Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CB1OB(C)OB(C)O1.[C:10]([NH:14][C:15]([C:17]1[C:22]([CH2:23][C:24](=[O:26])[CH3:25])=[C:21](Cl)[CH:20]=[CH:19][N:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:28](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([NH:14][C:15]([C:17]1[C:22]([CH2:23][C:24](=[O:26])[CH3:25])=[C:21]([CH3:28])[CH:20]=[CH:19][N:18]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)Cc1c(Cl)ccnc1C(=O)NC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cc1c(C)ccnc1C(=O)NC(C)(C)C
Temperature: 100 °C
Yield: 77.9 %

Procedure:
Trimethylboroxine (5.7 mL, 41 mmol) is added to 4-chloro-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (3.63 g, 13.5 mmol), potassium carbonate (9.33 g, 67.5 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (1.10 g, 1.35 mmol) in DMF (60 mL) and the reaction mixture is heated at 100° C. overnight. Volatiles are evaporated under reduced pressure and the residue dissolved with EtOAc/water. The organic layer is separated, dried and evaporated under reduce pressure to give a residue that is purified by flash chromatography (eluent 0-30% EtOAc/cyclohexane) to furnish 4-methyl-3-(2-oxo-propyl)-pyridine-2-carboxylic acid tert-butylamide (2.61 g, 78%).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:15])=[CH:12][CH:13]=1)([C:4]([OH:6])=[O:5])[CH3:3].C(O[CH:27]([CH3:29])[CH3:28])(=O)C.C(=O)([O-])[O-].[K+].[K+].BrC(C)C>CS(C)=O>[CH3:28][CH:27]([O:5][C:4]([C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH3:3])=[O:6])[CH3:29]
Reactant: CC(=O)OC(C)C
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 kg (3.14 mol) of fenofibric acid (II), 500 ml of dimethyl sulfoxide and 1 l of isopropyl acetate were charged into a jacketed 5 l reactor under nitrogen. 433.5 g (3.14 mol) of potassium carbonate were then added, with stirring at ambient temperature, and the reaction mixture was brought to 85-90° C. for 45 min. The temperature of the reaction mixture was subsequently reduced to approximately 80° C. and 354 ml (3.77 mol) of 2-bromopropane and then 100 ml of isopropyl acetate were added over a period of 50 min. The mixture was kept stirring at 85-95° C. for 5 hours and then slightly cooled to approximately 80° C. In-process monitoring showed that the degree of conversion to give fenofibrate was approximately 99.5%. The content of the reactor was hot-filtered and the salts separated on the filter were washed with 1 l of isopropyl acetate, which was combined with the filtrate. The isolated salts, which essentially comprise potassium bromide, were dried and kept for recycling. The filtrate was concentrated under reduced pressure while maintaining a bulk temperature of approximately 80° C., and of 95° C. at the end of concentrating. After removal of the solvents, 2.27 l of isopropanol and 455 ml of pure water were added. The mixture was brought to gentle reflux for 10 min and then hot-filtered. Under stirring, the filtrate was slowly cooled down to a temperature of 0° C. The crystallized fenofibrate was separated by filtration on a filtering device, washed on the filtering device with approximately 500 ml of ice-cold isopropanol and then dried under vacuum at 45-50° C. 1075 g of fenofibrate with a purity of greater than 99.5% and comprising no impurity at a level of greater than 0.05% were thus obtained (yield=94.9%).
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.O.[S:13]([Cl:17])(Cl)(=[O:15])=[O:14]>ClC1C=CC=CC=1>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([S:13]([Cl:17])(=[O:15])=[O:14])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1ccc([N+](=O)[O-])cc1
Solvent: Clc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 95.2 %

Procedure:
A 2-liter, 4-necked flask equipped with a stirrer, thermometer, condenser and a dropping funnel having a by-pass was charged with 20.4 g (0.10 mole) of 4-nitrophenyl methyl sulfide, 10 g of water and 200 g of monochlorobenzene. Then, 94.5 g (0.70 mole) of sulfuryl chloride was added dropwise at 10° C. over a period of about 2 hours. Thereafter the mixture was stirred at 10° C. for 6 hours to complete the reaction. After completion of the reaction, the oil layer was separated and 10 g of water was added to accomplish washing. Then, the oil layer was separated and left to stand for about 1 hour with the addition of about 5 g of anhydrous sodium sulfate to remove the water. The solvent was distilled off to give crude crystals. The crude crystals were dissolved in monochlorobenzene and a poor solvent was added for recrystallization, giving 21.1 g of 4-nitrobenzenesulfonyl chloride as white crystals in a yield of 95% as calculated based on 4-nitrophenyl methyl sulfide.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[OH:19][C:17]1[CH:16]=[CH:15][N:14]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[C:13](=[O:12])[CH:18]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: Oc1ccnc(O)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Temperature: 150 °C

Procedure:
A mixture of methyl 4-iodobenzoate (0.421 g, 1.6 mmol), 2,4-dihydroxypyridine (0.174 g, 1.34 mmol), CuI (25 mg, 0.134 mmol) and K2CO3 (200 mg) in DMF (2 mL) was heated to 150° C. in a sealed vial for 4 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL), dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/e 246 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[CH:6][N:5]=2.[SH-:19].[Na+]>C(O)C>[CH2:12]([N:3]1[C:2]([SH:19])=[N:10][C:9]2[C:4]1=[N:5][CH:6]=[N:7][C:8]=2[NH2:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnc2c1nc(Br)n2Cc1ccccc1
Reactant: [SH-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ncnc2c1nc(S)n2Cc1ccccc1
Yield: 99 %

Procedure:
910 mg (3.0 mmol) of 8-bromo-9-benzyladenine and 1.08 g of sodium hydrosulfide were added to 50 ml of ethanol and heated for 12 hr under refluxing. After the solvent was removed by distillation, the reaction product was dissolved in distilled water and neutralized with 1 N hydrochloric acid. Deposited crystals were collected by filtration to thereby obtain the captioned compound (770 mg; yield: 99%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]4)=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Reactant: COc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1cc(CC)n(-c2cccc3nc(Nc4c(C)cc(Br)cc4OC)n(C)c23)n1
Temperature: 110 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of 83 mg (0.287 mmol) of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole, 186 mg (0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 20 hours. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to give 112 mg (83%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1C=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[C:13]([F:30])=[CH:14][C:15]3[C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]4[CH:18]([CH3:22])[CH2:19]OC=1[C:16]=34)[CH2:6]2.C(OC(C1C(=O)C2C(=NC(Cl)=C(F)C=2)[N:38](C2CC2)C=1)=O)C.NC1C=CC=C2C=1CNC2.C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:12]1[N:38]=[C:16]3[C:15]([C:25](=[O:26])[C:24]([C:27]([OH:29])=[O:28])=[CH:23][N:17]3[CH:18]3[CH2:22][CH2:19]3)=[CH:14][C:13]=1[F:30])[CH2:8]2
Reactant: CC1COc2c(N3Cc4ccc(CN)cc4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Nc1cccc2c1CNC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1cccc2c1CN(c1nc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
310 mg of 1 cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 270 mg of 4-aminoisoindoline, 0.42 ml of triethylamine, and 5 ml of anhydrous chloroform were processed in a similar manner as in Example 107 to produce 88 mg of 7-(4-amino-2- isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O[N:25]1[C:29](=[O:30])[CH2:28][CH2:27][C:26]1=[O:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18]([O:20][N:25]2[C:29](=[O:30])[CH2:28][CH2:27][C:26]2=[O:31])=[O:19])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(ON1C(=O)CCC1=O)c1ccc(-c2ccc(S(=O)(=O)NCCO)cc2)[nH]c1=O

Procedure:
From 3.8 g. of 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid and 1.34 g. of N-hydroxysuccinimide in 60 ml. of dimethylformamide, and 2.56 g. of N,N'-dicyclohexylcarbodiimide in 5 ml. of dimethylformamide, following the procedure of a) above, there is obtained 6-[4-[(2-hydroxyethyl)aminosulfonyl]phenyl]-1,2-dihydro-2-oxonicotinic acid, 2,5-dioxo-1-pyrrolidinyl ester; m.p. 203.5°-205° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2N)[C:13]1=[O:23])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].N([O-])=O.[Na+].CS(C)=O.[IH:32].C([O-])(O)=O.[Na+]>>[C:1]([O:4][CH2:5][CH:6]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[I:32])[C:13]1=[O:23])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)n1ccc2c(N)cccc2c1=O
Reactant: I
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OCC(COC(C)=O)n1ccc2c(I)cccc2c1=O
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
2-(5-Amino-1-oxoisoquinolin-2(1H)-yl)propane-1,3-diyl diacetate (4.2 g, 0.013 mol) was added to a solution of sodium nitrite (4 g, 0.05 mol) in dimethyl sulfoxide (70 mL, 1 mol) at 35° C. Aqueous hydrogen iodide (7 mL, 0.05 mol) in dimethyl sulfoxide (70 mL, 1 mol) was added, the mixture was stirred at 35° C. for 45 minutes. The cooled mixture was neutralized with sat. aq. NaHCO3, extracted with CH2Cl2 (50 mL×3), washed with brine, and dried over MgSO4. Filtered, evaporated and purified via flash column chromatography (12 g of silica gel, 50-100% EtOAc/Hexane) to give the desired product as a yellow oil. MS m/z (M+H) 430.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2S(C1C=CC(C)=CC=1)(=O)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:30]([C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21])(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cccc32)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(Br)cccc21

Procedure:
The procedure for Intermediate 3 was followed using (2-methoxy-5-methylphenyl)sulfonyl chloride. Yield 1.4 g (72%). MS (ESI+) for C16H14BrNO3S m/z 382 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:26]([CH3:27])=[CH:25][C:24]([Cl:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:9][C:20](=[O:21])[C:19]3[CH:23]=[C:24]([Cl:28])[CH:25]=[C:26]([CH3:27])[C:18]=3[N:17]=2)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Product: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
A procedure analogous to that of Example 1, Step E was used to convert 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (i.e. the pyrazolecarboxylic acid product of Example 5, Step D) (1.5 g, 4.96 mmol) and 2-amino-3-methyl-5-chlorobenzoic acid (i.e. the product of Example 1 Step A) (0.92 g, 4.96 mmol) to the title product as a solid (1.21 g).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][CH2:12][NH2:13].[C:17]([NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([CH2:31]Br)=[CH:26][CH:27]=2)[N:22]=1)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([CH2:31][NH:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=3)=[CH:26][CH:27]=2)[N:22]=1)(=[O:19])[CH3:18]
Reactant: NCCc1cccc(F)c1
Reactant: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2ccc(CNCCc3cccc(F)c3)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Anhydrous Cs2CO3 (0.295 g, 0.906 mmol) was diluted in anhydrous DMF (10 mL). 3-Fluorophenethylamine (22, 0.126 g, 0.906 mmol) was added, and the mixture was stirred at room temperature for 30 min before a solution of 21 (0.220 g, 0.788 mmol) in DMF (4 mL) was added slowly over 5 min. The cloudy yellow mixture was stirred at room temperature for 16 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with H2O (2×50 mL) and sat. aq. NaCl (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (SiO2) eluting with 10% MeOH in EtOAc to yield the product as a clear yellow oil (0.187 g, 70%). 1H-NMR (500 MHz; CDCl3): δ 8.95 (s, 1 H), 8.40 (br d, J=8.2 Hz, 1 H), 8.15 (d, J=8.9 Hz, 1 H), 7.74 (d, J=8.3 Hz, 1 H), 7.72 (s, 1 H), 7.41 (dd, J=8.3, 1.5 Hz, 1 H), 7.26-7.22 (m, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.93-6.88 (m, 2 H), 4.00 (s, 2 H), 2.95 (t, J=7.0 Hz, 2 H), 2.85 (t, J=7.0 Hz, 2 H), 2.23 (s, 3 H); 13C NMR (126 MHz; CDCl3): δ 169.3 (1 C), (163.9+162.0, 1 C), 151.3 (1 C), 146.5 (1 C), (142.47+142.41, 1 C), 142.37 (1 C), 138.5 (1C), (129.95+129.88, 1 C), 127.8 (1 C), 125.76 (1 C), 125.71 (1 C), 125.4 (1 C), (124.42+124.40, 1 C), (115.63+115.46, 1 C), 114.0 (1 C), (113.23+113.06, 1 C), 53.7 (1 C), 50.1 (1 C), 36.1 (1 C), 24.9 (1 C); ESIMS m/z (rel. intensity) 338 (MH+, 80).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:23]3[CH2:22][CH2:21][NH:24][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.0 g. (50 mmole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The solvents were removed by evaporation and the residue containing starting material and the product was washed with water, chromatographed over Florisil, and recrystallized from petroleum ether to give the above-titled product as yellow prisms, m.p. 100° -102°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[O:22]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:20][C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)=[O:22])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)COC(=O)Cc2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a stirred solution of 4.45 g (28.9 mmol) of 4-fluorophenylacetic acid in 3.26 g (31.8 mmol) of triethylamine and 275 mL of acetonitrile was added 8.9 g (28.9 mmol) of 2-bromo-4'-(methylsulfonyl)acetophenone (prepared in Step 3) at ambient temperature. The reaction mixture was stirred for 30 minutes, concentrated in vacuo, and partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography with ethyl acetate/hexane (1:1) gave 6.87 g (68%) of 2-(4-fluorophenyl)-1-[2-[4-(methylsulfonyl)phenyl]-2-oxoethoxy]ethanone as a colorless solid: NMR (CDCl3) δ3.08 (s, 3 H), 3.79 (s, 2 H), 5.35 (s, 2 H), 7.06 (s, t, J=9 Hz, 2 H), 7.32 (dd, J=6 and 9 Hz, 2 H), 8.06 (s, 4 H).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])[C:2]([CH3:4])=[O:3].[N+:13]([O-])([OH:15])=[O:14].O>C(OC(=O)C)(=O)C>[NH:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[OH:12])[C:2]([CH3:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Yield: 31 %

Procedure:
Under ice cooling, a solution of 2-acetamino-4-chlorophenol (1.0 g, 5.4 mmol) in acetic anhydride (90 mL) was added with 70% nitric acid (0.38 mL, d=1.42) with stirring. After stirring for 2 hours, the mixture was added with water (100 mL), and the mixture was further stirred for 1 hour. The mixture was extracted by adding diethyl ether, and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=5:1 v/v) to obtain the title compound (0.38 g, 31%).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].[Cl:29][CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(N(CC)CC)C>[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 74082.7 %

Procedure:
To a solution of 1.018 g (2.95 mM) of 3-hexadecylthio-2-methoxypropylamine IV a2 in 15 ml of dichloromethane and 0.534 ml (3.83 mM) of triethylamine is added 0.563 mg (3.24 mM) of 3-chloropropanesulfonyl chloride with ice-cooling and the mixture is stirred at 0° C. for 3 hours. After the solvent is evaporated, the residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (4:1) mixture as an eluent. The product is recrystallized from chloroform-n-hexane to give 1.275 g (2.62 mM) of 3-(3-chloropropylsulfonylamino)-1-hexadecylthio-2-methoxypropane III a2 as a colorless powder in 89% yield.
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([O:13][CH3:14])=[O:12].[Br-:15].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>N1C=CC=CC=1>[Br:15][C:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:2][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: [Br-]
Reactant: COC(=O)c1cc2cccnc2[nH]1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1[nH]c2ncccc2c1Br
Temperature: 0 °C
Yield: 32.5 %

Procedure:
To a solution of 3.2 g of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride in 165 mL of pyridine is added dropwise, at 0° C. under an argon atmosphere, a solution of 5.04 g of pyridinium tribromide in 35 mL of pyridine. The reaction mixture is then stirred at 0° C., and then poured onto a mixture of 250 g of crushed ice and 750 ml of distilled water. The suspension is filtered and the solid is washed with twice 25 mL of distilled water and then dried in the open air. 0.87 g of methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate is obtained in the form of a beige-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([S:8][CH2:9][CH2:10][Cl:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClC1C=CC=C(C(OO)=[O:20])C=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([S:8]([CH2:9][CH2:10][Cl:11])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCSCCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCS(=O)CCCl
Temperature: -20 °C
Reaction time: 3 h
Yield: 111 %

Procedure:
Dissolve 2-chloroethyl heptyl sulfide (1.0 g, 5.13 mmol) in methylene chloride (50 mL), cool to -20° C. and place under nitrogen atmosphere. Add, by dropwise addition, a solution of meta-chlorperbenzoic acid (1.25 g, 6.0 mmol) in methylene chloride. Stir at -20° C. for 3 hours, then allow to warm to room temperature. Treat with saturated sodium meta bisulfite (until negative starch-iodide test) and basify with saturated sodium hydrogen carbonate. Extract with methylene chloride (2×25 mL), dry (MgSO4) and evaporate in vacuo to yield 1.2 g of 2chloroethyl heptyl sulfoxide as white crystals; MS (CI/CH4) m/z 211(M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C

Procedure:
10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine are dissolved in 100 ml of dichloromethane and combined with 10.7 g (63 mmol) of 4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine. The mixture is refluxed for 12 hours. After cooling to ambient temperature the reaction solution is washed several times with water. The organic phase is dried over magnesium sulphate and then evaporated to dryness.