Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[C:14](=[O:22])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[CH3:29].Cl>CC(O)C.C1COCC1>[OH:4][C:5]1[C:27]([CH3:28])=[CH:26][C:8](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=2)[C:14](=[O:22])[S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]=1[CH3:29]
Reactant: COCOc1c(C)cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cc1cc(/C=C/c2cccc(C(=O)Sc3ccccc3)c2)cc(C)c1O
Reaction time: 18 h

Procedure:
To a solution of (E)-S-phenyl 3-(4-(methoxymethoxy)-3,5-dimethylstyryl)benzothioate (80 mg, 0.198 mmol) in i-PrOH and THF (½ mL) was added 0.5 mL of concentrated HCl. The reaction mixture was stirred overnight (about 18 hours). After removal of solvent under reduced pressure, the residue was dissolved in EtOAc. The solution was washed with brine and dried with Na2SO4. The solution was filtered and concentrated. The compound was purified by column chromatography (9:1 Hexane:EtOAc) to afford (E)-S-phenyl 3-(4-hydroxy-3,5-dimethylstyryl)-benzothioate in quantitative yield. Azo-linked compounds of Formula I are prepared following usual syntheses for preparing aromatic or heteroaromatic azo compounds. A typical scheme is shown in Scheme 3.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:2][CH3:3]
Reactant: C=CCc1c(O)ccc2c1ccn2Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c1ccn2Cc1ccc(F)cc1

Procedure:
4-allyl-5-hydroxy-N-(4-fluorobenzyl)indole (Step C; 0.40 g, 1.42 mmol) was taken up in 10 mL ethyl acetate and hydrogenated (1 atm) at ambient temperature using 5% palladium on charcoal (15 mg) for 2 hours. The reaction was filtered through celite and concentrated in vacuo to provide the title compound which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[C:21](F)[CH:20]=1>CS(C)=O>[Cl:25][C:24]1[C:19]([Cl:18])=[CH:20][C:21]([O:1][C:2]2[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Reactant: Cn1nc(C(F)(F)F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
5-Hydroxy-1-methyl-3-trifluoromethylpyrazole (7.0 g, 40 mmol) and powdered potassium carbonate (11.4 g, 80 mmol) were stirred together in dimethylsulfoxide (40 ml) for 30 minutes. 4,5-Dichloro-2-fluoronitrobenzene (7.9 g, 50 mmol) was added and the mixture stirred at room temperature for 18 h. The mixture was partitioned between diethyl ether and water, the ethereal extract washed with water and brine, dried over magnesium sulfate, filtered and the filtrate evaporated. The residue was further purified by flash column chromatography over silica gel, to give the desired product (5.9 g) as a light yellow solid, m.p. 99°-100° C.
Reaction SMILES: [CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[SH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:16]I>C(O)C>[CH:1](=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1nccn1N=Cc1ccccc1
Reactant: CI
Agent: [Na]
Solvent: CCO
Product: CSc1nccn1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.16 g of 1-benzylideneamino-2-mercaptoimidazole are suspended in 30 ml of absolute ethanol and treated with a solution of 1.15 g of sodium in 70 ml of absolute ethanol. After the addition of 7.1 g of methyl iodide, the reaction mixture is stirred at room temperature for 3 hours. For the work-up, the resulting yellow solution is concentrated to a quarter and 100 ml of water are added. The resulting crystalline crude product is removed by filtration, washed three times with water and recrystallized from methanol/water. There is obtained 1-benzylideneamino-2-methylmercaptoimidazole of m.p. 95°-97°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH3:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH3:14])[N:5]=1
Reactant: CC1CCCN1c1nc(Cl)cc(Cl)n1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CCCN1c1nc(Cl)cc(-c2ccc(F)cc2)n1

Procedure:
Heat a mixture of 4,6-dichloro-2-(2-methylpyrrolidin-1-yl)pyrimidine (2.25 g, 9.74 mmol), 4-fluorophenylboronic acid (10.23 mmol), Pd(PPh3)4 (562 mg, 0.487 mmol), and a 2M potassium phosphate solution (9.74 mL) in dioxane (35 mL) under nitrogen at 80° C. for 16 h. Evaporate the mixture and add water (50 mL). Extract with EtOAc (3×50 mL), dry (Na2SO4), and evaporate. Purify by SiO2 flash chromatography, eluting with 9:1 hexanes:EtOAc to provide the title compound as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccc(F)cc2)CC1
Yield: 64.7 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide (24 mg, 0.088 mmol), 4-fluorobenzene boronic acid (15 mg, 0.11 mmol) and tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1) to give impure title compound (19 mg) which was further purified by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1) to furnish the title compound as a white solid, LC-MS (ESI, 3.5 min) Rt 1.71 min, m/z 334 (100%, [M+H]+); m/z (ESI) C17H18ClFN3O requires 334.1117 found [M+H]+ 334.1116.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27]OC.CCOC(C)=O.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][C:19](=[O:26])[C:18]2=[CH:27][NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:8][CH:9]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(-c2ccncc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(-c2ccncc2)cc1
Yield: 77.1 %

Procedure:
4-Pyridin-4-yl-phenylamine (130 mg, 0.76 mmol) and 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (200 mg, 0.71 mmol) is heated in N,N-dimethylformamide (10 mL) at 100° C. for 2 h. EtOAc (100 mL) and H2O (20 mL) is then added. The EtOAc layer is washed with H2O (3×20 mL) and brine (15 mL) and dried over MgSO4. After removal of EtOAc, the precipitate is collected and washed with MeOH and Et2O and dried to provide the title compound (230 mg, 77%). 1H NMR (300 MHz, DMSO) δ 12.59 (1H, d, J=12.9 Hz), 11.50 (1H, s), 9.0 (1H, d, J=12.6 Hz), 8.53-8.64 (3H, m), 7.43-7.95 (8H, m). MS (ESI) m/z 420.0, 422.0 (M+H)+1; Anal. Cacl. for C21H14BrN3O2: C, 60.02; H, 3.36; N, 10.00. Found: C, 59.4; H, 3.26; N, 9.34.
Reaction SMILES: O=O.[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[Li+].CC([N-]C(C)C)C>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:3]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:20][N:19]=2)=[C:14]([F:25])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1ccc(-c2ccc(C)cn2)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: O=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCCCCCCCCc1ccc(-c2ccc(OCCCCCCCC)cc2F)nc1
Temperature: 25 °C

Procedure:
With atmospheric oxygen and moisture being excluded, 7.9 mmol of 2-(4-octyloxy-2-fluorophenyl)-5-methylpyridine dissolved in THF and, about 15 minutes later, 8.7 mmol of 1-bromooctane are added at -70° C. to a solution of 8.7 mmol LDA (prepared from BuLi and diisopropylamine) in THF in the presence of 1.04 ml of DMPU. The reaction mixture is allowed to heat up to room temperature, stirring is continued for a further hour and working up is carried out as usual.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28]>C1(O)C=CC=CC=1>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: C[C@H](N)C(=O)O
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Solvent: Oc1ccccc1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H](C)C(=O)O)c2c1
Temperature: 150 °C

Procedure:
The mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1) and L-alanine (360 mg, 4.0 mmol) in phenol (360 mg) was heated at 150° C. overnight. After being cooled to room temperature, the mixture was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 8.16-7.92 (m, 3 H), 7.84 (d, J=8.34 Hz, 1 H), 7.78-7.62 (m, 1 H), 7.61-7.42 (m, 2 H), 5.86 (s, 1 H), 5.24 (brs, 2 H), 4.65-4.35 (m, 3 H), 3.69 (brs, 2 H), 3.37 (s, 3 H), 2.53-2.39 (m, 3 H), 1.76-1.57 (m, 3 H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CN(C)CC1C=CC=CC=1.[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>CC(CC(C)=O)C>[OH:4][CH2:3][CH2:2][S:1][CH2:15][CH:16]([OH:17])[CH2:18][OH:19]
Reactant: OCC1CO1
Reactant: OCCS
Agent: CN(C)Cc1ccccc1
Solvent: CC(=O)CC(C)C
Product: OCCSCC(O)CO
Temperature: 50 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In a reaction vessel equipped with a stirrer, a cooling tube, a nitrogen introducing tube and a thermometer, 78.1 parts of 2-mercaptoethanol was charged, and 2-mercaptoethanol was diluted with 159.6 parts of MIBK. Then, 0.41 part of dimethylbenzylamine was added, and after heating to 50° C., 81.5 parts of glycidol was added dropwise with stirring over 3 hours in a dry nitrogen atmosphere. The reaction vessel was cooled and maintained at 50° C. 2 Hours after dropping, it was confirmed that an absorption of --SH (2540 cm-1) and an absorption of a glycidyl group (910 cm-1) are disappeared by the measurement of infrared spectra. Further, the reaction product had no mercapto-like odor. Thereafter, MIBK was removed under reduced pressure to give 1-(2-hydroxyethylthio)-2,3-propanediol as a viscous liquid. Yield was 90% of the charge weight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.COC1C=CC(CNC2CCC2)=CC=1>CO>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: COc1ccc(N)nc1
Reactant: COc1ccc(C=O)cc1
Agent: COc1ccc(CNC2CCC2)cc1
Solvent: CO
Product: COc1ccc(CNc2ccc(OC)cn2)cc1

Procedure:
5A was prepared from 4-methoxybenzaldehyde and 5-methoxypyridin-2-amine following the procedure employed for the preparation of 4A. HPLC: Rt=1.30 min (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=244.9 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:5]=1.C1COCC1.O.[Li+].[OH-]>CC(O)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:30])=[O:2])=[C:12]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3cccc(C(=O)O)c3)ccnc2n1
Temperature: 60 °C
Yield: 41.6 %

Procedure:
The product from Example 208c (447 mg, 1.065 mmol) was dissolved in 5 ml of a 1:1 (THF:water) solution. To this was added LiOH (51 mg, 2.129 mmol) and the reaction mixture was heated to 60° C. for 2 h the reaction mixture was then allowed to cool to room temperature and brought to neutral with HOAc. The product was extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (180 mg, 42%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:18]>>[C:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[CH2:14][Cl:15])[C:10]([NH2:11])=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccc1NC(=O)CCl
Reactant: O=S(=O)(O)O
Product: CC(=O)c1cc(C(N)=O)ccc1NC(=O)CCl
Reaction time: 8 h
Yield: 61.6 %

Procedure:
15.7 Parts of N-(2-acetyl-4-cyanophenyl)-2-chloroacetamide were added portionwise to 146.4 parts of concentrated sulfuric acid at room temperature. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was poured into 500 parts of crushed ice while stirring. The precipitated product was filtered off and suspended in water. The precipitated product was filtered off, washed with water and suspended in 20 parts of acetonitrile. The product was filtered off, boiled in 20 parts of acetonitrile and filtered off, after cooling, yielding 10.4 parts (61.6%) of 3-acetyl-4-[(2-chloroacetyl)amino]benzamide (int. 114).
Reaction SMILES: [Cl:1][C:2](=[CH2:18])[CH2:3][C:4]1([CH3:17])[CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([Cl:14])=[C:9]([OH:13])[CH:10]=2)[C:5]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29]CC)=[O:28]>CN(C=O)C>[O:16]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:13][CH2:26][C:27]([OH:29])=[O:28])=[C:8]([Cl:14])[C:7]=2[Cl:15])[CH2:12][C:4]1([CH2:3][C:2]([Cl:1])=[CH2:18])[CH3:17]
Reactant: C=C(Cl)CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC1(C)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
[1-Oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid is prepared following substantially the same procedure described in Example 4, Step D, using the following reagents: 2-(2-chloroallyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (4.8 g., 0.0157 mole), potassium carbonate (6.0 g.), ethyl bromoacetate (4.5 ml.) and DMF (55 ml.). The above procedure gives 2.7 g. (48%) of [1-oxo-2-(2-chloroallyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which after recrystallization from butyl chloride melts at 160°-162°C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]([F:27])([F:26])[C:9]1[N:10]=[CH:11][C:12]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:13]=2[N:14]=1>C(OCC)(=O)C.[Ru](=O)=O>[O:2]=[C:15]1[C:13]2[N:14]=[C:9]([C:8]([F:7])([F:26])[F:27])[N:10]=[CH:11][C:12]=2[CH2:18][CH2:17][N:16]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(C(F)(F)F)nc2C1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cnc(C(F)(F)F)nc2C1=O
Reaction time: 4 h

Procedure:
To a mixture of 51 mg (0.328 mmol) of ruthenium dioxide and 25.9 mL (11.9 mmol) of 10% sodium periodate aqueous solution was added a solution of 766 mg (2.53 mmol) of tert-butyl 2-(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate in 20 mL of ethyl acetate. The mixture was stirred vigorously for 4 h and then partitioned between ethyl acetate and water. The aqueous phase was extracted with 2 additional portions of ethyl acetate. The combined organic fractions were concentrated. Flash chromatography of the residue on silica gel (9:1 hexanes/ethyl acetate) afforded material that was collected on a filter and washed with diethyl ether to give the title compound as a white solid. LC-MS 318 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][C:4](=[N:8][OH:9])[C:5](=[O:7])[CH3:6].[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:11][O:9][N:8]=[C:4]([CH2:3][C:2]([CH3:1])=[CH2:10])[C:5](=[O:7])[CH3:6]
Reactant: C=C(C)CC(=NO)C(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: C=C(C)CC(=NOC)C(C)=O
Temperature: 23 °C
Reaction time: 4 h

Procedure:
141 g of 5-methylhex-5-ene-2,3-dione 3-oxime from Example 1 were dissolved in 750 ml of acetone and admixed with 165.6 g of potassium carbonate. 145 g of dimethyl sulfate in 100 ml of acetone were then added dropwise, and the mixture was stirred at 23° C. for 4 hours. The solvent was then removed under reduced pressure, the residue was taken up in methyl tert-butyl ether/water and the aqueous phase was extracted repeatedly with methyl tert-butyl ether. The combined organic phases were washed with 15% strength ammonia solution and water and dried over sodium sulfate, and the solvent was removed under reduced pressure. This gave 141 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:10]#[N:11])[C:3]=1[CH3:21].[CH3:22][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])([CH3:22])[C:10]#[N:11])[C:3]=1[CH3:21]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1cc(C)c(C(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(C)(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
A solution of (6-chloro-2,5-dimethylpyrimidin-4-yl)-(2,4,6-trimethylphenyl)-acetonitrile (0.250 g, 0.834 mmol) in 4 ml of dry THF was cooled to −78° C. and treated with lithium bistrimethylsilylamide (1.0 M in THF, 0.92 ml) and stirred at that temperature for 45 minutes. Methyl iodide (0.426 g, 3.00 mmol) was added. The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a yellow oil. The oil residue was purified through silica gel chromatotron using ethyl acetate/hexane (4:6) as eluent to give 161 mg (62%) of yellow solid, mp 181–183° C. 1H NMR (CDCl3) δ 6.980 (s, 2H), 3.45 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.25 (s, 3H) ppm.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O1CCCC1.C1(N=C=NC2CCCCC2)CCCCC1.[C:30]([NH:51][CH2:52][CH2:53]O)(=[O:50])[CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH:43]=[CH:44][CH2:45][CH:46]=[CH:47][CH2:48][CH3:49]>CN(C)C1C=CN=CC=1.ClCCCl>[C:1]([O:9][CH2:53][CH2:52][NH:51][C:30](=[O:50])[CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH2:36][CH:37]=[CH:38][CH2:39][CH:40]=[CH:41][CH2:42][CH:43]=[CH:44][CH2:45][CH:46]=[CH:47][CH2:48][CH3:49])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CCC=CCC=CCC=CCC=CCC=CCCCC(=O)NCCOC(=O)c1cccnc1
Yield: 96.5 %

Procedure:
To a solution of 77 mg (0.63 mmol) of nicotinic acid in a mixed solvent of tetrahydrofuran (2 ml) and 1,2-dichloroethane (2 ml) at room temperature were successively added in an atmosphere of argon 7 mg (0.06 mmol) of 4-dimethylaminopyridine, 129 mg (0.63 mmol) of N,N'-dicyclohexylcarbodiimide and 196 mg (0.57 mmol) of N-5,8,11,14,17-eicosapentaenoyl-2-aminoethanol, which were dissolved in 1,2-dichloroethane (1.5 ml), respectively. The mixture was reacted overnight, and precipitates then produced were separated by filtration and washed with benzene. To the mother liquor was added water, and the mixture was extracted three times with dichloromethane. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure to give 311 mg of extraction residue, which was subjected to silica gel column chromatography. From a fraction eluted with chloroform-methanol (98:2) was obtained 246 mg (0.55 mmol) of N-(5,8,11,14,17-eicosapentaenoyl)-2-aminoethyl nicotinate. Physicochemical properties of the product supports the formula (III) shown below.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]2[NH:22][CH:23]=[C:24]([NH2:25])[C:13]=12>N1C=CC=CC=1>[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]2[NH:22][CH:23]=[C:24]([NH:25][C:8](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[C:13]=12
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
Picolinoyl chloride hydrochloride (270 mg, 1.53 mmol) was added to 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (240 mg, 1.02 mmol, Example 11, step G) in pyridine (5 mL). The reaction was stirred at 0° C. for 10 minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THF was removed, and water (20 mL) was added. The solid formed was collected by filtration and dried to give N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (280 mg, 79% yield) as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1COCC1>[CH3:14][O:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN2CCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Methyl 4-bromomethyl-3-methoxybenzoate (1.0 g; 3.9 mmol) (Part D) was dissolved in THF (10 mL) and pyrrolidine (1.3 mL; 15.4 mmol) was added at room temperature. The mixture was stirred overnight at room temperature, then poured into 50 mL of water. Extraction was carried out with EtOAc (4×25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound was isolated (0.92 g; 96% yield) by flash chromatography on silica gel eluting with EtOAc(100-95%)/Et3N(0-5%).