Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-hydroxy-3-phenylbenzoate (9.5 g, 41.7 mmol) in DMF (80 ml) was treated with K2CO3 (8.6 g, 62.5 mmole) and benzyl bromide (10.6 g 62.2 mmol). The reaction was stirred at ambient temperature overnight, then partitioned between ethyl acetate/and water. The organic phase was washed well with water, dried (MgSO4) and evaporated. The residue was purified by chromatography (eluant: ethyl acetate/hexane) to give methyl 2-benzyloxy-3-phenylbenzoate (11.23 g, 8.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][N:8]=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:6]2=O.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[N:8][C:7]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1n[nH]c2cc(OC)c(OC)cc2c1=O
Product: CCOC(=O)c1nnc2cc(OC)c(OC)cc2c1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a 50 mL round bottom flask charged with a magnetic stir bar and ethyl 6,7-dimethoxy-4-oxo-1,4-dihydrocinnoline-3-carboxylate (1.00 g, 3.6 mmol) (Method 5) was added phosphorous oxychloride (15 mL). The reaction flask was fitted with a reflux condenser and heated to reflux for 2 h before being allowed to cool to rt. The crude reaction mixture was concentrated in vacuo, and the residue was treated with aqueous NaHCO3 (˜25 mL). The crude product precipitated from solution and was collected via vacuum filtration using a Buchner funnel. The solid was washed water (1×100 mL) and diethyl ether (1×100 mL) to yield 0.941 g (88%) of the title compound as a light brown solid that was used without further purification. 1H NMR: 7.98 (s, 1H), 7.50 (s, 1H), 4.55 (q, 2H), 4.13 (s, 6H), 1.45 (t, 3H); m/z 298.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C:10]#C)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:13]Cl>>[Br:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:13]=[C:9]([CH3:10])[O:8][C:7]=12
Reactant: ClCCl
Reactant: C#CCOc1cccnc1Br
Product: Cc1cc2ccnc(Br)c2o1
Yield: 46 %

Procedure:
2-Bromo-3-propargyloxypyridine (9.4 g) was heated under reflux under nitrogen in dichloromethane (100 ml) for 64 hours, then the solvent was removed in vacuo and the residue purified by column chromatography on silica using dichloromethane as eluant to give 7-bromo-2-methylfurano[2,3-c]pyridine as a tan solid (4.3 g, 46%).
Reaction SMILES: [F:1][C:2](I)([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].[Br-:27]>[Cu](Br)Br>[F:1][C:2]([Br:27])([F:25])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10]
Reactant: [Br-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: Br[Cu]Br
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
13.0 g (0.09 mol) of finely ground copper bromide of the formula CuBr are put into a bomb tube of capacity 25 cm3 and made of glass, and are subjected to a temperature of 200° C. under a pressure of 10 Pa for 4 hours, in order to remove residual water. After the bomb tube has cooled to room temperature, anhydrous nitrogen is passed into it and 16.4 g (0.03 mol) of perfluorooctyl iodide are added, and the bomb tube is sealed by fusion and shaken for 50 hours at 240° to 250° C. 3 mol of bromide ions are employed per mol of bound iodine atom. When the reaction is complete, the bomb tube is opened and the organofluorine products are distilled out of the bomb tube by heating at 200° C. This gives 12.8 g of distillate which, according to analysis by gas chromatography is composed of 97.7% by weight of perfluorooctyl bromide; 1.9% by weight of unreacted perfluorooctyl iodide and 0.3% by weight of CF3 (CF2)7H. This corresponds to a yield of 83.5% of perfluorooctyl bromide, relative to perfluorooctyl iodide employed.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([CH2:10][CH2:11][OH:12])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CC(C)=O>[CH2:20]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=1[CH2:10][CH2:11][OH:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: OCCc1cc(F)c(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCc1cc(F)c(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.1 %

Procedure:
To a solution of 4,5-difluoro-2-(2-hydroxyethyl)phenol (450 mg, 2.58 mmol) in acetone (10 mL) was added K2CO3 (714 mg, 5.17 mmol) followed by (bromomethyl)benzene (0.461 mL, 3.88 mmol) and the resulting mixture was stirred at room temp for 16 h. Water was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (5-30% EtOAc/hexane) to afford 2-(2-(benzyloxy)-4,5-difluorophenyl)ethanol (580 mg, 2.195 mmol, 85% yield) as viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.48-7.33 (m, 5H), 7.10-7.01 (m, 1H), 6.78 (dd, J=12.1, 6.7 Hz, 1H), 5.05 (s, 2H), 3.85 (q, J=6.0 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H), 1.52 (t, J=5.5 Hz, 1H).
Reaction SMILES: [F:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[C:12](=[O:21])[C:11]=2[CH:22]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][C:19]([S:2]([F:1])(=[O:5])=[O:3])=[CH:20][C:13]=3[C:12](=[O:21])[C:11]=2[CH:22]=1
Reactant: O=S(=O)(O)F
Reactant: O=C1c2ccccc2CCc2ccc(Br)cc21
Product: O=C1c2cc(Br)ccc2CCc2ccc(S(=O)(=O)F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fluorosulfonic acid, 100 ml., is placed in a 300 ml. 3-necked round bottom flask equipped with polyethylene inlet tube and polyethylene exit tube with drying tube half-filled with anhydrous sodium fluoride. A nitrogen atmosphere is maintained throughout the reaction. With stirring, 17.0 g. (0.059 mole) of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one is added in portions over 20 minutes. After stirring another 10 minutes, the dark green solution is heated on the steam-bath for 61/2 hours. The mixture then is cooled to room temperature, poured cautiously with stirring into 1.5 kg. of crushed ice, and allowed to stand overnight at room temperature. The brown solid is collected, washed with water, dried in a vacuum desiccator over sodium hydroxide, and then extracted in a Sohxlet extractor with 700 ml. of boiling cyclohexane for 16 hours. On cooling, the cyclohexane extract deposits 11.65 g. (53%) of 3-bromo-7-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one as dark yellow flakes, m.p. 148°-151°C. Recrystallizations from ether and cyclohexane give an analytical sample, m.p. 150°-152°C.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][O:7][C:8]1[C:9](=[O:45])[C:10]([CH3:44])=[C:11]([CH2:17][C:18]2[CH:39]=[CH:38][C:21]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[O:23])=[C:20]([O:40]C(=O)C)[CH:19]=2)[C:12](=[O:16])[C:13]=1[O:14][CH3:15]>CO>[CH3:6][O:7][C:8]1[C:9](=[O:45])[C:10]([CH3:44])=[C:11]([CH2:17][C:18]2[CH:39]=[CH:38][C:21]([C:22]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([C:34]([F:35])([F:36])[F:37])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[O:23])=[C:20]([OH:40])[CH:19]=2)[C:12](=[O:16])[C:13]=1[O:14][CH3:15]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c(OC(C)=O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c(O)c2)=C(C)C1=O
Reaction time: 1 h
Yield: 33.2 %

Procedure:
An aqueous saturated sodium hydrogencarbonate solution (7 ml) was added to a methanol solution (15 ml) of N-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(trifluoromethylsulfonyl)aniline (114 mg, 0.196 mmol) and the resulting solution was stirred for 1 hour. The reaction solution was extracted with ethyl acetate, then washed with water and dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (35 mg, 0.065 mmol, 33%).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](NC2C=CC(CN)=CC=2S(O)(=O)=O)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccc(Nc2cc(S(=O)(=O)O)c(N)c3c2C(=O)c2ccccc2C3=O)c(S(=O)(=O)O)c1
Agent: Clc1nc(Cl)nc(Cl)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(4'-Aminomethyl-2'-sulfoanilino)anthraquinone-2-sulfonic acid (27.3 parts), cyanuric chloride (9.3 parts) and 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation in an aqueous medium one after another in a usual manner. Successively, the resulting condensate was further subjected to condensation with 1-amino-4-(4'-aminomethyl-2'-sulfoanilino)anthraquinone-2-sulfonic acid (24.5 parts) at 60° to 70° C. under a weak acid condition, and thereafter, the reaction mixture was salted-out to separate crystals, thereby obtaining an anthraquinone compound of the following formula in the free acid form. ##STR512##
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:31]([CH3:35])[CH2:32][CH2:33][OH:34])[C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:34][CH2:33][CH2:32][CH:31]([CH3:35])[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([F:12])=[CH:18][CH:17]=2)[C:20]([NH:22][NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(CCO)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)C(C(=O)NNC(=O)OC(C)(C)C)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
p-Toluenesulfonyl chloride (321 mg) was added to a solution of tert-butyl N′-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate (520 mg) in pyridine (6 mL). The reaction solution was stirred at room temperature for 12 hours and then concentrated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 335 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: P(Cl)(Cl)Cl.[CH:5]([O:18][C:19]([C:21]1[N:22]2[CH:25]([S:26](=O)[CH2:27][C:28]=1[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31])[CH:24]([NH:39][C:40](=[O:70])[C:41](=[N:67][O:68][CH3:69])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[S:45][CH:46]=1)[C:23]2=[O:71])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CC(N(C)C)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH:5]([O:18][C:19]([C:21]1[N:22]2[CH:25]([S:26][CH2:27][C:28]=1[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31])[CH:24]([NH:39][C:40](=[O:70])[C:41](=[N:67][O:68][CH3:69])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[S:45][CH:46]=1)[C:23]2=[O:71])=[O:20])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -8 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Phosphorus trichloride (0.81 cc) is added, in the course of 1 minute, to a solution of the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (4.3 g) and dimethylacetamide (1.88 cc) in methylene chloride (43 cc), cooled to -8° C., and the mixture is left for 1 hour at -8° C., whilst stirring. The mixture is then poured into a saturated solution of sodium bicarbonate (20 cc) and ethyl acetate (100 cc). The organic phase is washed with water (30 cc), dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is dissolved in ethyl acetate (15 cc) and the solution is filtered on Merck silica gel (0.06-0.2) (13 g) and washed through with ethyl acetate (20 cc). The filtrate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene (3.6 g) in the form of a beige solid.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[N:14][CH:15]=[CH:16][C:10]=3[N:9]([C:17](=[O:19])[CH3:18])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Product: CC(=O)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 76 %

Procedure:
3-Phenyl-1,4-dihydropyrido[3,4-e]-as-triazine is reacted with acetic anhydride as described in Example 11 to obtain 3-phenyl-1-acetyl-1,4-dihydropyrido[3,4-e]-as-triazine with a yield of 76%; m.p.: 208°-209° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:13][C:11]=2[N:12]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:55][C:56]1[CH:61]=[CH:60][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([O:66]CC)=[O:65])=[CH:58][CH:57]=1>CN(C)C=O>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([CH2:17][C:18]([NH:55][C:56]3[CH:57]=[CH:58][C:59]([C@H:62]([CH3:69])[CH2:63][C:64]([OH:66])=[O:65])=[CH:60][CH:61]=3)=[O:20])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2o1
Yield: 30.6 %

Procedure:
A solution of 2-(o-tolylaminobenzoxazol-6-yl)acetic acid (1.0 g, Reference Example 4) in dimethylformamide (75 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.35 g), then with diisopropylethylamine (1.2 mL) and then with ethyl (R)-3-(4-aminophenyl)butanoate (0.74 g, Reference Example 1). The mixture was kept at room temperature for an hour and then evaporated to low bulk. The residue was partitioned between hydrochloric acid (1M) and dichloromethane. The organic phase was washed with aqueous bicarbonate solution (5%) then with water, then dried, and then evaporated. The residue was suspended in ethanol (about 50 mL). The mixture was treated with aqueous sodium hydroxide (about 5 mL, 1M), then refluxed for 2 hours, then evaporated. The residue was triturated with aqueous hydrochloric acid (1M) then filtered. The insoluble material was washed with water, and then dried to give the title compound (0.48 g) as a white powder. MS: accurate mass=444.1936 (calculated 444.1923 MH+). LC-MS: RT=3.19 minutes (100% by ELSD); MS (ES+), 444 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:4][C:3]2[C:2]([Br:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Br:9])=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(=O)Nc2c(Br)cccc2Br)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
2,6-Dibromoaniline (1.0 g, 3.98 mmol) was dissolved in dioxane (20 mL) and treated with diisopropylethylamine (1.39 mL, 7.96 mmol) followed by 4-tert-Butylbenzoyl chloride (1.70 g, 7.96 mmol). The solution was warmed to 60° C. and stirred overnight. The mixture was concentrated under reduced pressure and the residue was re-dissolved in ethyl acetate (50 mL). The organic solution was washed with 10% HCl (2×50 mL), saturated sodium carbonate (50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 20% acetone/hexane to yield 1.33 g (81%) of product. MS (ESI) m/z 409.9772; HPLC Method B, purity 92.3% at 210-370 nm, 10.4 min.; 89.7% at 232 nm, 10.4 min.; HRMS: calcd for C17H17Br2NO+H+, 409.97496; found (ESI, [M+H]+), 409.9772.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:16][NH:17][C:18]([NH2:20])=[S:19].C(O)C>C(O)(=O)C.O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[N:16][NH:17][C:18]([NH2:20])=[S:19])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reactant: NNC(N)=S
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=S)NN=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 96 h
Yield: 95 %

Procedure:
Stir 4.14 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde together with 2.0 g. of thiosemicarbazide, 2 drops of glacial acetic acid and 40 ml of ethanol for 2 hours at 50° C and then for 4 days at room temperature. Dilute the resulting product with water to produce a 95% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde-thiosemicarbazone [m.p. above 350° C (with decomposition)].
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C@H:8]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][CH2:22]3)[CH:16]=[N:17][CH:18]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][C@H:8]([NH:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][CH2:22]3)[CH:16]=[N:17][CH:18]=1)[CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)[C@@H](Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1)C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)[C@H](CO)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
In a 10 mL round-bottomed flask, 6-{5-[(R)-1-(tert-butyl-dimethyl-silanyloxymethyl)-2-methyl-propylamino]-pyridin-3-yl}-1-methyl-3,4-dihydro-1H-quinolin-2-one (60 mg, 132 μmol) was dissolved in THF (1.5 mL) to give a light yellow solution and cooled down to 0° C. TBAF, 1 M sol. in THF (132 μl, 132 μmol) was added dropwise. The solution was stirred at 0° C. for 1.5 h and partitioned between aqueous sat. NaHCO3 solution and AcOEt (3×). The organic layers were collected, dried over Na2SO4 and evaporated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 100% EtOAc followed by 1% MeOH in EtOAc) to give the title compound (22 mg, 49%) as a light yellow foam. MS: 340.2 (M+H+).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@@H:11]1[N:17]2C(=O)[O:19][N:20]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:4]([OH:6])=[O:5].[K].[OH-].[Na+]>>[ClH:1].[NH2:2][C@@H:3]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](=[N:20]/[OH:19])/[NH:17]1)[C:4]([OH:6])=[O:5]
Reactant: N[C@@H](C/C=C\C[C@H]1CCCCc2noc(=O)n21)C(=O)O
Agent: Cl
Agent: [K]
Agent: [Na+]
Product: N[C@@H](C/C=C\C[C@H]1CCCC/C(=N/O)N1)C(=O)O

Procedure:
A sample of the product of Example 9 is converted to the title compound by reaction with aqueous potassium or sodium hydroxide.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].CO>C(#N)C.ClCCl>[OH:18][CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Temperature: 95 °C
Yield: 79.6 %

Procedure:
A mixture of tert-butyl piperazine-1-carboxylate (2.75 g, 14.8 mmol), 1-bromo-3-propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25 mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95° C. for 4 hours. The solvent was removed under reduced pressure, and the residue was taken up in dichloromethane (300 mL) and washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with methanol in dichloromethane (0-10%) gave a tan solid 2.88 g (80% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C1COCC1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOC(C)=O>[F:14][C:9]([F:15])([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(Br)cc1
Reactant: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4-(perfluoroethoxy)benzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled in an ice bath for 10 min. A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min. The ice bath was removed after 1 hour, and the reaction was warmed to room temperature and stirred overnight. GC/MS showed the presence of starting material. The reaction was cooled in an ice bath and 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room temperature for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −86.05, −87.84; ESIMS m/z 284 ([M+11]+).