Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([NH2:42])(=[O:40])=[O:41])=[CH:37][CH:38]=3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NCCc3ccc(S(N)(=O)=O)cc3)n2)cc1
Yield: 49 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (30 mg, 49% yield.) MS/ES+: m/z=514.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14]>Cl.O1CCOCC1>[CH3:11][CH:10]1[CH2:9][C:5]2[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]([C:19]2[CH:22]=[CH:23][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[O:12]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(CC(C)O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Yield: 93.3 %

Procedure:
To a solution of 1-(3′-methoxyphenyl)-2-propyl alcohol 2 (0.98 g, 5.8 mmol) in 25 ml of HCl solution in 1,4-dioxane was added 4-nitrobenzaldehyde (0.91 g, 6.0 mmol) in one portion. The solution was refluxed for 4 hours. After removing the solvent under reduced pressure, the residue was washed with cold ethanol three times, affording the product 3 (1.62 g, yield 90%). 1HNMR(CDCl3): 8.20 (d, J=8.7 Hz, 2H), 7.50 (d, J=8,7 Hz, 2H), 6.65-6.48 (m, 3H), 5.78 (s, 1H), 4.01 (m, 1H), 3.76 (s, 3H), 2.80 (m, 2H), 1.40 (d, J=6.1 Hz).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:40])[NH:12][CH:13]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:24][CH:25]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=4)[NH:28][CH:27]=3)[CH:19]12)=[O:17])[CH2:14][CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([CH:25]3[CH:19]4[N:18]([C:16]([CH:13]([NH:12][C:11](=[O:40])[CH:9]([NH:7][CH3:6])[CH3:10])[CH2:14][CH3:15])=[O:17])[CH2:22][CH2:21][CH:20]4[N:23]([S:36]([CH3:39])(=[O:38])=[O:37])[CH2:24]3)=[CH:27][NH:28]2)=[CH:33][CH:32]=1
Reactant: CCC(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(NC(=O)C(C)NC)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2S(C)(=O)=O
Reaction time: 1 h

Procedure:
To a solution containing 66 (160 mg, 0.27 mmol) in DCM (3 mL) was added TFA (3 mL) at 0° C. After 1 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax C18, 5-40% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 100 mg (38%, 3 steps) of 67. 1H NMR (300 MHz, CDCl3/d4-MeOH), mixture of amide rotamers: δ10.34 (br s, 0.1H), 9.76 (br s, 0.3H), 7.92 (br d, 0.3H), 7.55 (dd, J=8.9, 5.3 Hz, 0.7H), 7.38 (m, 0.3H), 7.35 (s, 0.3H), 7.25 (m, 0.3H), 7.22 (s, 0.7H), 7.02 (m, 1H), 6.82 (dt, J=9.2, 2.0 Hz, 0.7H), 5.11 (t, J=7.8 Hz, 0.7H), 4.79 (m, 0.3H), 4.30 (br s, 2H), 4.24 (m, 1.7H), 4.14 (m, 1.3H), 4.00 (m, 1H), 3.82 (m, 1H), 3.71 (m, 2H), 3.51 (q, J=6.9 Hz, 0.7H), 3.38 (m, 0.3H), 3.29 (m, 0.3H), 3.15 (app q, J=9.0 Hz, 0.7H), 3.01 (s, 0.7H), 2.98 (s, 2.3H), 2.44 (s, 2.3H), 2.34 (s, 0.7H), 2.20 (m, 0.7H), 2.00 (br s, 3.3H), 1.57 (m, 0.3H), 1.35 (d, J=6.9 Hz, 2.3H), 1.17 (d, J=6.9 Hz, 0.7H), 0.71 (m, 1.5H), 0.47 (m, 1.5H) ppm. 13C NMR (75 MHz, CDCl3/d4-MeOH), mixture of amide rotamers: δ176.6, 171.3, 171.2, 170.7, 170.5, 169.1, 161.6, 158.4, 136.2, 136.0, 135.9, 124.3, 122.9, 122.8, 122.7(2), 120.2, 120.1, 108.3, 108.1, 107.8, 97.6, 97.5, 97.2, 65.0, 64.9, 62.3, 57.9, 57.5, 55.4, 53.4, 52.3, 52.2, 51.7, 47.4, 46.8, 43.1, 38.5, 37.6, 34.4, 33.9, 33.2, 32.2, 32.0, 25.9, 24.2, 22.1, 17.1, 16.8, 10.0, 9.1 ppm. Mass spectrum, m/z [494.2] (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:17])N(OC)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Mg]Br)[CH3:19].OS([O-])(=O)=O.[K+].CCOC(C)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:17])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:18][CH3:19])[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)C1
Reactant: COc1ccccc1[Mg]Br
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 3-(methoxy-methyl-carbamoyl)-azetidine-1-carboxylic acid tert-butyl ester (3.48 g, 14.2 mmol) in dry ether (150 mL) at 0° C. was added 2-methoxylphenylmagnesium bromide (1.0 M in THF, 17 mL, 17 mmol). The reaction was allowed to slowly warm to rt and stirred for 36 h. Then a solution of 1M KHSO4 and EtOAc were added and the aqueous portion was extracted once with EtOAc. The combined organic fractions were dried (Na2SO4) and concentrated to provide the title compound. This material was used in subsequent reactions without additional purifications. MS (ESI): mass calcd. for C16H21NO4, 291.1; m/z found, 236.1 [M-t-Bu]+. 1H NMR (CDCl3): 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.51 (ddd, J=8.5, 7.3, 1.8 Hz, 1H), 7.06-6.95 (m, 2H), 4.13-4.03 (m, 5H), 3.90 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C@@H:9]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11])=[O:7])[CH2:2][CH2:3][CH3:4].[N:20]([O-])=[O:21].[Na+]>O.C(O)(=O)C>[CH2:1]([N:5]([N:20]=[O:21])[C:6]([NH:8][C@@H:9]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]1[OH:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=N[O-]
Reactant: CCCCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 90.6 %

Procedure:
1-n-butyl-3-(β-D-glucopyranosyl)urea (0.50 g) was dissolved in a mixture of water (2 ml) and acetic acid (2 ml), and to the resulting solution was added sodium nitrite (186 mg, 1.5 mol. equivalents). The nitrosation was conducted in the same manner as in Example 1(a). The reaction mixture was treated with Amberlite IR-120 (H+ form) for the removal of sodium cation and then freeze-dried, affording 0.5 g of the titled compound as a glassy substance of pale yellow color. [α]D26 -1.5° (c 1.0, H2O). This substance gave a single spot at Rf 0.51 in a thin layer chromatography on silica gel using chloroform-methanol (4:1 by volume) as eluent.
Reaction SMILES: COCCOC.Br[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[F:19][C:20]1[CH:25]=[C:24]([CH:23]=[CH:22][CH:21]=1)[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cc(CBr)on1
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: COCCOC
Solvent: O
Product: CCOC(=O)c1cc(Cc2cccc(F)c2)on1
Yield: 60.9 %

Procedure:
1,2-Dimethoxyethane (8 mL) and water (2 mL) were added to the mixture of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (0.710 g; 3.03 mmol), 3-fluorophenylboronic acid (0.481 g; 3.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.176 g; 0.151 mmol) and sodium carbonate (0.646 g, 6.07 mmol). The mixture was irradiated in a microwave oven at 130° C. for 15 min and was evaporated. The residue was partitioned between dichloromethane (30 mL) and brine (20 mL). The organic layer was separated and concentrated. The residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to afford 0.460 g (61%) of ethyl 5-(3-fluorobenzyl)isoxazole-3-carboxylate as a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:34])[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]([F:32])([F:33])[F:31])[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCCO2)c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCCO2)C(=O)Nc2ccc(CO)cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.2 %

Procedure:
A solution of 6-[2-(4-methylsulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 15, 129 mg, 0.25 mmol) in ethyl ether (6 mL) cooled to 0° C. was treated with a 1.0M solution of lithium aluminum hydride solution in diethyl ether (0.30 mL, 0.30 mmol). The orange-colored reaction mixture was stirred at 0° C. for 1 h. The reaction was then quenched by the dropwise addition of water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S Silica, 8/2 hexanes/ethyl acetate) afforded N-(5-hydroxymethyl-pyridin-2-yl)-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionamide (44 mg, 36%) as a cream foam: EI-HRMS m/e calcd for C22H25F3N2O5S (M+H)+ 487.1509, found 487.1514.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1cc(F)cc(F)c1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(F)cc(F)c1

Procedure:
Using the procedure of Example 84, the title compound was prepared using a mixture of 9.9 g (0.076 mole) of 3,5-difluorophenol and 7.0 ml (0.08 mole) of chlorosulfonyl isocyanate in 50 ml of toluene. The solid product was recrystallized from benzene to yield 11.7 g (74%) of white solid, mp 85°-88° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH:3]1[C:12]#[C:13][C:14]1[N:22]=[C:21]3[C:17]([NH:18][CH:19]=[N:20]3)=[C:16]([NH2:23])[N:15]=1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:41][CH:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)(=O)=O)=CC=1>CN(C=O)C>[CH:42]1([CH2:41][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([C:13]#[C:12][CH:3]2[CH:4]4[CH2:5][CH:6]5[CH2:7][CH:8]([CH2:9][C:2]2([OH:1])[CH2:11]5)[CH2:10]4)=[N:15][C:16]=3[NH2:23])[CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Nc1nc(C#CC2C3CC4CC(C3)CC2(O)C4)nc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(C#CC2C3CC4CC(C3)CC2(O)C4)nc2c1ncn2CC1CCCC1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (44 mg, 0.1422 mmol) was dissolved in DMF (20 mL) with heating. Anhydrous potassium carbonate (51 mg, 0.3690 mmol) and cyclopentylmethyl 4-methylbenzenesulfonate (54 mg, 0.2123 mmol) were added and the mixture stirred at 70° C. for 72 h. Extra cyclopentylmethyl 4-methylbenzenesulfonate (82 mg, 0.3224 mmol) was added and stirring continued at 100° C. a further 4.5 h. The reaction mixture was adhered to silica and purified by column chromatography, eluting with a gradient of DCM/MeOH (0–6%) to afford the pure 47 as a white solid: yield 38 mg, 68%. 1H NMR (CD3OD) δ 8.15 (s, 1H), 4.14 (d, 2H, J=7.7 Hz), 2.48 (quintet, 1H, J=7.5 Hz), 2.37–2.22, 2.08–2.02, 1.89–1.58, 1.37–1.24 (4×m, 22H). LRMS ESI (M+H+) 392.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O.[NH2:22]N>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:7]2[NH:22][N:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:19]=1
Reactant: NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1OC
Solvent: CCO
Product: CCOC(=O)c1cn[nH]c1-c1cc(Cl)ccc1OC

Procedure:
A solution of ethyl 2-(5-chloro-2-methoxybenzoyl)-3-(dimethylamino)acrylate (2.49 g, 8.00 mmol, 1 eq) and hydrazine (0.40 mL, 13 mmol, 1.6 eq) in 20 mL ethanol was heated at 70° C. for 2 hours. Solvent and excess hydrazine were then evaporated to provide ethyl 5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate, which was used without further purification. LCMS (ESI) m+H=281.3.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>ClCCl>[Cl:11][C:4]1[N:3]=[C:2]([NH:22][CH2:19][CH:20]=[CH2:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: C=CCN
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This was prepared by a modification of the method of Schmid, S., et al, Synthesis (2005), (18), 3107-3118. A solution of 2,6-dichloro-3-nitropyridine (8.0 g, 41.45 mmol) in anhydrous dichloromethane (180 ml) was cooled to −15° C., under argon. Triethylamine (6.0 ml, 43 mmol) was added and then allylamine (3.23 ml, 43 mmol) was added in small portions over 3 hours, keeping the temperature at −15° C. The reaction mixture was stirred overnight during which time it warmed to room temperature. The reaction mixture was washed with 0.2M aqueous citric acid (100 ml), saturated aqueous NaHCO3 solution (100 ml), passed through a hydrophobic frit and evaporated to a yellow oil which was purified by chromatography on silica eluting with a 0 to 50% ethyl acetate in hexane giving a yellow solid (7.49 g, 85%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.CCOC(C)=O>CN(C=O)C>[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([O:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at room temperature, solid K2CO3 (30 mmol) was added followed by addition of 4-hydroxybiphenyl (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to room temperature to room temperature, the reaction mixture was poured into EtOAc (100 mL), washed with water (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuo to afford the desired 4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCC1
Temperature: 60 °C

Procedure:
4-Nitroindazole (3.00 g, 18.4 mmol) and potassium carbonate (7.50 g, 54.4 mmol) in 60 mL of DMF was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g 28.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel. The silica gel was rinsed with triethylamine/ethyl acetate (1/4), the combined filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.45 (m, 4H), 2.92 (t, 2H, J=6.45), 4.65 (t, 2H, J=6.45), 7.65 (m, 1H), 8.10 (m, 1H), 8.30 (m, 1H), 8.52 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].O1CCOCC1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C([O-])(O)=O.[Na+].O>[CH2:1]([C:3]1[C:4](=[O:14])[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:2]
Reactant: CCC1Nc2ccc(F)cc2NC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2ccc(F)cc2[nH]c1=O
Yield: 94.8 %

Procedure:
To a homogeneous solution of 3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (60.61 g, 312.1 mmol) and 1,4-dioxane (1350 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (75.91 g, 327.7 mmol) and the mixture was stirred using an overhead stirrer at rt for 2.5 h. At this time, the mixture was concentrated under reduced pressure to give a brown residue. The brown residue was suspended in saturated aqueous NaHCO3 (2 L), stirred for 30 min, filtered, washed with saturated aqueous NaHCO3 (1 L) to give a light green solid. The light green solid was re-suspended in saturated aqueous NaHCO3 (500 mL), well mixed, filtered, and washed with saturated aqueous NaHCO3 (500 mL) to give an off-white solid. The off-white solid was suspended in water (500 mL), well mixed, filtered, washed with water (1 L), air-dried overnight, and dried under high vacuum at 22° C. for 2 h to give 3-ethyl-7-fluoroquinoxalin-2(1H)-one (56.87 g, 94.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. S, 1H), 7.76 (dd, J=9.0, 5.9 Hz, 1H), 7.11 (td, J=8.8, 2.7 Hz, 1H), 7.00 (dd, J=9.6, 2.7 Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H) Mass Spectrum (ESI) m/e=193.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14](O)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.P(Cl)(Cl)([Cl:19])=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C>[Cl:19][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH3:1])[CH:15]=1
Reactant: Cc1cc(O)c2ccc3cccnc3c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(Cl)c2ccc3cccnc3c2n1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask equipped with a reflux condenser containing 2-methyl-[1,10]phenathrolin-4-ol, (10.20 g, 48.5 mmol), was slowly added phosphorus oxychloride (200 mL) and the mixture was refluxed for 3 hours. The reaction flask was allowed to cool down to room temperature and the solvent was removed in a rotary evaporator. The solid obtained was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL) and transferred to a separatory funnel. The aqueous layer was further extracted with methylene chloride (200 mL) and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue obtained was treated with ethyl ether (100 mL), filtered and dried yielding a light brown solid (9.00 g). A second crop of 0.60 g of material was obtained from the mother liquors as a light yellow solid, with an overall yield of 9.60 g (87% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:22][N:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1cccc(F)c1
Product: Fc1cccc(-c2ccc(Cn3ccnc3)cn2)c1

Procedure:
Synthesized using 3-fluorophenylboronic acid (230 mg, 1.68 mmol) and 1a (200 mg, 0.84 mmol) according to Method C. Yellow solid. Yield: 135 mg, 0.53 mmol, 64%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.19 (s, 2H), 6.93 (s, 1H), 7.11 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 7.13 (dd, J=2.5, 0.9 Hz, 1H), 7.43 (ddd, J=8.2, 7.9, 6.0 Hz, 1H), 7.50 (dd, J=8.2, 2.5 Hz, 1H), 7.59 (brs, 1H), 7.69-7.76 (m, 3H), 8.58 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.0, 113.9 (d, J=23.0 Hz), 116.1 (d, J=21.1 Hz), 119.0, 120.6, 122.4 (d, J=2.9 Hz), 130.3 (d, J=7.6 Hz), 130.4, 130.7, 135.8, 137.3, 140.8 (d, J=7.6 Hz), 148.6, 156.3 (d, J=2.9 Hz), 163.5 (d, J=245.7 Hz); MS (ESI): m/z=254.13 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[N:8]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:18][O:17][C:11]1[CH:10]=[C:9]2[C:14]([N:15]=[CH:16][C:7]([NH2:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2cnc3ccc(OC)cc3n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N)nc2c1
Yield: 98.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (0.79 g, 2.428 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous NaHCO3 (200 mL) was added to the red residue, which precipitated a yellow solid. The mixture was extracted extensively with DCM. The organic layer was concentrated and dried under vacuum to yield 7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (0.70 g, 2.4 mmol, 99% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[S:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>C(O)(=O)C>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([S:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[C:16]([NH:2][C:1]3[C:3]4[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=4[N:10]=[CH:11][N:12]=3)[CH:21]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4nc(C)ccc34)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A solution of the product of Example 9B (28.4 mg, 0.151 mmol), and the product of Example 9E (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130° C. for 20 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum, and the resultant residue triturated with methanol to provide the title compound as a tan solid (26.5 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 9.92 (s, 1 H), 9.63 (s, 1 H), 8.70 (d, J=8.09 Hz, 1 H), 8.55 (s, 1 H), 7.52 (d, J=8.46 Hz, 1 H), 7.38 (d, J=8.82 Hz, 2 H), 7.27 (s, 1 H), 7.06-7.18 (m, 3 H), 6.94 (d, J=8.46 Hz, 3 H), 6.61-6.72 (m, 2 H), 5.02 (s, 2 H), 3.75 (s, 3 H), 2.66 (s, 3 H); MS (ESI+) m/z 497.2 (M+H)+, (ESI−) m/z 495.3 (M−H)−.