Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[NH2:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[C:27]([CH3:32])[N:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:24][C:25]1[N:30]=[C:29]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([NH:14][C:12]([C:9]3[CH:10]=[C:11]4[C:6](=[CH:7][CH:8]=3)[N:5]=[C:4]([CH3:23])[CH:3]=[C:2]4[NH2:1])=[O:13])=[CH:16][CH:17]=2)[CH:28]=[C:27]([CH3:32])[N:26]=1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NCc2ccc(NC(=O)c3ccc4nc(C)cc(N)c4c3)cc2)nc(N)n1
Yield: 82.2 %

Procedure:
The solution of 27 mg (0.05 mmol) 4-{[(4-amino-2-methyl-6-quinolinyl)carbonyl]amino}benzylamine, 15 mg (0.1 mmol) 2-amino-4-chloro-6-methylpyrimidine, and 0.05 ml (0.3 mmol) diisopropyl ethylamine in 1 ml DMF was stirred at 120° C. for 5 h. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (51%) of the title compound. MS 414.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.19 (s, 3H), 2.60 (s, 3H), 4.56 (d, 2H), 5.94 (s, 1H), 6.65 (s, 1H), 7.33 (d, 2H), 7.75 (d, 2H), 7.88 (d, 1H), 8.35 (d, 1H), 8.97 (s, 1H), 8.96-9.01 (m, 2H), 10.51 (s, 1H), 12.30 (br. 1H), 13.60 (br. 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:23])[S:7]([C:10]1[CH:11]=[C:12]([C:20](O)=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]>>[CH3:5][N:6]([CH3:23])[S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]
Reactant: CN(C)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: O=S(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Yield: 100.1 %

Procedure:
190 g of thionyl chloride and 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated and then the excess thionyl chloride was distilled off. 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 160°-162° C.; yield: 100%).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1
Reactant: N#Cc1cc(-n2nnnc2CO)ccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(-n2nnnc2CCl)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 521 %

Procedure:
Thionyl chloride (4.25 g, 3.57 mmol) was added dropwise to a solution of 5-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 40, 8.0 g, 29.7 mmol) in toluene (200 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 4 hr. The mixture was diluted with EtOAc and washed with ice-water, and saturated NaHCO3, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% ethyl acetate/pet ether to give the title compound (5.35 g) as a white powder.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]2[N:15]([CH2:25][CH3:26])[C:16](=[O:24])[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:13]=2[CH:12]=1)C>O>[CH2:25]([N:15]1[C:16](=[O:24])[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH3:20])[C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][C:8]([OH:29])=[O:7])[CH:28]=[CH:27][C:14]1=2)[CH3:26]
Reactant: CCOC(=O)CCc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
50% Sodium hydroxide aqueous solution (1 ml) was added to a methanol (20 ml) solution of 3-(1-ethyl 3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) propionic acid ethyl ester (1.1 g). The mixture was stirred at room temperature overnight. Water was added to the reaction liquid, followed by washing with ether. A hydrochloric acid was added to the aqueous layer, followed by extraction using ethyl acetate and drying using magnesium sulfate. The dried product was condensed under reduced pressure to give the title compound (0.97 g) as a colorless oily matter.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:3]=1[O:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=[C:7]([CH3:18])[N:6]=1.Br.[N:26]([O-])=O.[Na+].[OH-].[NH4+]>O>[CH2:14]([CH:13]([N:12]1[C:9]2[CH:8]=[C:7]([CH3:18])[N:6]=[C:5]([O:4][C:3]3[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=3[CH3:1])[C:10]=2[N:11]=[N:26]1)[CH2:16][CH3:17])[CH3:15]
Reactant: O=N[O-]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Agent: Br
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCC(CC)n1nnc2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Temperature: 25 °C
Yield: 107.6 %

Procedure:
To a solution of 2-(2,4,6-trimethylphenoxy)-N4-(1-ethylpropyl)-6-methyl-pyridine-3,4-diamine (640 mg, 1.95 mmol) and 7 ml of 48% hydrobromic acid was added a solution of sodium nitrite (146 mg, 2.11 mmol) in 2 ml of water dropwise over 5 min at 0° C. The resulting mixture was treated with cuprous bromide Cu(I)Br (145 mg, 1.01 mmol) and then heated at reflux for 15 min. The mixture was cooled to room temperature and diluted with water, basified with ammonium hydroxide and extracted twice with ethyl acetate. The organic layer was dried and concentred to give 710 mg (93% yield) of the title compound as brown crystals, which was further recrystallized from isopropyl ether to give the title compound as golden crystals. 1H NMR (CDCl3) δ 6.92(s,2H), 6.84(s,1H), 4.5(m,1H), 2.40(s,3H), 2.32(s,3H), 2.13(s,6H), 2.0–2.4(m,4HO, 0.83(t,6H)ppm.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[Cl:21].Cl>[Cu].O.C1(C)C=CC=CC=1.CS(C)=O>[Cl:21][C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Oc2ccccc2)c(Cl)c1
Temperature: 155 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
In this example 2143 g (22.77 mol) of phenol and 906 g (22.66 mol) of sodium hydroxide were mixed together in a stirred mixture of 5.5 liters of dimethyl sulfoxide and 5.5 liters of toluene at room temperature. The mixture was then heated at reflux for 54 hours. The water formed by the reaction was removed from the reflux trap along with a substantial portion of the toluene and a small amount of the dimethyl sulfoxide (total volume collected 4910 ml of which 690 ml were water). The temperature of the remaining reaction mixture, now containing sodium phenolate, was permitted to drop to 155° C. and 44 g of powdered copper was added. 4730 g (22 mol) of 1,2-dichloro-4-trifluoromethylbenzene was then added dropwise while maintaining the reaction mixture at 153°-155° C. After addition of the 1,2-dichloro-4-trifluoromethylbenzene, the reaction mixture was maintained at 155° C. for about 30 minutes and then allowed to stand overnight (about 12 hours) at room temperature. The reaction mixture was poured onto cold 0.5% HCl. phase separated and extracted with methylene chloride. Combined organics were washed with 5% sodium hydroxide and with water, dried over magnesium sulfate and silica, and filtered. The filtrate was then stripped (evaporated) affording 5906 g of 4-(2-chloro-4-trifluoromethylphenoxy)benzene as a yellow oil.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH2:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1
Reactant: O=S1(=O)CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 69.3 %

Procedure:
Using isothiazolidine 1,1-dioxide (53 mg) and (5-bromopyridin-2-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (170 mg) described in Preparation Example 138 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH:6]1[O:8][CH2:7]1.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>O1CCCC1>[CH2:18]([O:25][CH2:7][CH:6]([C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:11]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:9]=1)[OH:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cc(C2CO2)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 3,5-bis(trifluoromethyl)styrene oxide (Description 12, 0.5 g) and benzyl alcohol (1 g) in tetrahydrofuran (10 ml) was added sodium hydride (50% in mineral oil, 48 mg). The solution was stirred at room temperature for 16 hours. A further addition of sodium hydride (20 mg) was made and the solution heated to reflux for 2 hours. The cooled solution was evaporated to dryness and the residue purified by chromatography on silica (eluting with increasing concentrations of ethyl acetate in isohexane 0-20%) to provide the title compound. 1H NMR (360 MHz, CDCl3) δ 3.22 (1H, d J 3.1 Hz), 3.48 (1H, dd J 8.2 Hz and 9.6 Hz), 3.67 (1H, dd J 9.7 Hz and 3.5 Hz), 4.57 (1H, s), 4.98 (1H, m), 7.23-7.37 (5H, m), 7.80 (1H, s), 7.83 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: Sc1ccc(Br)cc1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1ccccc1Sc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 4-chloro-iodobenzene (0.63 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(2-chlorophenylsulfanyl)-benzene (0.35 g). MS calcd. for C12H9BrClS [(M+H)+] 300, obsd. 300.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@H:15]1[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:5])=[O:4])[CH3:2].[H][H]>CO.C1COCC1.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[C:7]([C@H:15]2[C@@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:17][N:16]2[C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH:8]=1
Reactant: [H][H]
Reactant: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)CC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)CC
Yield: 102.2 %

Procedure:
To 35F (2.2 g) in methanol (50 mL) and THF (30 mL) was added 10% Pd/C (580 mg). The mixture was hydrogenated with a hydrogen balloon for 6.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 35H (2.1 g, 95% yield). 1H NMR (500 MHz, DMSO-d6, 100° C.) δ ppm 0.88 (t, J=6.87 Hz, 3H) 1.16 (t, J=7.42 Hz, 3H) 1.26 (s, 9H) 2.07-2.13 (m, 2H) 3.13-3.21 (m, 2H) 3.49 (br s, 1H) 3.63-3.75 (m, 4H) 5.69 (d, J=8.25 Hz, 1H) 6.50-6.55 (m, 2H) 7.44 (d, J=8.79 Hz, 1H); LC-MS 427 (M+H).
Reaction SMILES: [C@@H:1]([NH:5][C:6]1[C:7](=[O:20])[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2].N1C=CC=CC=1.[O:27](S(C(F)(F)F)(=O)=O)[S:28]([C:31]([F:34])([F:33])[F:32])(=O)=[O:29]>ClCCl>[C@@H:1]([NH:5][C:6]1[C:7]([O:20][S:28]([C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:27])=[N:8][C:9]2[C:14]([N:15]=1)=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
To a solution of (S)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.10 mmol) in dichloromethane (40 mL) was added pyridine (344 mg, 4.36 mmol). Tf2O (615 mg, 2.18 mmol) was added drop-wise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with water (3×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (S)-methyl 3-(sec-butylamino)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red oil (390 mg, crude).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][NH:13]C(=O)C(F)(F)F)[CH:10]=[CH:11][C:4]=2[O:3]1>N.CO>[CH3:1][C:2]1([CH3:20])[C:6](=[O:7])[C:5]2[CH:8]=[C:9]([CH2:12][NH2:13])[CH:10]=[CH:11][C:4]=2[O:3]1
Reactant: CC1(C)Oc2ccc(CNC(=O)C(F)(F)F)cc2C1=O
Agent: N
Solvent: CO
Product: CC1(C)Oc2ccc(CN)cc2C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 26.1 %

Procedure:
Dissolve N-(2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-ylmethyl)-2,2,2-trifluoro-acetamide (253 mg, 0.88 mmol) in 7M ammonia in methanol and stir at ambient temperature for 5 days. Remove volatiles in vacuo, purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (92:8) to give the title compound (44 mg, 26%). MS (ES+) m/z: 175 (M+H—NH3)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccccc1Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccccc1OC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
Triphenylphosphine (1.91 g, 7.31 mmol) was added to an ice-cooled solution of di-isopropylazodicarboxylate (1.48 g, 7.31 mmol) in dichloromethane (15 mL) and the mixture was stirred for 10 minutes. A solution of 2-chlorophenol (806 mg, 6.27 mmol) and 1-benzyl-4-hydroxypiperidine (1 g, 5.22 mmol) in dichloromethane (5 mL) was then added dropwise to the ice-cooled reaction mixture and stirring continued for a further 72 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in diethyl ether and extracted with saturated citric acid solution (5×10 mL). The combined aqueous solution was then basified with sodium hydroxide and extracted with dichloromethane (2×20 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a clear oil in 89% yield, 1.4 g. 1H NMR (CDCl3, 400 MHz): 1.85-1.95 (m, 2H), 1.97-2.08 (m, 2H), 2.32-2.47 (m, 2H), 3.58 (s, 2H), 4.46-4.34 (m, 1H), 6.87-6.95 (m, 2H), 7.16-7.22 (m, 1H), 7.20 (dd, 1H), 7.26-7.37 (m, 6H)
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O.[ClH:33]>[OH-].[Na+].CS(C)=O>[ClH:33].[CH2:26]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: O=C(O)c1ccc(N2CCN(c3cccc(O)c3)CC2)cc1
Reactant: CCCCCCBr
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCOc1cccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[4-(3-hydroxyphenyl)piperazin-1-yl]benzoic acid dihydrobromide (2.396 g) in a mixture of 5% NaOH aq. (16.7 ml) and dimethylsulfoxide (33.3 ml) was stirred for 30 minutes at 80° C. Then, 1-bromohexane (0.88 ml) was added thereto and stirred for 8 hours at 80° C. The reaction mixture was added to water and adjusted to pH 2.0 with 1N HCl. The produced precipitate was collected by filtration and dried under reduced pressure to give 4-[4-(3-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (3.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC1C=CC=CC=1)=O)[C:6](=[O:20])[C:5]2([C:31]1[C:32]([O:37][CH2:38][CH3:39])=[N:33][CH:34]=[CH:35][CH:36]=1)[O:21][C:22]([O:24]C1C=CC=CC=1)=O.[CH3:40][N:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C1COCC1>ClCCl>[CH3:40][N:41]1[CH2:42][CH2:43][CH:44]([N:47]2[CH2:52][CH2:51][N:50]([C:22]([O:21][C:5]3([C:31]4[C:32]([O:37][CH2:38][CH3:39])=[N:33][CH:34]=[CH:35][CH:36]=4)[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][C:6]3=[O:20])=[O:24])[CH2:49][CH2:48]2)[CH2:45][CH2:46]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 79 %

Procedure:
A mixture of 1.29 g (2.37 mmol) of phenyl 5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate, 1.73 g (9.46 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 10 ml of dry THF was stirred at room temperature for 72 hours. The reaction mixture was diluted with dichloromethane and extracted with water and saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was stirred with diethyl ether. 963 mg of the title compound were obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])N(C)OC)=[CH:19][N:18]2[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1>[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])=[CH:19][N:18]2[C:29]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Fc1ccccc1Br
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(C(=O)c3ccccc3F)cn2c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 50.7 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (191 mL, 1.75mmol) in dry THF (2 mL) under an argon atmosphere was added t-butyl lithium dropwise. After stirring for 50 minutes at −78° C., a solution of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.5 mmol) in dry THF (3 mL) was added. The resulting red-orange solution was stirred at the same temperature for another 50 minutes and then allowed to warm to RT. The solution was poured into H2O (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with H2O, dried (Na2SO4), and removed in vacuo to give a brown solid. The crude solid was purified by column chromatography (CH2Cl2/CH3CN 2.5/1) to give 84.0 mg (50.6%) of product as a yellow solid. MS(FAB) m/z 332.2 (M++1, 51.99), NMR (200 MHz, CDCl3) d 4.27 (bs, 2H, NH), 7.12-7.58 (m, 11H, ArH+H7+H8), 8.71 (s, H5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55]O>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH2:55][O:20][C:19](=[O:21])[CH2:18][S:17][C:14]1[N:15]=[CH:16][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:12][N:13]=1
Reactant: O=C(O)CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCc1cccc(F)c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCc1cccc(F)c1
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid (40 mg, 0.13 mmol) in THF (1 mL) was added diisopropylethylamine (45 μL, 0.26 mmol) and TSTU (55 mg, 0.18 mmol). After stirring for 5 min, 3-fluorobenzyl alcohol (18 μL, 0.17 mmol) and DMAP (18 mg, 0.15 mmol) were added and the solution was stirred for 18 h. Ethyl acetate was added, and the reaction was quenched with 3% HCl. The layers were separated, and the organic layer was washed successively with 5% NaHCO3, water, and brine. The brown organic layer was passed through a plug of SiO2 and washed with 50% ethyl acetate/hexane. The filtrate was concentrated to afford a yellow solid. Flash chromatography through SiO2 using 25% ethyl acetate/hexane afforded 15.0 mg (28% yield) of the titled product as a white solid. ESI-MS m/z 416 (MH+), 414 (M−H)−.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[C:11](=[O:18])[NH:10]2.[N+:19]([O-])([O-:21])=[O:20].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[NH:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N+:19]([O-:21])=[O:20])[NH:13][C:12](=[O:17])[C:11](=[O:18])[NH:10]2
Reactant: O=c1[nH]c2ccc(-c3ncc[nH]3)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(-c3ncc[nH]3)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 70 °C
Yield: 52.3 %

Procedure:
In 5 ml of sulfuric acid was dissolved 0.5 g of 6-imidazolylquinoxaline-2,3-(1H,4H)-dione hydrochloride followed by addition of 0.21 g of potassium nitrate, and the resulting mixture was heated at 70° C. for 5 minutes. After spontaneous cooling to room temperature, the reaction mixture was poured in ice-water and adjusted to pH 4-5 with aqueous sodium hydroxide solution, whereupon crystals separated out. These crystals were recovered by filtration and recrystallized from DMF-water to provide 0.27 g of 6-imidazolyl-7-nitroquinoxaline-2,3-(1H,4H)-dione.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[CH3:13]N(C=O)C>>[CH3:13][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After stirring for 1 h, the mixture was treated with iodometharc (13.5 ml. 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).