Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].[OH-].[K+]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Cc1ccc(CCO)cc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 87.5 %

Procedure:
2-(4-Methylphenyl)ethyl alcohol (VIII) (2.72 g, 0.02 mole), 4-nitrochlorobenzene (IX: X=Cl) (3.15 g, 0.02 mole) and potassium hydroxide (1.4 g, 0.025 mole) were added to benzene (60 ml), and dicyclohexyl-18-crown-6 (0.2 g) was added thereto, followed by reaction at 60° C. for 10 hours. The reaction mixture was washed with water and concentrated, and the precipitated crystals were recrystallized from 95% ethanol to obtain 4.5 g of 4-[2-(4-methylphenyl)ethoxy]nitrobenzene (VI) as white crystals (yield, 87.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Reaction time: 12 h
Yield: 30.9 %

Procedure:
The general procedure above was followed using 4-methylchlorobenzene (127 mg, 1.0 mmol) and PhB(OH)2 (183 mg, 1.5 mmol) with Pd2(dba)3 (20 mg, 0.0218 mmol) and PhPH(O)(CHMe2) from Experiment 1 (14.7 mg, 0.0874 mmol) and CsF (456 mg, 3.0 mmol) in 4.0 mL of 1,4-dioxane. After 12 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 52 mg (31% yield) of 4-phenyltoluene. It was >95% pure by 1H NMR and GC/MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[NH:7]2.[H-].[Na+].CCCCCC.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]2[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2[nH]c(C)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4-Methoxy-2-methyl-1H-indole (1 g, 6.2 mmol) was added to 248 mg (6.2 mmol) of 60% sodium hydride/mineral oil (washed with hexane before adding DMF) in 15 mL of DMF and after stirring for 0.5 hour, 0.74 mL (6.2 mmol) of benzyl bromide was added. The mixture was stirred at room temperature for 18 hours, diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4) and after concentrating at reduced pressure, the residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 1.3 g (84% yield) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole, melting at 96°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([OH:12])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.B(O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([O:12][CH3:18])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CO
Agent: OB(O)O
Product: COC(=O)C(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
25.0 g of 3,5-difluorophenylhydroxyacetic acid (D2) are dissolved in 325 ml of methanol. 3.9 g of boric acid are subsequently added, and the reaction mixture is stirred at room temperature for 18 hours. The resultant solution is then evaporated to dryness. The residue is extracted using 100 ml of ethyl acetate and 100 ml of water. The aqueous phase is subsequently extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo, giving 25.5 g of the title compound as crude product. Recrystallisation from 17 ml of ethyl acetate and 170 ml of cyclohexane give 23.5 g of the pure compound C2 having a melting point of 61.8° C. (MS 201.9 (M+)).
Reaction SMILES: CN1CCOCC1.Cl.[NH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=[O:12].[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])[O:25][C:24]1([CH3:57])[CH3:56])=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21]([N:23]1[C@@H:27]([CH2:28][C@@H:29]([CH:45]([CH3:47])[CH3:46])[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[C@H:26]([CH2:48][C@H:49]([C:53](=[O:54])[NH:9][C:10]([C:11](=[O:12])[NH2:13])([CH3:15])[CH3:14])[CH:50]([CH3:51])[CH3:52])[O:25][C:24]1([CH3:56])[CH3:57])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)NC(C)(C)C(N)=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Temperature: 40 °C
Reaction time: 192 h

Procedure:
106 μl of 4-methyl-morpholine, 66 mg of 2-aminoisobutyric acid amide hydrochloride and 91 mg of O-benztriazol-1-yl-N,N,N','-tetramethyluronium hexafluorophosphate (HBTU) are added in succession to 119 mg of 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124 c) in 8 ml of dimethylformamide. The reaction mixture is stirred for 8 days at 40° C. The mixture is concentrated by evaporation and the residue is partitioned between ethyl acetate and saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by means of FC (60 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.30.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1>[Pd].COCCO>[CH:1]1([CH2:7][CH:8]2[NH:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NC(=O)C(=CC2CC=CCC2)N1
Agent: [Pd]
Solvent: COCCO
Product: O=C1NC(=O)C(CC2CCCCC2)N1
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
Forty milliliters of ethyleneglycol monomethyl ether, 3.84 g of 5-(3-cyclohexene-1-yl)methylenehydantoin and 0.43 g of wet 10% palladium on carbon (moisture 50%) were placed in a reactor equipped with a mechanical stirrer and a reflux condenser, and the mixture was reduced while stirring at 50° C. under a hydrogen pressure of 3 kg/cm2. After 4 hours, the reaction mixture was heated to 90° C. and the resulting precipitate was dissolved, after which the palladium on carbon was removed by filtering the hot mixture. To the slurry obtained by concentrating the filtrate to about 20 ml was added 100 ml of water, by which were obtained white crystals which were then collected by filtration and washed with water, and then dried under reduced pressure at 60° C. overnight to obtain 3.50 g of 5-cyclohexylmethylhydantoin. The yield was 89.2%. The crude crystals were recrystallized from ethanol to obtain a pure product.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.C1C2C(=CC=CC=2)C=CC=1.OC1CC2C(=CC=CC=2)C1=O>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C1Cc2ccccc2C1
Agent: O=C1c2ccccc2CC1O
Solvent: c1ccc2ccccc2c1
Product: C1=Cc2ccccc2C1

Procedure:
As a diagnostic reaction to assess similarities or differences between aromatic dioxygenases from the present heterocyclic indole oxidase, crude SCF as prepared in Example 6 was tested in its ability to oxidatively transform indene. This was carried out under conditions identical to those described in Example 9 for indigo accumulation. Indene removal from reaction mixtures was evident from GC/MS analyses (see Materials and Method Section above). A single detectable product accumulated constituting approximately 20% of the total ion current. This product had a retention time of 7.5 min and its mass spectrum exhibited a molecular ion at m/z=132. Both the retention time and mass spectrum of this product were identical to those of authentic 2-indanone. The identification of 2-indanone as the sole product from indene demonstrates a major difference between the indole oxidation activity in strain WW2 and the well characterized toluene and naphthalene dioxygenase systems. The latter have been shown to oxidize indene to cis-1,2-indandiol and 1-indenol in about equal amounts (Gibson, D. T., S. M. Resnick, K. Lee, J. M. Brand, D. S. Torok, L. P. Wackett, M. J. Schocken, B. E. Haigler (1995) “Desaturation, dioxygenation and monooxygenation reactions catalyzed by naphthalene dioxygenase from Pseudomonas sp. strain 9816-4,” J. Bacteriol. 177:2615-2621). Neither toluene nor naphthalene dioxygenase form 2-indanone. It is also notable that the 2-indanone formed by strain WW2 SCF accumulates and does not appear to be further oxidized. Naphthalene dioxygenase has been shown to oxidize 2-indanone to 2-hydroxy-1-indanone (Resnick, S. M., D. S. Torok, K. Lee, J. M. Brand, D. T. Gibson (1994) “Regiospecific and stereoselective hydroxylation of 1-indanone and 2-indanone by naphthalene dioxygenase and toluene dioxygenase,” Appl. Environ. Microbiol. 60:3323-3328); this product was not observed in the present study.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:7]([C:1]1[CH:6]=[CH:5][C:4]([C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:16])=[CH:3][CH:2]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)c1ccc(C(=O)CCC(=O)O)cc1
Yield: 83 %

Procedure:
Cumene 10d (99%, 4.8eq) was reacted with succinic anhydride (99%, 1 eq) and AlCl3 (95%, 2 eq) for 120 h according to the general procedure. Extractive purification of the crude product afforded white crystals of 11d were obtained in 83% yield. 1H-NMR: 7.92 (d, 2H, Ar--H); 7.32 (d, 2H, Ar--H); 3.30 (t, 2H, CH2CH2COOH); 2.97 (sept., 1H,CH(CH3)2); 2.81 (t, 2H, CH2CH2COOH); 1.27 (d, 6H, CH(CH3)2).
Reaction SMILES: [C:1]([C@:3]([NH:14][C@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=[O:17])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)#[N:2].C(Cl)Cl.[OH:28]S(O)(=O)=O.N>CCOC(C)=O>[C:16]([C@H:15]([NH:14][C@@:3]([CH3:13])([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:1]([NH2:2])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: COc1ccc(C[C@@](C)(C#N)N[C@@H](C(N)=O)c2ccccc2)cc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 500 mL flask were added nitrile 2 (10.0 g, 30.95 mmol) and CH2Cl2 (130 mL). The solution was cooled to −10° C. and H2SO4 (10 mL) was added dropwise over 15 min. The mixture was stirred for 2 h at 0° C. Ice (200 g) was added and the mixture was stirred for 1 h. The mixture was basified with 32% aq NH3 to pH 8-9, EtOAc (400 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×250 mL). The combined organic phases were dried over MgSO4 and were concentrated to provide 3 (11.1 g (9.99 g theoretical, the sample contains 10% w/w of EtOAc by NMR) 94%, 92.9% chemical purity, 97% de by HPLC/MS) as a white solid. HPLC/MS tR=3.04 min; m/z=342.1 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[N:6][C:7]=1[O:8][CH:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].[CH:18]1([B-](F)(F)F)[CH2:20][CH2:19]1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(PC12CC3CC(CC(C3)C1)C2)CCC.O>[CH:18]1([C:2]2[CH:3]=[CH:4][C:5]([C:15]([OH:17])=[O:16])=[N:6][C:7]=2[O:8][CH:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[CH2:20][CH2:19]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CC(Oc1nc(C(=O)O)ccc1Br)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCPC12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Temperature: 120 °C
Yield: 78.7 %

Procedure:
5-Bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid (2 g, 6.37 mmol), potassium cyclopropyltrifluoroborate (952 mg, 6.43 mmol), cesium carbonate (6.22 g, 19.1 mmol) and palladium(II)acetate (28.6 mg, 127 μmol) were suspended in toluene (55 mL) and water (6.11 mL) under an argon atmosphere. Butyl-1-adamantylphosphin (68.5 mg, 191 μmol) was added, the reaction mixture was heated to 120° C. for 1 d, poured onto icewater/1N HCl (150 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were washed with icewater/brine (150 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.38 g, 79%) as a yellow solid. MS (EI): m/e=276.2 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8].[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[S:14]([C:11]1[CH:12]=[C:6]([CH:5]=[O:13])[C:7]([OH:8])=[CH:9][CH:10]=1)([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: O=Cc1ccccc1O
Solvent: O=S(Cl)Cl
Product: O=Cc1cc(S(=O)(=O)O)ccc1O

Procedure:
The 3-(thiazolidin-2'-yl)-4-hydroxy-phenyl sulfonic acid hydrochloride used as the starting material for reaction with the thionyl chloride is prepared without isolating intermediates by reacting the salicylaldehyde with fuming sulfuric acid (25-45% SO3) to give 5-sulfosalicylaldehyde. Usually, the fuming sulfuric acid is employed in a quantity sufficient to provide a slight excess of SO3 over equimolar amounts of the starting aldehyde. The reaction is exothermic, usually reaching a temperature of 70° to 75° C. and may be cooled to lower temperatures of 40° to 50° C., if desired.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[N+:13]([C:16]1[CH:17]=[C:18]([C:26]([O-:28])=O)[CH:19]=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22])([O-:15])=[O:14].[CH2:29]([NH:32][CH2:33][CH2:34][CH3:35])[CH2:30][CH3:31]>C1COCC1>[CH2:29]([N:32]([CH2:33][CH2:34][CH3:35])[C:26]([C:18]1[CH:19]=[C:20]([CH:25]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1)[C:21]([O:23][CH3:24])=[O:22])=[O:28])[CH2:30][CH3:31]
Reactant: CCCNCCC
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
Carbonyl diimidazole (3.90 g, 24.0 mmol) is added to a mixture of mono-methyl 5-nitro-isophthalate (XXVIII, 4.50 g, 20.0 mmol) in dry THF (50 mL). The mixture is stirred for 0.5 hours. Dipropylamine (3.28 mL, 24.0 mmol) is added slowly to the mixture. The reaction mixture is then stirred for 4 hours. The solvent is removed under reduced pressure and the mixture is partitioned between ethyl acetate and water. The organic phase is separated and washed with saline, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (silica gel; ethyl acetate/hexanes, 15/85) gives the title compound, NMR (300 MHz, CDCl3) delta 8.88, 8.41, 8.35, 4.00, 3.48, 3.15, 1.72, 1.57, 1.00 and 0.77; MS (ESI+) for C15H20N2O5 m/z (M+H)+=309.2.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:20]N1C(=O)CCC1=O.O>C1COCC1>[Br:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][O:1][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(Br)CCOC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5.0 g (38.419 mmol) of methyl tetrahydrofuran-3-carboxylate (prepared analogously to: J. Org. Chem. 1996, 2690) were dissolved in 200 ml of THF and cooled to −78° C., and then 76.83 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added. After 30 min at −78° C., 10.26 g (57.63 mmol) of N-bromosuccinimide suspended in 50 ml of THF were added gradually. Thereafter, the mixture was left to warm up to RT overnight. The mixture was then admixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated. The crude product was purified by means of chromatography on silica gel (eluent: dichloromethane). This gave 491 mg (6% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH2:8])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1F
Solvent: CC#N
Product: Nc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 140.9 %

Procedure:
To a solution of 3-fluoro-pyridin-2-ylamine (1.0 g, 8.92 mmol) in 300 mL of acetonitrile, NBS (794 mg, 4.46 mmol) was added at 0° C. The reaction mixture was stirred vigorously for 15 minutes (protected from light) at 0° C. and then at room temperature for 1 hour. The additional portion of NBS (794 mg, 4.46 mmol) was added at 0° C. and the solution was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition Na2S2O3 (saturated aqueous solution, 40 mL) and the product was extracted with EtOAc (3×40 mL). The combined organic extracts were washed with brine (2×50 mL), dried over MgSO4 and concentrated in vacuo. The obtained crude yellowish solid was purified by Biotage using 3-20% EtOAc in hexane to afford 5-bromo-3-fluoro-pyridin-2-ylamine (1.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.93 (d, J=1.56 Hz, 1 H) 7.37 (dd, J=9.76, 1.95 Hz, 1 H) 4.63 (br. s., 2 H)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:25][C:26]1[C:31]([CH2:32][CH2:33][CH3:34])=[C:30]([SH:35])[CH:29]=[CH:28][C:27]=1[C:36](=[O:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[C:36]([C:27]1[CH:28]=[CH:29][C:30]([S:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=2)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:31]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:25])(=[O:38])[CH3:37]
Reactant: CCCc1c(OCCCCl)ccc(C(C)O)c1OCCCC(=O)O
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(SCCCOc2ccc(C(C)O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 35.9 %

Procedure:
A mixed solution of 55.9 mg of (-)-4-[3-(3-chloropropoxy)-6-(1-hydroxyethyl)-2-propylphenoxy] butanoic acid, 39.3 mg of (2-hydroxy-4-mercapto-3-propylphenyl) ethanone, 51.7 mg of potassium carbonate and 1 ml of dimethylformamide was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, acidified with 1N-hydrochloric acid, and extracted with ethyl acetate. After washed with water and saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and subjected to distillation off of the solvent under reduced pressure to afford residue, which was then purified through silica gel column chromatography (methylene chloride: methanol=20:1) and further purified through preparative thin layer chromatography (methylene chloride: methanol=15:1) to afford 29.8 mg of yellow oily matter as the title compound (35.9%). [α]D20 -13.8° (c=2.98, ethanol)
Reaction SMILES: [C:1]1(=O)[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[NH2:16][NH2:17]>O>[N:16](=[C:1]1[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3)[NH2:17]
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Reactant: NN
Solvent: O
Product: NN=C1C(=O)Nc2ccc3ncccc3c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
3-H-Pyrrolo[3,2-f]quinoline-1,2-dione (3.89 g, 19.6 mmol) was combined with 12.0 mL of anhydrous hydrazine and 10.25 mL of water and heated at 100° C. under a condenser and nitrogen atmosphere, with stirring, for 1 hr. The reaction occasionally foamed into the condenser and heat was removed as needed to allow foaming to subside. The reaction was cooled and poured into 200 mL of water. The product was collected by filtration and dried under vacuum at 55° C. to give 2.86 g (69%) of 1-hydrazono-1,3-dihydropyrrolo[3,2-f]quinoline-2-one as a brown solid. Mass spectrum (positive ion electrospray): m/z=213. NMR (DMSO-d6): δ7.37 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.81 (d, J=8.8 Hz, 1H), 8.71 (dd, J=4.2, 1.6 Hz, 1H), 8.80 (d, J=8.4 Hz, 1H), 9.90 (br d, J=14.7 Hz, 1H), 10.89 (br d, J=14.7 Hz, 1H), 10.95 (br s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][OH:5].S(=O)(=O)(O)O.[CH2:11]=[C:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>C(OCC)C>[C:12]([O:5][N:4]=[CH:3][CH2:2][Cl:1])([CH3:14])([CH3:13])[CH3:11]
Reactant: ON=CCCl
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)ON=CCCl

Procedure:
Then, 0.47 g of chloroacetoaldehyde oxime, 0.1 ml of concentrated sulfuric acid, and 10 ml of diethyl ether are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the stirring is further continued at room temperature. After completion of the reaction, the reaction mixture is slowly poured into saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with 10% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetoaldehyde O-tert-butyloxime.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][C:7]([O:9][CH2:10][C:11]1[CH2:28][S:27][C@@H:14]2[C@H:15]([NH:18]C(CCCC(O)=O)=O)[C:16](=[O:17])[N:13]2[C:12]=1[C:29]([OH:31])=[O:30])=[O:8]>C(O)(=O)C>[CH3:6][C:7]([O:9][CH2:10][C:11]1[CH2:28][S:27][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:29]([OH:31])=[O:30])=[O:8]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCCC(=O)O)[C@H]2SC1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
1 g of the cellular paste so obtained was suspended in 50 ml. of phosphate buffer 0,1M, pH 8,0, containing 2% glutaryl-7ACA, and incubated for 10 min. at 37° C. After such period of time, the reaction was stopped by the addition of 20% acetic acid, at the rate of 3 ml for 1 ml of the reaction mixture. The suspension obtained was centrifuged and the 7-ACA formed was quantified in the clear supernatant.