Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]=[CH2:13].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[Br:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:13][O:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1Br)COC2=O
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution 4-bromo-5-ethenyl-2-benzofuran-1(3H)-one (2.00 g, 8.37 mmol) in DCM (20 mL) was slowly added mCPBA (2.60 g, 8.37 mmol) at 0° C. The flask was warmed to room temperature and the mixture was then stirred for 12 hours. Analysis by TLC as well as LC indicated that reaction had gone to completion. The reaction mixture was washed with aqueous Na2S2O3, NaHCO3, and water. The organic layer was washed with brine and then concentrated to dryness. The residue was purified over silica gel to give 4-bromo-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CCO.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)c(N)n1

Procedure:
6-(Methyloxy)-3-nitro-2-pyridinamine (26 g, 129 mmol) was suspended in EtOH (500 ml) at room temperature under argon and then treated with palladium on carbon (15 g, 14.10 mmol) (10% paste). The reaction was stirred under 1 atmosphere of hydrogen overnight. The reaction was filtered through a Celite pad and the pad washed with EtOH (500 ml). EtOH was evaporated to afford the product as a purple oil (20.68 g, slightly impure).
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[O:6])[CH:3]=1.[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C(C1C=CC=CC=1)C>[C:5]([O:7][CH:8]1[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([O:37][CH:33]([CH3:36])[C:35]2[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=2)[C:12]([CH3:14])([CH3:15])[CH2:13]1)(=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([C:1]([O:22][CH:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]([CH3:36])[C:35]3[CH:19]=[CH:20][CH:2]=[CH:3][CH:4]=3)[C:27]([CH3:30])([CH3:29])[CH2:28]2)=[O:21])[CH:3]=1
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)NC(C)(C)C3)c2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: CCc1ccccc1
Product: CC(ON1C(C)(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC(C)c4ccccc4)C(C)(C)C3)c2)CC1(C)C)c1ccccc1
Yield: 129.1 %

Procedure:
a mixture of 40.0 g (90.0 mmol) of di-(2,2,6,6-tetramethylpiperidin-4-yl) isophthalate, 2.0 g of molybdenum trioxide, and 250 ml of ethylbenzene is heated to 110° C. t-Butyl hydroperoxide (70%, 69.5 g, 540 mmol) is added dropwise over a 45 min. period. The reaction mixture turns red during the addition. Water is removed by azeotropic distillation. The mixture is refluxed for 4 hours after the addition is complete. The catalyst is filtered, and the filtrate is evaporated to obtain a yellow oil. A Kugelrohr distillation (110° C., 0.1 mm Hg) is performed to remove volatile by-products. The residue, a viscous oil, is dissolved in hexane and passed through silica gel. Evaporation yields a crude solid which is recrystallized from ethanol to yield 39.8 g (65% yield) of the title compound, a white powder, m.p. 118°-34° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=O)[CH2:34]Br)=[CH:31][CH:30]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH:34]=[C:33]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:39])[F:40])=[CH:38][CH:37]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-n2cc(-c3ccc(OC(F)(F)F)cc3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 82.5 °C
Yield: 42.3 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (25 mL), 4-(trifluoromethoxy)phenacyl bromide (950 mg, 3.36 mmol) was added. After heating the reaction mixture at 80-85° C. for 22 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[4-(trifluoromethoxy)phenyl]-1H-imidazole (467 mg, 42%) as a pale yellow solid: mp 95-97° C. Anal. Calc'd. for C23H16N2SO3F3Cl: C, 56.05, H, 3.27, N, 5.68, S, 6.51. Found: C, 55.90, H, 3.04, N, 5.62, S, 6.74.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N+:3]=1[O-:10].[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N+:3]([O-:10])=[CH:4][C:5]([CH2:8][N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: [O-][n+]1cc(CCl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(Cl)[n+]([O-])c1
Reaction time: 16 h
Yield: 88.5 %

Procedure:
2-Chloro-5-chloromethylpyridine 1-oxide (1.78 g, 10.0 mmol; described in: Tilley, J. W. et al, J. Heterocyclic Chem. 1979, 16, 333), diethyl amine (1.46 g, 20.0 mmol), and potassium carbonate (1.38 g, 10.0 mmol) were mixed in acetonitrile (50 mL) at room temperature. The mixture was stirred for 16 h, the solvent was removed in vacuo, and the residue was purified on a silica gel column using chloroform/methanol, (9:1), as the eluent to give 1.90 g (88% yield) of the title compound as a pale orange oil: MS (EI) m/z 215 and 217 (M++1).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.ClC(Cl)(Cl)C(=N)O[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])(O)=O.[Na+]>CCCCCC.C1COCC1>[CH:1]1([CH2:4][CH2:5][C:6]([O:8][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(O)CCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cool (0° C., precooled for at least 15 min), stirred solution of 3-cyclopropylpropanoic acid (5 g, 43.8 mmol) in hexane (30.0 mL) and THF (30 mL) under N2 was added tert-butyl 2,2,2-trichloroacetimidate (15.7 mL, 88 mmol) portion wise over 5 min. The reaction mixture was stirred for 15 min. Boron trifluoride ether complex (0.555 mL, 4.38 mmol) was added and the reaction mixture was allowed to warm to room temperature as the bath warmed overnight. To the clear reaction mixture was added NaHCO3 (5 g) and stirred for 60 min. The suspension was filtered through MgSO4 and washed with 300 mL hexane. The filtrate was allowed to sit, then the formed solid was filtered through the same MgSO4 filter, washed with hexane (100 mL). The filtrate was concentrated under vacuo with the water bath not turned on. The residue was purified by silica gel chromatography (hexanes/EtOAc) to provide Intermediate I1B (6.05 g, 81%) as clear oil: 1H NMR (400 MHz, CDCl3) δ 2.29 (2H, t, J=7.48 Hz), 1.35-1.54 (11H, m), 0.60-0.75 (1H, m), 0.29-0.46 (2H, m), −0.06-0.10 (2H, m).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[S:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[S:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1csc(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CSc1cc(S(N)(=O)=O)sc1Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.4 %

Procedure:
To a solution of 4-methylsulfanylthiophene-2-sulfonamide (210 mg, 1.00 mmol) in CHCl3 (10 mL) and AcOH (10 mL) is added N-bromosuccinimide (231 mg, 1.30 mmol). The reaction mixture is stirred at room temperature for 7 hr. After 7 hr, the reaction mixture is neutralized with 1 M NaOH and the solution is extracted with EtOAc (200 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (3:1) to afford the title compound (200 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](=[O:33])(=[O:32])[NH2:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[C:34](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([S:30](=[O:33])(=[O:32])[NH:31][CH3:34])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A mixture of 6-bromo-2-(4-sulfamoylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (264 mg), potassium carbonate (152 mg), methyl iodide (34 μl) and dimethylformamide (DMF) (5 ml) was stirred at room temperature for 5 hrs. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (83 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[O:30][N:29]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1cc(CN)no1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 98.5%, 454.1122 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:12])[CH2:3][CH2:2]1.O.O[Li].O>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:12])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(=O)C2CCOc3ccccc32)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC(=O)C2CCOc3ccccc32)ccc1C(=O)O
Temperature: 45 °C

Procedure:
To a stirred solution of methyl 4-(4-chromanoyloxy)-2-methoxybenzoate (260 mg, 0.82 mmol) in THF:H2O (4 mL:0.8 mL) was added LiOH.H2O (172 mg, 4.1 mmol). The reaction was heated to 45° C. over 12 h and then cooled to ambient temperature. The solvent was removed under reduced pressure. The crude solid was passed through a small plug of silca gel packed in 90:10 CH2Cl2 :MeOH(NH3) and eluted with same. The solvent was removed under reduced pressure to afford 4-(4-chromanoyloxy)-2-methoxybenzoic acid as a foam.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1([CH3:30])[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[CH2:30]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A solution containing lithium diisopropylamide (0.1 mole) was prepared by treating a solution of diisopropylamine (14.1 ml, 0.1 mole) in tetrahydrofuran (200 ml) at 0° C. with n-butyl lithium (41.2 ml of a 2.43M solution, 0.1 mole), and stirring for 5 minutes. To this was added a solution of o-toluic acid (6.8 g, 0.05 mole) in tetrahydrofuran (50 ml). The ice bath was removed and the intense red solution was stirred for 30 minutes. This solution was slowly pipetted into a solution of undecylbromide (11.8 g, 0.05 mole) in tetrahydrofuran (50 ml) at -20° C. After the addition, the cooling bath was removed and the solution stirred for 30 minutes. A small amount of water was added and most of the tetrahydrofuran was removed under reduced pressure. The residue was poured into water, acidified with 3N hydrochloric acid and extracted with ether. The ether was dried, evaporated and the residue was recrystallized from acetonitrile, then from hexane, to give the product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[NH:13][N:12]=[CH:11][C:10]=2[NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])[CH:8]=1)#[N:2].[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:26][CH3:27])=[C:7]([C:9]2[C:10]([NH:14][C:15]([C:17]3[CH:18]=[N:19][N:20]4[CH:25]=[CH:24][CH:23]=[N:22][C:21]=34)=[O:16])=[CH:11][N:12]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[N:13]=2)[CH:8]=1)#[N:2]
Reactant: CC1(C)CO1
Reactant: COc1ccc(C#N)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1-c1nn(CC(C)(C)O)cc1NC(=O)c1cnn2cccnc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 11.3 %

Procedure:
To a solution of N-(5-(5-cyano-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (200 mg, 0.557 mmol) in 20 mL DMF was added isobutylene oxide (0.20 mL, 2.2 mmol) and cesium carbonate (363 mg, 1.11 mmol). The reaction mixture was stirred at 80° C. for 6 hours, then diluted with ethyl acetate and filtered, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 27.2 mg (11%) of desired product. LCMS (ESI) m+H=431.9. 1H NMR (CDCl3, 400 MHz): 69.68 (s, 1H), 8.78 (dd, J=2.0, 6.8 Hz, 1H), 8.71 (s, 1H), 8.56 (q, J=1.6 Hz, 1H), 8.37 (s, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.0, 8.4 Hz, 1H), 7.1 (d, J=8.8 Hz, 1H), 7.01 (dd, J=4.4, 7.2 Hz, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 1.23 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:30]=[CH:29][C:17]([O:18][CH:19]([CH3:28])[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:28])[C:20]([O:26][CH3:27])=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:29][CH:30]=1)[CH:11]=[N:10]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: COC(=O)C=C(OC)C(C)Oc1ccc(O)cc1
Product: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
The procedure of Example 37 is repeated using 2,6-dichloroquinoxaline and methyl 4-(4-hydroxyphenoxy)-3-methoxy-2-pentenoate as the starting materials to yield methyl 4-[4-(6-chloro-2-quinoxalyloxy)phenoxy]-3-methoxy-2-pentenoate which is treated with 35% HClO4 to yield the 3-oxo ester. Methyl 4-[4-(6-chloro-2-quinoxalyloxy)phenoxy]-3-oxopentanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:33][CH2:32]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][OH:17])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:45][O:46][CH2:47]Cl>COCCOC>[C:1]([O:5][C:6]([N:8]([C@@H:15]([CH2:18][C:19]([N:21]([CH:31]1[CH2:32][CH2:33]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30])=[O:20])[CH2:16][O:17][CH2:45][O:46][CH3:47])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Reactant: COCCl
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@H](CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)N(CCC(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 53.1 %

Procedure:
Into a 250 mL round bottom flask was added 4D (12.42 g, 24.7 mmol) and DME (137 mL). Di-isopropylethylamine (DIEA) or Hunig's base (23.6 mL, 135.7 mmol, 5.5 eq) and sodium iodide (14.79 g, 98.7 mmol, 4.0 eq) was added to the solution and cooled with an ice bath. Methoxymethyl chloride (MOMCl) (10.7 mL, 127.1 mmol, 5.15 eq) was added slowly at 0° C. The reaction was allowed to warm to room temperature overnight. Solvent was removed under vacuum and the residue was portioned between water (150 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were combined and washed once with brine (100 mL). The organic phase was dried over sodium sulfate and filtered. Solvent was removed under vacuum and the residue was purified by column chromatography (30% ethyl acetate/hexanes) to give 4E (7.18 g, 53%) as a viscous oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 (m, 4H) 1.46 (br. s., 9H) 2.63 (br. s., 4H) 3.36 (s, 3H) 3.66 (s, 8H) 4.06-4.30 (m, 1H) 4.62 (m, 3H) 4.79 (m, 1H) 6.94 (d, J=7.83 Hz, 1H) 7.11-7.17 (m, 1H) 7.36 (dd, J=8.08, 1.26 Hz, 1H). ESI-MS:m/z 547.4 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)C>[CH3:14][N:13]([CH2:12][CH2:11][CH2:10][O:9][C:8]1[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N+:29]([O-:31])=[O:30])[CH:25]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Reactant: CNCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC#N
Product: CN(CCCOc1ccc([N+](=O)[O-])cc1)Cc1ccc2cc([N+](=O)[O-])ccc2n1

Procedure:
N-[3-(4-Nitrophenoxy)propyl]methylamine hydrochloride (3.08 g, 12.49 mmol), 2-(chloromethyl)-6-nitroquinoline (2.78 g, 12.49 mmol), and potassium carbonate (3.45 g, 25.0 mmol) were stirred in 2:1 acetonitrile/ethanol (120 mL) at reflux for 18 hours. The mixture was concentrated and the residue was partitioned between 10% aqueous K2CO3 and 4:1 dichloromethane/isopropanol. The organic phase was dried, decolorized and concentrated to afford crude product which was purified by column chromatography (1:2 hexane/ethyl acetate). Yield: 2.63 g (53%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[NH:16])OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30]>C1(C)C=CC=CC=1>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[NH:16]
Reactant: NCCCCCCCCCCCCN
Reactant: CCOC(=N)NC(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: N=C(NCCCCCCCCCCCCN)NC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A mixture of N-benzyloxycarbonyl-O-methyl-isourea (II-OMe) (0.42 g, 2.0 mmol), toluene (3.5 mL) and 1,12-diaminododecane (If) (1.02 g, 5.0 mmol) was stirred at 40° C. for 12 h and at 20° C. for 1 h. The crystalline product was collected by filtration, washed with toluene (3×1 mL), and vacuum dried (35° C., 1.5 h) to afford 0.55 g (73%) of white crystals of N-(12-Aminododecyl)-N'-benzyloxycarbonyl guanidine (IIIf).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]([CH3:8])[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[O:3]1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:11]1[CH:12]=[CH:13][C:4]2[O:3][C:2]([CH3:1])([CH3:14])[CH:7]([CH3:8])[C:6](=[O:9])[C:5]=2[CH:10]=1)([O-:17])=[O:16]
Reactant: CC1C(=O)c2ccccc2OC1(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC1C(=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one (81 g, 0.426 mol) in concentrated sulfuric acid (695 ml) at 0° C. was added a solution containing concentrated sulfuric acid (30 ml) and nitric acid (65%, 175 ml) while maintaining the temperature below 5° C. After stirring for three hours at 5° C., the mixture was added to ice/water and the crude product recovered by filtration. This product was dried and washed with diisopropyl ether to give 44 g of 6-nitro-2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one, m.p. 78° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:7]=2[CH:35]=1)#[N:2].[OH-:36].[K+]>CC(O)(C)C>[CH2:11]([C:9]1[N:8]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=2)[C:7]2[CH:35]=[C:3]([C:1]([NH2:2])=[O:36])[CH:4]=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: CCc1nc2ccc(C#N)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCc1nc2ccc(C(N)=O)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 62.9 %

Procedure:
To a solution of 6-cyano-2-ethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-benzimidazole (Example 85, 162 mg, 0.33 mmol) in 2-methyl-2-propanol (10 mL) was added powdered KOH (66 mg, 1.0 mmol). The resulting mixture was heated at reflux temperature for 3 h. After removal of solvent, the reaction mixture was partitioned between dichloromethane (50 mL) and phosphate buffer (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residual solids were recrystallized from ethyl acetate to afford 105 mg (63%) of the title compound as white solids: 1H-NMR (CDCl3) δ: 7.79 (2H, d, J=8.4 Hz), 7.75 (1H, d, J=8.8 Hz), 7.71-7.63 (2H, m), 7.35-7.25 (4H, m), 7.16 (2H, d, J=8.4 Hz), 6.75 (2H, br.s), 6.55 (1H, br.s), 3.54 (2H, t, J=6.4 Hz), 2.88 (2H, t, J=6.4 Hz), 2.79 (2H, q, J=7.5 Hz), 2.40 (3H, s), 1.34 (3H, t, J=7.5 Hz).