Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][NH2:19])([O-:8])=[O:7].O.[C:21]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][N:19]=[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:8])=[O:7]
Reactant: O=C1CCCCC1
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(NN=C2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 95 %

Procedure:
Concentrated sulfuric acid (2 mL) and 0.4456 g of 2,4-dinitrophenylhydrazine (2,4-DNP) were combined in a 25-mL Erlenmeyer flask. Water was added (2 to 3 mL) dropwise with swirling until the 2,4-DNP dissolved. This was followed by 10 mL of 95% ethanol. This solution was added, dropwise with swirling, to a solution of cyclohexanone, 0.5725 g, dissolved in 20 mL of 95% ethanol. A precipitate formed within 5 minutes. The mixture was refrigerated overnight. The precipitate was filtered to yield a yellow-orange crystalline solid. The product was re-crystallized from approximately 30 mL of absolute ethanol to afford 0.4 g of cyclohexanone 2,4-dinitrophenylhydrazone as orange flakes. The yield was 95%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:10][CH3:11])[CH2:8][CH2:7][C:6](=[O:9])[CH:5]=[CH:4]1)[CH3:2].[H][H]>C(O)(=O)C.[C].[Pd]>[CH2:10]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[CH3:11]
Reactant: CCC1(CC)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCC1(CC)CCC(=O)CC1
Yield: 85.2 %

Procedure:
In 22 ml of acetic acid was dissolved 2.20 g of 4,4-diethyl-2-cyclohexen-1-one, to which was added 0.22 g of 5% palladium-carbon. Under a pressure of 5 atmospheres, the mixture was stirred at ambient temperature for one hour under a stream of hydrogen. The reaction mixture was filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by column chromatography [eluent: hexane:ethyl acetate=10:1] gave 1.90 g of 4,4-diethyl-1-cyclohexanone as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])=[O:4].Cl.[C:15]([OH:19])([CH3:18])([CH3:17])[CH3:16]>CN(C)C1C=CN=CC=1>[C:15]([O:19][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)O
Reactant: COC(=O)CCCCCCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Product: COC(=O)CCCCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Di-tert-butyl dicarboxylate (9.58 mL, 41.7 mmol) and 4-dimethylaminopyridine (1.02 g, 0.34 mmol) were successively added to a tert-butanol solution (56 mL) of 7-methoxycarbonylheptanoic acid (1) (5.00 mL, 5.24 g, 27.8 mmol) at room temperature under the argon atmosphere, and the mixture was stirred at room temperature for 1 hour. A 0.2 N hydrochloric acid solution (20 mL) was added to the reaction solution to make the mixture weakly acidic, and the reaction solution was concentrated to about ⅓ volume, and extracted with chloroform (50 mL) three times. The organic layer was washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated. The resulting brown oily crude product (6.5 g) was separated and purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain t-butyl-7-methoxycarbonylheptanoate (2) as a colorless liquid substance (5.58 g, 82%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1)#[N:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CC(=O)Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)Cc2ccc(C#N)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl- 6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(4-Cyanophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-[α-(4-cyanophenyl)acetyloxy]-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[C:38]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)[CH:43]=2)[CH:39]=[CH:40][CH:41]=1>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:37]=[C:38]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]6[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]6)[CH:43]=5)[CH:39]=[CH:40][CH:41]=4)=[O:27])[CH:29]=[CH:30][CH:31]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.072 g, 0.16 mmol) in DMF (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperazinecarboxylate (0.061 g, 0.16 mmol), (1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinylphosphorus hexafluorophosphate (0.100 g, 0.192 mmol), and TEA (0.045 mL, 0.320 mmol) and this mixture was stirred at room temperature for 16 h. The resultant mixture was purified using a Gilson HPLC (with 0.1% TFA) and concentrated by GeneVav EZ-2 evaporator to afford the title compound. It was used in the next reaction step without further purification. LC-MS m/z 815 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH3:30][NH:31][NH2:32].O1CCCC1>C(OCC)(=O)C>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26]3[CH2:27][CH2:28][N:31]([CH3:30])[N:32]=3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: CNN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
A mixture of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (250 mg), methylhydrazine (0.050 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 3 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, the insoluble substance was filtered off, and the filtrate was concentrated. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (156 mg, yield: 59%) as colorless needle crystals. MS: 474 (MH+). melting point 149-150° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Br-].[CH3:11][C:12]1[CH:37]=[CH:36][CH:35]=[CH:34][C:13]=1[CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:11]/[C:12]1[CH:37]=[CH:36][CH:35]=[CH:34][C:13]=1[CH3:14]
Reactant: O=Cc1cccc(I)c1
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: Cc1ccccc1/C=C/c1cccc(I)c1

Procedure:
Coupling of 3-iodobenzaldehyde with (2-methylbenzyl)triphenylphosphonium bromide followed by flash chromatography (silica gel, eluent: hexanes) gave (E)-1-(3-iodostyryl)-2-methylbenzene as a colorless oil. Yield (0.498 g, 36%): 1H NMR (500 MHz, CDCl3) δ 7.87-7.86 (m, 1H), 7.59-7.55 (m, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.30 (d, J=16.2 Hz, 1H), 7.23-7.18 (m, 3H), 7.09 (t, J=7.9 Hz, 1H), 6.86 (d, J=16.2 Hz, 1H), 2.43 (s, 3H) and (Z)-1-(3-iodostyryl)-2-methylbenzene as a colorless oil. Yield (0.0.540 g, 39%): 1H NMR (500 MHz, CDCl3) δ 7.47-7.45 (m, 2H), 7.21-7.15 (m, 2H), 7.11-7.01 (m, 3H), 6.85 (t, J=7.8 Hz, 1H), 6.68 (d, J=12.2 Hz, 1H), 6.49 (d, J=12.1 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][NH:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:23]12[CH2:30][CH2:29][CH:26]([NH:27][CH2:28]1)[CH2:25][N:24]2[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16]
Reactant: C1CC2CNC1CN2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4CCC3CN4)c(F)cc2c1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 0.28 g (1 mmole) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.2 g (1.1 mmole) 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 0.45 ml (3.0 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 10 ml of acetonitrile was heated at reflux for four hours. After cooling to room temperature, the reaction mixture was filtered and the solid washed with ethanol and dried to give 0.27 g of the title compound, mp 275°-280° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:27])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:17][C:18]([CH3:27])=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (9.31 g, 52.0 mmol) in N,N-dimethylformamide (120 ml) was added at 0° C. under nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 2.11 g, 52.8 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added a solution of 1-(3-bromo-2-methyl-1-propenyl)-4-methylbenzene (12.48 g, 55.44 mmol) in N,N-dimethylformamide (20 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-isopropyl ether to obtain 7.34 g (44% yield) of the title compound. Melting point: 167-169° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+].CO>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(C(=O)C(C)CC(=O)O)cc1

Procedure:
The ester from Step B (1.07 g) was saponified with 1N NaOH (5 ml) and methanol (5 ml) and THF (5 ml) to provide after acidification, extraction into CH and evaporation to dryness the title compound, mp 69°-71° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9]2)[CH:5]=[CH:4][C:3]=1[CH:20]1N(C)C(=O)N(C)C(=O)N1C.[OH-:31].[Na+]>O>[CH3:13][C:11]1[C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:9][N:8]([C:6]2[CH:7]=[C:2]([OH:1])[C:3](=[CH:4][CH:5]=2)[CH:20]=[O:31])[N:12]=1
Reactant: [OH-]
Reactant: Cc1nn(-c2ccc(C3N(C)C(=O)N(C)C(=O)N3C)c(O)c2)nc1-c1ccccc1
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2ccc(C=O)c(O)c2)nc1-c1ccccc1
Temperature: 102 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A mixture of 570 g of 6-[2-hydroxy-4-(4-methyl-5-phenyl-1,2,3-triazol-2-yl)-phenyl]-2,4-dioxo-1,3,5-trimethyl-hexahydro-s-triazine, 2,940 ml of water and 560 g of sodium hydroxide is heated for 22 hours at 102° C. It is then cooled to 15° C. and the sodium salt which has separated out is filtered off and introduced into a mixture of 700 g of ice, 700 ml of water and 237 ml of 37% strength hydrochloric acid. After stirring for four hours, the salicylaldehyde produced is filtered off, washed with ice water and dried at 80° C. This gives 353 g of product of melting point 121°-123° C., the product being 98.6% pure, according to analysis. The yield is 89% of theory.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=O)[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[S:25])[C:13]2=[C:17]([CH3:23])[N:18]=[C:19]([CH2:20][CH2:21][CH3:22])[N:12]2[N:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nc(C)c2c(=S)[nH]c(-c3ccccc3OCC)nn12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-5-methyl-7-n-propyl-3H-imidazolo[5,1-f][1,2,4]triazine-4-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol (300 ml) were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:8][CH:7]=1.O>C(O)(C(F)(F)F)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]2[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16](=[O:19])[NH:17][CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=c1ccc(Cc2ccc(F)cc2)c[nH]1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1[nH]cc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 90% HNO3 (57 mL, 1.22 mol) was added slowly to a stirred solution of 5-[(4-fluorophenyl)methyl]-2(1H)-pyridinone (249 g, 1.22 mol) in TFA (750 mL). The solution was heated at 75° C. for 2 h during which time additional 90% HNO3 (25 mL, 0.5 mol) was added. Water (1L) was added slowly and most of the TFA was removed by distillation. The mixture was allowed to cool to rt and the product was isolated by filtration as a yellow solid: 1H NMR (d6-DMSO) δ 12.76 (1H, br), 8.31 (1H, d, J=2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 7.30 (2H, dd, J=8.6, 5.7 Hz), 7.11 (2H, t, J=8.6 Hz), 3.76 (2H, s); ES+ MS: 249 (M+H+, 100).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])=[CH:16][CH2:17][CH2:18][OH:19])[CH3:8].[H][H]>[Pd].CO>[CH2:7]([O:9][C:10]([CH3:23])([CH2:21][CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][OH:19])[CH3:8]
Reactant: [H][H]
Reactant: CCOC(C)(CC)CCCCC(C)=CCCO
Agent: [Pd]
Solvent: CO
Solvent: c1ccccc1
Product: CCOC(C)(CC)CCCCC(C)CCCO

Procedure:
A suspension of 0.5 g. of 5% palladium-on-carbon catalyst in 50 ml. of benzene is hydrogenated for 30 minutes. A mixture of 1.5 g. of 9-ethoxy-4,9-dimethylundec-3-en-1-ol in 75 ml. of methanol is added and hydrogenated with agitation until the theoretical amount of hydrogen is absorbed. The catalyst is removed by filtration and the solution evaporated to yield 9-ethoxy-4,9-dimethylundecan-1-ol which is purified by chromatography. The product is treated with phosphorus tribromide to yield 1-bromo-9-ethoxy-4,9-dimethylundecane which can be used as the alkylating agent for preparation of compounds of the present invention of formula I.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][C:26]=2[OH:41])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CC(C)=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][C:26]=2[O:41][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.6 %

Procedure:
Methyl bromoacetate (47 L, 0.495 mmol), followed by potassium carbonate (136.7 mg, 0.99 mmol) were added to a solution of 3-[4-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (198.7 mg, 0.471 mmol) in acetone (5 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 4 hours, then filtered and the solvent was evaporated under reduced pressure to give 240.9 mg of 3-[4-(3-fluoro-benzenesulfonyl)-2-methoxycarbonylmethoxy-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, which was used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]([F:16])([F:15])[C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11]C.C(O)(=O)C.Br>O>[Br:1][C:2]([F:15])([F:16])[C:3]([F:13])([F:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11]
Reactant: COc1ccccc1OC(F)(F)C(F)(F)Br
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccccc1OC(F)(F)C(F)(F)Br
Temperature: 20 °C
Reaction time: 43 h
Yield: 83.9 %

Procedure:
A solution of 54.42 g of 1-(2-bromo-1,1,2,2-tetrafluoroethoxy)-2-methoxybenzene in 500 ml of an acid mixture of acetic acid (96% by weight)/hydrobromic acid (48% by weight) 2.5:1 was stirred for 43 hours under reflux, the completeness of the reaction being monitored by gas chromatography (GC). The reaction mixture was then cooled to 20° C. and poured into water. The organic phase was separated off and the aqueous phase was extracted twice with dichloromethane. The extracts were added to the organic phase, and the mixture was dried over magnesium sulfate and evaporated in vacuo. Distillation of the residue gave 43.55 g (83.9% of theory) of 2-(2-bromo-1,1,2,2-tetrafluoroethoxy)-phenol of boiling point 84° C./20 mbar.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4](O)=[O:5].[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([NH:34][C:4](=[O:5])[C:3]([CH3:7])([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]3[C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH3:2])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCCCC1
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)NC3CCCCC3)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 128, the above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and cyclohexylamine.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+]>O>[O:11]([CH2:3][CH2:2][Br:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Oc1ccccc1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccccc1
Reaction time: 6 h
Yield: 86.8 %

Procedure:
In a mixed solution consisting of 50 g of 1,2-dibromoethane, 18.5 g of phenol and 100 ml of water was added dropwise 30 ml of water containing therein 7.9 g of sodium hydroxide at a temperature of 130° C. over 30 minutes with stirring. The reaction solution was further stirred for 6 hours. After completion of the reaction, the organic layer was separated from the reaction solution, washed twice with a saturated aqueous potassium carbonate solution, washed twice with water and dried with anhydrous sodium sulfate. The organic layer was separated by filtration and condensed under reduced pressure to give 34.3 g of 2-phenoxyethyl bromide having a boiling point of 105° C. to 107° C. at 6 mmHg in a yield of 85%.
Reaction SMILES: [Cl-].[CH2:2]([Al+:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:3]([CH3:5])[CH3:4].[CH3:11][N:12]([CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([Li])=[CH:20][CH:19]=[CH:18]2>C(OCC)C>[CH3:11][N:12]([CH3:24])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[C:21]([Al:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:20][CH:19]=[CH:18]2
Reactant: CC(C)C[Al+]CC(C)C
Reactant: [Li]c1cccc2cccc(N(C)C)c12
Agent: [Cl-]
Solvent: CCOCC
Product: CC(C)C[Al](CC(C)C)c1cccc2cccc(N(C)C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70907.1 %

Procedure:
9.5 g (0.048 mmol) of diisobutylaluminium chloride were added dropwise to a suspension, cooled to −40° C., of 12.1 g (0.048 mmol) of [8-(dimethylamino)naphth-1-yl]lithium etherate and 100 ml of diethyl ether in an inert nitrogen atmosphere. After slow warming to room temperature, the mixture was stirred for a further 24 hours in order to complete the reaction. Filtration through a D4 frit and removal of the solvent by distillation gave 10.6 g of [8-(dimethylamino)naphth-1-yl]diisobutylaluminium (71%) as a colourless, oily liquid by fractional distillation from the residue.