Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([OH:3])=[O:2].[C:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(=[O:16])[CH3:15].[OH-].[Na+].C(C1(OCC(O)=O)C=CC(C(=O)C=CC2C=CC=CC=2)=CC1)(O)=O.[Na].[Na].[Na][Na].Cl>O.C(O)C>[C:21]([C:20]1[CH:24]=[CH:25][C:17]([C:14](=[O:16])[CH:15]=[CH:10][C:9]2[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=2)=[CH:18][CH:19]=1)([OH:23])=[O:22]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Agent: Cl
Agent: O=C(O)COC1(C(=O)O)C=CC(C(=O)C=Cc2ccccc2)=CC1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(C=CC(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
9.0 g. 4-Carboxymethoxy-benzaldehyde (see Example 5) and 8.2 g. 4-acetylbenzoic acid were dissolved in 50 ml. 10% aqueous sodium hydroxide solution and the solution stirred at ambient temperature for 2.25 hours. 150 ml. Ethanol were added and the solid precipitate obtained was filtered off, washed with ethanol and dried to give 16.9 g. disodium 4'-carboxy-4'-carboxymethoxy chalcone. This disodium salt was converted into the acid by dissolving in water, acidifying the solution with concentrated hydrochloric acid, filtering off the solid obtained, washing with water and drying, the yield being 15.1 g. Thin layer chromatography showed the presence of about 7% of polar impurities, most of which were removed by refluxing the solid with methanol, filtering and drying the undissolved solid, the yield being 11.9 g. Thin layer chromatography then showed the product to be about 98% pure. The solid was dissolved in dimethyl formamide and the solution was filtered and evaporated to a small volume. 200 ml. Methanol was added and the solid precipitate obtained was filtered off, washed with methanol and dried to give 8.0 g. of product, thin layer chromatography of which showed it to be more than 99% pure. The 4'-carboxy-4-carboxymethoxy-chalcone thus obtained had a melting point of 312°-314° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[F:9][C:10]([F:23])([F:22])[C:11]1[CH:12]=[C:13]([C:17](=O)[C:18](=O)[CH3:19])[CH:14]=[CH:15][CH:16]=1.Cl>O>[CH3:19][C:18]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:22])[F:23])[CH:12]=2)=[N:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=1
Reactant: CC(=O)C(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccccc1N
Agent: Cl
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
A mixture of 1,2-phenylenediamine (1.00 g, 9.25 mmol) and 1-[3-(trifluoromethyl)phenyl]propane-1,2-dione (2.00 g, 9.25 mmol) in water (80 mL) was heated at 60° C. overnight, then for 5 h with vigorous stirring. The reaction mixture was allowed to cool to r.t. then acidified with 2N HCl (ca 20 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with heptane to give the title compound (1.44 g, 54%) as a cream-coloured solid. δH (CDCl3) 8.05-8.16 (m, 2H), 7.96 (s, 1H), 7.85-7.90 (m, 1H), 7.72-7.82 (m, 3H), 7.64-7.71 (m, 1H), 2.79 (s, 3H). LCMS (ES+) 289.3 (M+H)+, RT 4.21 minutes (Method 3).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][N:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:6]1[C:7]([NH2:10])=[CH:8][CH:9]=[C:4]([F:3])[N:5]=1
Reactant: Nc1ccc(F)nc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc(F)nc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.1 %

Procedure:
Bromine (1.96 g, 12.2 mmol) is added to a mixture of 2-fluoro-5-aminopyridine (1.37 g, 12.2 mmol) and sodium acetate (2 mg, 24.4 mmol) in acetic acid (30 mL) and stirred at rt for 4 hours. Acetic acid is evaporated off in vacuo. The residue is dissolved in EtOAc (50 mL), washed with saturated aqueous Na2CO3 (10 mL), water (20 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford 2-bromo-3-amino-6-fluoropyridine (2.1 g) as a solid. MS: 190 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.04 (br, 2H), 6.77 (dd, H), 7.17(dd, H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6](Cl)=[N:7]2.Cl.[NH2:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=3)[CH:14]=[CH:13][C:5]=1[C:6]([NH:24][CH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[N:7]2
Reactant: Cn1cc(-c2ccc3c(Cl)nc4ccnc(Cl)c4c3c2)cn1
Reactant: NCc1nccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cn1cc(-c2ccc3c(NCc4nccs4)nc4ccnc(Cl)c4c3c2)cn1
Temperature: 130 °C

Procedure:
To a solution of 1,6-dichloro-9-(1-methyl-1H-pyrazol-4-yl)benzo[c]-1,6-naphthyridine (50 mg, 0.152 mmol) and 2-aminomethylthiazole hydrochloride (92 mg, 0.608 mmol) in DMA (1.5 mL), triethylamine (85 μl, 0.608 mmol) was added. The reaction mixture was heated to 130° C. for 1 h via microwave irradiation. After cooling to room temperature, aqueous sodium hydrogen carbonate (saturated) was added. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford 1-chloro-9-(1-methyl-1H-pyrazol-4-yl)-N-(1,3-thiazol-2-ylmethyl)benzo[c]-1,6-naphthyridin-6-amine as a yellow solid. LRMS (APCI) calc'd for (C20H16ClN6S) [M+H]+, 407.1; found 407.0.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])=[CH:20][C:19]=1[C:30]([F:33])([F:32])[F:31].Cl.CC(=O)OCC>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:26]([F:27])([F:28])[F:29])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)=[CH:20][C:19]=1[C:30]([F:31])([F:32])[F:33]
Reactant: C=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(/C(Cl)=N/O)cc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4ccc(F)c(C(F)(F)F)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of (Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (522 mg, 2.18 mmol) in DMF (5 mL) was successively added 1-fluoro-2-(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (563 mg, 2.18 mmol) and TEA (440 mg, 4.36 mmol) below −10° C. The mixture was stirred at rt overnight, poured into 1N HCl solution and extracted with EA (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by pre-TLC eluted with PE:EA (1:1, 1% HOAc) and pre-HPLC to give the final title compound (200 mg, yield 20.0%) as white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.03-8.00 (m, 1H), 7.91-7.89 (d, J=12 Hz, 1H), 7.77-7.68 (m, 4H), 4.52-4.46 (d, J=18 Hz, 1 H), 4.36-4.30 (d, J=18 Hz, 1 H), 1.48 (s,6H). LC-MS: 462 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[CH2:10]1[O:13][CH:11]1[CH3:12]>CO>[CH3:1][N:2]([CH2:10][CH:11]([OH:13])[CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1
Reactant: CC1CO1
Reactant: CNc1ccc(C)cc1
Solvent: CO
Product: Cc1ccc(N(C)CC(C)O)cc1

Procedure:
N-methyl-p-toluidine, 29.3 g, and methanol, 50 g, were placed in a reactor. Propylene oxide, 25.4 g, was slowly added to the reactor over two hours. Afterwards, the reactor was heated under reflux for 6 hours. The low boilers were removed by distillation. Then, the mixture was vacuum distilled to give 2HPMT. The boiling point is 92° C. at 5 mm Hg.
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[NH2:11][C:12]1[C:13]([SH:20])=[N:14][C:15]([Br:19])=[C:16]([Br:18])[N:17]=1>>[Br:18][C:16]1[N:17]=[C:12]2[N:11]=[CH:1][S:20][C:13]2=[N:14][C:15]=1[Br:19]
Reactant: CCOC(OCC)OCC
Reactant: Nc1nc(Br)c(Br)nc1S
Product: Brc1nc2ncsc2nc1Br
Yield: 73 %

Procedure:
Fifty ml. of triethylorthoformate and 8.6 g. of 3-amino-5,6-dibromopyrazinethiol were mixed and heated to boiling under reflux for 22 hours. The reaction mixture was then concentrated under reduced pressure and diluted with petroleum-ether. The resulting precipitate of yellowish brown crystalline material weighed 6.7 g. (73% yield), m.p. 142°-4° C.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.Cl[CH2:12][CH2:13][O:14][Si](C)(C)C.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[N+:7]([C:6]1[CH:5]=[CH:4][C:3]([O:10][CH2:12][CH2:13][OH:14])=[CH:2][CH:1]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[Si](C)(C)OCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A mixture of p-nitrophenol (1.39 g, 10 mmol), 2-chloroethoxytrimethylsilane (3.2 ml, 20 mmol), potassium carbonate (4.15 g, 30 mmol), cesium carbonate (163 mg, 0.5 mmol), and sodium iodide (149 mg, 1 mmol) in N,N-dimethylformamide (10 ml) is heated at 75° for 19.5 hours. After cooling to ambient temperature, the mixture is diluted with ethyl acetate and filtered. The filtrate is washed with saturated aqueous sodium bicarbonate, then washed 2× with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified on Silica gel (1:1 ethyl acetate/hexanes) to give 4-nitro-(2-Hydroxyethoxy)benzene (1.25 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1.C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(CC)(CC)C=3C=CC=2)C=CC=CC=1.[SH:88][CH2:89][CH2:90][C:91]([O:93][CH3:94])=[O:92]>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(OCC)(=O)C.O1CCOCC1>[CH3:94][O:93][C:91](=[O:92])[CH2:90][CH2:89][S:88][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCS
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)CC1
Agent: [Pd]
Agent: CCC1(CC)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc(CC3CCN(C(=O)OC(C)(C)C)CC3)cs2)c(Oc2ccccc2)c1
Temperature: 95 °C
Yield: 94.4 %

Procedure:
The atmosphere above a mixture of tert-butyl 4-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)piperidine-1-carboxylate (1.52 g, 2.79 mmol), N-ethyl-N-isopropylpropan-2-amine (0.971 mL, 5.57 mmol), 4,5-bis(diphenylphosphino)-9,9-diethyl-9H-xanthene (0.161 g, 0.279 mmol), and dioxane (25 mL) was purged with nitrogen. Methyl 3-mercaptopropanoate (0.332 mL, 3.07 mmol) and Pd2dba3 (0.128 g, 0.139 mmol) were added, and the reaction was heated at 95° C. overnight. The reaction was cooled to ambient temperature and filtered through celite. The filtrate was concentrated and purified by MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the title compound (1.54 g, 94.5% yield) as a tacky white solid: 1H NMR (CDCl3) δ 8.70 (s, 1H), 8.16 (s, 1H), 7.40 (t, 2H), 7.24 (t, 1H), 7.14 (s, 1H), 7.06 (d, 2H), 6.46 (s, 1H), 4.08 (m, 2H), 3.65 (s, 3H), 2.99 (t, 2H), 2.67 (m, 2H), 2.56 (d, 2H), 2.55 (t, 2H), 1.85 (m, 1H), 1.66 (m, 2H), 1.45 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:6]=[C:5]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)Cc1c[nH]c2ccc(F)cc12
Product: CC(C)(C)OC(=O)Cc1cn(C(=O)c2ccccc2)c2ccc(F)cc12

Procedure:
Prepare by a method similar to Example 116 using t-butyl [5-fluoro-indol-3-yl]-acetate and benzoyl chloride.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:31](OC)[N:32]([CH3:34])[CH3:33]>>[C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH:21]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 95.6 %

Procedure:
1-(4′-Diphenylaminobiphenyl-4-yl)ethanone (1.0 g, 2.75 mmol) was reacted with N,N-dimethylformamide dimethylacetal (1.0 g, 8.25 mmol) for 12 hours at 100° C. Non-reacted N,N-dimethylformamide dimethylacetal was removed using a vacuum pump, and water (50 mL) and dichloromethane (100 mL×2) added. The organic layer was separated, filtered, dried and evaporated to obtain the title compound (1.1 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C:5]([NH2:17])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1.N1C=CC=CC=1.Cl.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH3:2][O:3][C:4](=[O:18])[C:5]([NH:17][C:26](=[O:28])[CH3:27])=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][C:12]([Cl:16])=[CH:13][CH:14]=2)[NH:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C(N)=Cc1c[nH]c2cc(Cl)ccc12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)NC(C)=O
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A 2-l. three-necked flask, equipped with a thermometer, a mechancal stirrer and a dropping funnel was charged with 101.2 g (ca. 0.35 moles) of crude pulverized alpha-amino-6-chloro-3-indoleacrylic acid methylester hydrochloride and 400 ml of acetic anhydride. The slurry was cooled to 15°. Then 32 g (0.40 moles) of pyridine was added with stirring over a 5 minute period, while the temperature was kept between 15° and 22°; after complete addition, virtually all starting hydrochloride went into solution. Stirring at 22° was continued for 20 minutes during which the product began to crystallize out. 200 ml of water was then added over 40 minutes, keeping the temperature at ca. 25°. Stirring at this temperature was continued for 11/2 hours. 900 ml of water was then added over 5 minutes and the slurry stirred at room temperature for an additional hour. The precipitate was collected by suction filtration, washed with 750 ml of water and dried at 60° (constant weight) to afford 92.9 g (90%) of product, as yellow crystals, m.p. 202-203°.
Reaction SMILES: [C:1]([O-:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].OC(C=CC=CCC=CCC=CCCCCC)CCCC(OO)=O>>[C:1]([OH:22])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)[O-]
Agent: CCCCCC=CCC=CCC=CC=CC(O)CCCC(=O)OO
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O

Procedure:
The enzyme activity was measured according to the modified method of Ochi et al. [K. Ochi, T. Yoshimoto, S. Yamamoto, K. Taniguchi, T. Miyamoto: Arachidonate 5-lipoxygenase of guinea pig peritoneal polymorphonuclear leukocytes, J. Biol. Chem. 258, 5754-5758 (1983)]. The principle of the method is as follows: in in vitro systems, during the reaction catalysed by 5-LO 5-hydroxyperoxy-6,8,11,14-eicosatetraenoic acid (5-HPETE) is formed from arachidonic acid, then it is transformed to 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE). Both 5-HPETE and 5-HETE have absorption maximum at 236 nm, therefore it is possible to determine the activity of 5-LO enzyme by measuring the change of absorption at 236 nm. 5-LO was prepared from human polymorphonuclear leukocytes by a simple purification procedure. The cells were washed and lysed by a sonic disintegrator. The lysate was centrifuged and the enzyme in the cytosol was partially purified by ammonium sulphate fractionation (the enzyme precipitates at 50% saturation). The reaction mixture (50 mM tris-HCl pH=7.5, 2mM CaCl2, 0.1 mM ATP, 0.02 mM arachidonic acid) was incubated at 37° C. for 5 minutes. The reaction was started with the addition of arachidonic acid and stopped by the addition of 10 mM of citric acid. The thus-obtained 5-HPETE and 5-HETE were extracted with a 6:4 mixture of diethyl ether and hexane and the absorption of the organic phase was measured by spectrophotometry at 238 nm.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]1=[O:9]>[Ru].C(O)(C)C>[CH3:7][C:4]1([CH3:8])[CH:5]([OH:6])[C:2]([CH3:10])([CH3:1])[CH:3]1[OH:9]
Reactant: CC1(C)C(=O)C(C)(C)C1=O
Agent: [Ru]
Solvent: CC(C)O
Product: CC1(C)C(O)C(C)(C)C1O
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A 2 liter Parr autoclave was charged with 100 grams of 2,2,4,4-tetramethylcyclobutane-1,3-dione, 300 grams Isopar™ G, 100 grams of isopropyl alcohol, and 50 grams of 2% ruthenium on alumina (surface area=10 m2/g, purchased from BASF Catalysts). The autoclave was pressure purged three times with nitrogen and three times with hydrogen, and the pressure was increased to 3.5 MPa (500 psig) with hydrogen. The autoclave was heated to 80° C. with stirring at approximately 1400 rpm and held for 6 hours at 3.5 MPa (500 psig). Analysis of the product by gas chromatography indicated that complete conversion of the 2,2,4,4-tetramethylcyclobutane-1,3-dione was obtained with 100% selectivity to 2,2,4,4-tetramethycyclobutane-1,3-diol with a cis:trans ratio of 1.44:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)[CH:5]=[C:6]([Cl:13])[C:7]=1[CH2:8][O:9]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:13][C:6]1[CH:5]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]3)=[O:21])=[CH:18][CH:19]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][OH:9]
Reactant: CC(=O)OCc1c(Cl)cc(-c2ccc(C(=O)N3CCC(C(F)(F)F)CC3)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(c1ccc(-c2cc(Cl)c(CO)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Temperature: 33 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
Dissolve 20 g (1 eq.) of Acetic acid 3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl ester in 300 mL of methanol by heating to 33° C. Add 8.2 g of potassium carbonate at 25° C. and stir at ambient temperature for 5 hours. Add approximately 5 g of decolorizing carbon and filter the solution. Add water to the filtrate add remove some methanol on the rotary evaporator at 40° C. to afford a slurry. Collect the solid by filtration and dry under vacuum at 50° C. to afford 14.4 g (76% yield) of the titled compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:21])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:31][CH3:32])=[C:27]([Mg]Br)[CH:28]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[Si:1]([O:8][C@H:9]([CH2:10][CH:11]([C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[O:31][CH3:32])[OH:21])[CH2:13][NH:12][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1=O
Reactant: COc1ccc(F)cc1[Mg]Br
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(O)C[C@H](CNC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-carboxylate (6.00 g, 19.0 mmol) in THF (36 mL) at 0° C. was added a 0.5 M solution of (5-fluoro-2-methoxyphenyl)magnesium bromide in THF (50.0 mL, 25.0 mmol). The resulting mixture was stirred at 0° C. for 30 minutes, then treated with MeOH (60 mL) and NaBH4 (0.966 g, 25.2 mmol). After stirring at 0° C. for an additional 30 minutes, the reaction mixture was poured into saturated aqueous NH4Cl (40 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material which was purified by silica column chromatography, eluting with 0-2% MeOH/DCM to afford (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)-4-(5-fluoro-2-methoxyphenyl)-4-hydroxybutylcarbamate (which was assumed to be a mixture of the syn and anti isomers), (4.81 g, 57.0% yield). 1H NMR (CDCl3) δ 7.20 (m, 1H), 6.90 (m, 1H), 6.77 (m, 1H), 5.12 (m, 1H), 4.10 (m, 1H), 3.82 (m, 3H), 3.29 (m, 2H), 1.71-1.93 (m, 2H), 1.45 (s, 9H), 0.93 (d, 9H), 0.11-0.14 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1I.[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[SH:19].BrC1C=C(F)C=CC=1N.NC1C=CC=C(C)C=1.CC1C=CC=C(S)C=1>>[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(I)c(Cl)c1
Reactant: Fc1ccc(S)c(Br)c1
Agent: Cc1cccc(S)c1
Agent: Nc1ccc(F)cc1Br
Solvent: Cc1cccc(N)c1
Product: COc1ccc(Sc2ccc(F)cc2Br)c(Cl)c1

Procedure:
Prepared from 2-chloro-1-iodo-4-methoxy-benzene and 2-bromo-4-fluoro-benzenethiol (prepared from 2-bromo-4-fluoro-phenylamine by diazotization according to the procedure reported for the conversion of 3-toluidine to 3-thiocresol by Tarbell and Fukushima J. Am. Chem. Soc. 1946, 68, 1456-1460).
Reaction SMILES: [CH2:1]([O:3]C1C=CC(S(Cl)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C)N2N=1)[CH3:2].ON1CCNCC1.[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][N:48](O)[CH2:47][CH:46]2CC)(=[O:44])=[O:43])=[CH:38][C:37]=1[C:54]1[NH:59][C:58](=[O:60])[C:57]2=[C:61]([CH3:65])[N:62]=[C:63]([CH3:64])[N:56]2[N:55]=1)[CH3:34]>>[CH2:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:1][OH:3])[CH2:47][CH2:46]2)(=[O:43])=[O:44])=[CH:38][C:37]=1[C:54]1[NH:59][C:58](=[O:60])[C:57]2=[C:61]([CH3:65])[N:62]=[C:63]([CH3:64])[N:56]2[N:55]=1)[CH3:34]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: CCOc1ccc(S(=O)(=O)N2CCN(O)CC2CC)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Agent: ON1CCNCC1
Product: CCOc1ccc(S(=O)(=O)N2CCN(CCO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 100 mg (0.784 mmol) of 4-hydroxypiperazine, 45 mg (36.1% of theory) of 2-[2-ethoxy-5-(4-hydroxy-ethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one are obtained.