 1H NMR (CHLOROFORM-d) δ: 8.71 (s, 1H), 7.70 (s, 1H), 6.28 (dd, J=5.9, 2.0 Hz, 1H), 5.78 (dd, J=5.9, 2.0 Hz, 1H), 4.70-4.95 (m, 4H), 3.99-4.10 (m, 1H), 3.85-3.96 (m, 1H), 3.68 (br. s., 2H), 3.09-3.18 (m, 2H), 2.65 (dd, J=12.9, 7.4 Hz, 1H), 1.99-2.21 (m, 3H), 1.82-1.93 (m, 1H), 1.38-1.49 (m, 9H). Calculated for C22H28F3N3O4: 456.2 (M+1). found: 456.2.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH:10]=[N+:11]=[N-:12])([CH3:9])[CH3:8].[CH:13](=[C:20](C#C)[C:21]#[N:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(OCC)(=O)C>[C:14]1([C:13]2[C:20]([C:21]#[N:22])=[N:12][NH:11][C:10]=2[Si:7]([CH3:9])([CH3:8])[CH3:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CC(C#N)=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1[nH]nc(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
n-Butyl lithium (2.7 M solution in heptane) (3.3 ml, 9 mmol) was added drop wise to a stirred solution of trimethylsilyl diazomethane (2 M solution in diethyl ether) (4.5 ml, 9 mmol) in anhydrous THF (10 ml) at −78° C. under a nitrogen atmosphere, then stirred for a further 30 minutes. To this was added drop wise a solution of 2-benzylidene-but-3-yne nitrile (920 mg; 6 mmol) in anhydrous THF (5 ml), the mixture stirred for 30 minutes at −78° C. then gradually allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml) then washed with saturated ammonium chloride solution followed by brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1:8 then 1:4 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 1.0 g of 4-phenyl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+]>C(OCC)C.O>[N:1]([C:3]1[S:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1)=[N+:2]=[N-:15]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1sc(NN)nc1C
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To a cooled (0° C.) suspension of ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate (3.00 g, 14.92 mmol) in a mixture of diethyl ether (15 mL) and water (15 mL) was added hydrochloric acid (2.72 mL) dropwise. The reaction mixture was stirred for 10 minutes, and a solution of sodium nitrite (1.21 g, 17.46 mmol) in water (2 mL) was added. The mixture was stirred for 2 hours at 0° C. and extracted with diethyl ether. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexanes, 1:4) to afford the title compound as a yellowish solid (1.49 g, 47%): 1H NMR (300 MHz, CDCl3) δ 4.29 (q, J=6.0 Hz, 2H), 2.62 (s, 3H), 1.33 (t, J=6.0 Hz, 3H); MS (ES+) m/z 213.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.C[Si]([Br:26])(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Br:26])=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CO)cc2)c(Cl)c1
Reactant: C[Si](C)(C)Br
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CBr)cc2)c(Cl)c1

Procedure:
To a solution of {4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}methanol from II.1, step 3 (1 eq.) in CH2Cl2 (0.1M) at room temperature was added a solution of trimethyl silyl bromide (1.05 eq.) in CH2Cl2 (1.0M). The final mixture was stirred 1 h at room temperature and then concentrated in vacuo. To the resulting suspension was added silica gel and the mixture was evaporated in vacuo. Purification by column chromatography on silica gel, eluting with Hex/Et2O 5%, afforded the desired compound as a crystalline white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)cc2C1=O

Procedure:
A solution of 3.03 g (10 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylate and 0.44 g (11 mmol) of sodium hydroxide in 20 ml of ethanol and 10 ml of water is heated to boiling under reflux for 30 minutes. Subsequently, the mixture is treated with 11 ml of 1 N hydrochloric acid and concentrated to half of the volume. The precipitated crystals are filtered off under suction and dried. There is obtained 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 279°.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[O:16]=[C:17]1[C:22]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][NH:20][C:19]([C:31]([OH:33])=O)=[CH:18]1.[C:34]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1)(=[O:37])[NH:35][NH2:36].O.ON1C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:34]([NH:35][NH:36][C:31]([C:19]2[NH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17](=[O:16])[CH:18]=2)=[O:33])=[O:37])=[CH:45][CH:44]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: COc1ccc(COC(=O)NN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)NNC(=O)c2cc(=O)c(OCc3ccccc3)c[nH]2)cc1
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A solution of 4.54 g (0.022 moles) dicyclohexylcarbodiimide in 25 ml dry of dimethylformamide was added to a stirred suspension of 4.90 g (0.020 moles) of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 4.50 g (0.022 moles) of 4-methoxybenzyl carbazate, 0.12 g (1.0 mmol) of 4-dimethylamino-pyridine and 0.155 g (1.0 mmol) of 1-hydroxybenzotriazole hydrate in 25 ml of dry dimethylformamide at room temperature and stirring was continued overnight. The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue solidified by stirring with ether and aqueous sodium bicarbonate and the solid was collected, washed with water and finally dried in vacuo. The crude material (8.14 g) was extracted in a soxhlet-apparatus with 800 ml CHCl3 (7 hours). 5.70 g (67%) of pure 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[[(4-methoxyphenyl)methoxy]carbonyl]hydrazide crystallized directly from the cold CHCl3 -extract, and an additional impure amount (1.5 g, 18%) of the title compound could be obtained by evaporation of the CHCl3 -solution in vacuo; melting point 174.5°-178° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[S:6][CH:7]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.CO>CN(C)C=O>[Si:13]([O:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[S:6][CH:7]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: OCc1csc(N2CC(O)C2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1csc(N2CC(O)C2)n1
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a solution of 1-(4-hydroxymethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (226.5 mg, 1.22 mmol) (obtained as described in Reference Example 12(1)) in dimethylformamide (11.5 ml) were added t-butyldimethylsilyl chloride (220 mg, 1.46 mmol) and imidazole (120 mg, 1.76 mmol) in an ice bath. The reaction mixture was then brought to room temperature in 10 minutes, and stirred for 5 hours. After checking the completion of the reaction, methanol (2 ml) was added thereto in an ice bath, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1) as the eluant to afford 1-(4-t-butyldimethylsilyloxymethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (300.4 mg, yield 82%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To a stirred solution of 2-nitrophenol (1.5 g, 0.0101 mole) in DMF (15 mL) was added cesium carbonate (16.4 g, 0.0505 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 0.0101 mole). The reaction mixture was heated at 80° C. overnight. The mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (20% ethyl acetate in hexane) to afford 1.5 g (47%) of 4-(2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 323.15 (M+1)+, 98%,
Reaction SMILES: ClC(OCC(C)C)=O.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([NH:16][C:17]1([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O.C(N(CC)CC)C>O1CCCC1>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[O:25][C:23](=[O:24])[C:17]2([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[N:16]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(c2ccco2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
6.0 g (44 mmol) of isobutyl chloroformate was added dropwise to a solution of 10 g (42 mmol) of 1-[(2-furanylcarbonyl)amino]cyclohexanecarboxylic acid obtained in Reference Example 14 and 6.1 ml (44 mmol) of triethylamine in tetrahydrofuran (80 ml), and the mixture was stirred at room temperature for 1 hour. The precipitated crystal was removed by filtration, and the filtrate was concentrated. The obtained crystal was washed with water to obtain 8.95 g (97%) of the title compound.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12>>[CH3:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:22]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[CH2:25][N:19]3[CH:18]=[CH:17][CH:16]=[C:20]3[CH2:21]2)=[O:12])=[CH:9][CH:8]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CCCCCOc1ccc(C(=O)Cl)cc1
Product: CCCCCOc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
As described for Example 343 4-(n-pentyloxy)benzoyl chloride is reacted with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine to the desired product as a solid: mass spectrum(CI), 375(MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:32][C:33]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH2:5][CH2:6][N:7]([C:16]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:35](=[O:36])[C:34]4[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:33]=4[CH3:32])=[CH:21][CH:22]=3)=[O:24])[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(N)cc1)c1ccccc1-2
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(NC(=O)c3cc(F)ccc3C)cc1)c1ccccc1-2
Reaction time: 18 h

Procedure:
To a stirred solution of 0.235 g of 5,6-dihydro-2-methyl-6-(4-aminobenzoyl)4H-thiazolo[5,4-d][1]benzazepine in 6 ml of methylene chloride under argon is added 107 μl of triethylamine followed by the dropwise addition of 2-methyl-5-fluorobenzoyl chloride in 1 ml of methylene chloride. Stirring is continued at room temperature for 18 hours. The reaction mixture is washed with H2O, saturated NaHCO3 and brine. The organic layer is treated with activated carbon, filtered through MgSO4 and the filtrate evaporated in vacuo to a residue which is chromatographed on silica gel by elution with 15% ethyl acetate in methylene chloride to give 300 mg of the desired product as a white solid; Anal. Calc'd for C27H22FN3O2S: C,68.8; H,4.7; N,8.9; F,4.0; S,6.8 Found: C,67.7; H,4.6; N,8.5; F,3.7; S,6.4.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([C@@H:19]([NH2:41])[CH:20]([OH:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:26])=[O:25])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.CCOC(C)=O>[C:1]([NH:11][C@H:12]([C:17]([C@H:19]([NH2:41])[C:20](=[O:40])[CH:21]([NH:23][S:24]([C:27]1[CH:39]=[CH:38][C:30]2[O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:29]=2[CH:28]=1)(=[O:25])=[O:26])[CH3:22])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@@H](N)C(O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)[C@H](N)C(=O)C(C)NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
1-(Cbz-leucinyl)-amino-3-(2-dibenzofuransulfonamido)-(S)-butan-2-ol (240 mg, 0.4 mmol) was dissolved in acetone (2 ml). Jones reagent (0.5 ml, 1.5 M) was added dropwise and the reaction as stirred at RT overnight. The excess Jones reagent was then quenched with isopropanol (1.0 ml), then the reaction as diluted with EtOAc (20 ml) and was extracted with water (2×20 ml) to remove the inorganic salts. The combined organics were dried with magnesium sulfate, filtered, concentrated, and chromatographed (silica gel, 2-5% MeOH/methylene chloride) to give the title compound as a white solid (70 mg, 29%). MS(ES) M-H+ =578.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[C:45]5=[N:46][O:47][N:48]=[C:44]5[C:43]([N+:49]([O-:51])=[O:50])=[CH:42][CH:41]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:52])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]4[C:45]5=[N:46][O:47][N:48]=[C:44]5[C:43]([N+:49]([O-:51])=[O:50])=[CH:42][CH:41]=4)[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCCCCNc5ccc([N+](=O)[O-])c6nonc56)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 28.7 %

Procedure:
To a slurry of N-(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)-6-(7-nitrobenzofurazan-4-ylamino)hexanamide (22, 88 mg, 0.097 mmol) and K2CO3 (134 mg, 0.970 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (2 mL), was added thiophenol (79 μL, 0.767 mmol). After 18 h at 23° C., the suspension was filtered and solvent removed in vacuo. Purification by preparative reverse-phase HPLC (gradient: 69.9% MeCN, 30% H2O, and 0.1% TFA to 99.9% MeCN, 0% H2O, and 0.1% TFA over 10 min; retention time=7.7 min) afforded 8 (20 mg, 29%) mp 78-80° C.; 1H NMR (500 MHz, DMSO d6) δ 9.54 (br s, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.43 (br s, 1H), 7.99 (t, J=5.8, 1H), 6.38 (d, J=9.0 Hz, 1H), 5.34 (br s, 1H), 3.43 (m, 1H), 3.11 (m, 2H), 2.94-2.81 (m, 3H), 2.30 (m, 2H), 2.09 (t, J=7.3 Hz, 2H), 1.92-0.94 (m, 35H), 0.90 (s, 3H), 0.87 (d, J=6.4 Hz, 3H), 0.84 (d, J=2.4 Hz, 3H), 0.83 (d, J=2.4 Hz, 3H), 0.60 (s, 3H); 13C NMR (125.8 MHz, DMSO d6) δ 172.7, 145.1, 144.4, 144.1, 138.5, 137.9 122.4 (×2), 99.0, 56.6, 56.0, 55.5, 49.3, 43.3, 41.8, 41.7, 41.6, 36.4, 36.1, 35.6, 35.4, 35.1 (×2), 34.3, 31.2 (×2), 27.7, 27.4, 26.3, 26.1, 24.9, 24.4, 23.8, 23.7, 23.1, 22.6, 22.4, 20.4, 18.7, 18.5 (×2), 11.6; IR (film) νmax 3269, 2949, 2868, 1649, 1585, 1530, 1300 cm−1; CI m/z 719.5224 (MH+, C42H67N6O4 requires 719.5224).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[CH2:23]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:6]=2)[CH2:11][CH2:12]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 5-bromo-2-nitro-N-phenylbenzenamine (4.0 g, 13.6 mmol) and piperazine (4.7 g, 54.6 mmol) in 40 ml NMP was heated at 100° C. for 16 hours. The reaction was quenched with 100 ml water. The mixture was extracted with ethyl acetate (3×30 ml) and dried over anhydrous sodium sulfate. 2-Nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (3.5 g, 86%) was obtained by flash column chromatograph (10% methanol in dichoromethane). A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), benzyl bromide (0.2 g, 1.7 mmol) and triethylamine (0.60 ml, 4.19 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(5-(4-benzylpiperazin-1-yl)-2-nitrophenyl)benzenamine (0.30 g, 43%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.54 (t, J=5.0 Hz, 4H), 3.32 (t, J=2.0 Hz, 4H), 3.56 (s, 2H), 6.34 (dd, J=9.7, 2.1 Hz, 1H), 6.42 (d, J=2.5 Hz, 1H), 7.22-7.44 (m, 9H), 8.14 (d, J=9.7 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 47.3, 53.0, 63.3, 96.2, 106.2, 124.9, 125.8, 127.8, 128.9, 129.3, 129.6, 130.1, 138.0, 139.5, 145.9, 156.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1>O1CCOCC1.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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of Example A5 (3.83 g, 13.79 mmol) in dioxane (50 mL) was sparged with argon, treated with a solution of K2CO3 (3.81 g, 27.6 mmol) in H2O (10 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.44 g, 16.55 mmol) and Pd(PPh3)4 (0.637 g, 0.552 mmol) and heated at 80° C. for 16 h. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics washed with H2O, then brine, dried over Na2SO4 and concentrated to dryness. The material was suspended in 3:2 EtOAc/Hex, sonicated and the resulting solid collected via filtration and dried. The filtrate was concentrated to dryness, purified via silica gel chromatography (MeOH/DCM) and combined with the isolated solid to afford N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (3.88 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.58 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 324.1 (M+H+).