Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[Br:15]N1C(=O)CCC1=O>CS(O)(=O)=O>[Br:15][C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: CS(=O)(=O)O
Product: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Temperature: 25 °C

Procedure:
Fluorenone (41 grams (g); 0.228 mol) was dissolved in 225 milliliters (ml) of methanesulfonic acid and treated portion wise at room temperature with solid N-bromosuccinimide (NBS) (38.55 g; 0.217 mol). The mixture became dark and warm, and the temperature was maintained below 60° C. by controlling the rate of NBS addition. Upon completion of the NBS addition, the mixture was allowed to cool to room temperature and was poured into 1 liter of ice water. The yellow solid that separated was collected by filtration, washed with copious quantities of water, air dried, and then recrystallized from about 1.5 liters of ethanol. The yield was 40 g (71%) and the product contained 5-10% of 2,7-dibromofluorenone as indicated by LC analysis. A small sample was purified by column chromatography, but in general the contaminated material was carried on in subsequent steps.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:12])=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccn1

Procedure:
10.0% of pyridine-2-carboxylic acid were suspended in 150 ml of toluene and the suspension was heated to reflux for 2 hours with 17.7 ml of thionyl chloride and 3 drops of dimethylformamide. Thereafter, the mixture was evaporated to dryness under reduced pressure, the residue was treated with toluene and again evaporated to dryness. There was obtained picolinic acid chloride as dark green crystals which were used directly in the next step.
Reaction SMILES: [ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH:7]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN(CCOCC=C2c3ccccc3CCc3ccccc32)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(O)[C@@H]1CCCN(CCOCCC2c3ccccc3CCc3ccccc32)C1

Procedure:
The acid prepared in Example 3 (0.2 g, 0.5 mmol) was dissolved in methanol (10 ml) and stirred under an atmosphere of hydrogen for 16 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste). The mixture was filtered and the solvent was evaporated in vacuo to give an oily residue, which was re-evaporated from acetone and then crystallized from acetone (10 ml). This afforded 0.13 g (65%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:8][C:7]1[S:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenylthiazole (5.40 g), 4-hydroxybenzaldehyde (2.91 g), anhydrous potassium carbonate (4.95 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 3 hours. The reaction mixture was poured into water, the precipitated solid was collected by filtration, and air-dried to obtain crystals of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzaldehyde (6.85 g, yield 93%). This was recrystallized from ethyl acetate-hexane to obtain colorless prisms. Melting point: 118–119° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Cl:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][CH:66]=[C:65]([CH2:68]O)[C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:65]2[C:64]3[CH:70]=[C:60]([Cl:59])[CH:61]=[CH:62][C:63]=3[S:67][CH:66]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OCc1csc2ccc(Cl)cc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2csc3ccc(Cl)cc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-chloro-1-benzothien-3-yl)methanol (0.83 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 55%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22](Cl)=[O:23])[CH2:18][CH2:17]1)[CH2:14][CH3:15].[C:25]([O:28][CH2:29][CH3:30])(=[O:27])[CH3:26]>C1COCC1>[CH2:29]([O:28][C:25](=[O:27])[CH2:26][C:22](=[O:23])[C@H:19]1[CH2:20][CH2:21][C@H:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1)[CH3:30]
Reactant: CCOC(C)=O
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC[C@H]1CC[C@H](C(=O)CC(=O)OCC)CC1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
THF (1,000 ml) was added to diisopropylamine (162.9 g) in a reaction vessel under an atmosphere of nitrogen. n-Butyllithium was added dropwise, while the solution was kept at −40° C. or lower, and the stirring was continued for 30 minutes. The solution was cooled at −65° C. or lower, and ethyl acetate (141.9 g) and then a THF (200 ml) solution of trans-4-propylcyclohexanecarboxylic acid chloride (2) (189.9 g) prepared in the first step were added dropwise. After the reaction mixture had been slowly warmed up to room temperature with stirring, it was quenched with a saturated aqueous solution of ammonium chloride. Water (1,000 ml) was then added to give two layers. The water layer was extracted with toluene (500 ml) three times, and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 300 g, eluent: toluene) to give 3-oxo-3-(trans-4-propyl-cyclohexyl)-propionic acid ethyl ester (3) (220 g) in 90% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[CH2:12]([NH:19][S:20]([CH2:23][C:24]#[N:25])(=[O:22])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][S:20](/[C:23](=[CH:5]/[C:4]1[CH:3]=[C:2]([CH3:1])[C:9]([OH:10])=[C:8]([CH3:11])[CH:7]=1)/[C:24]#[N:25])(=[O:22])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Product: Cc1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C)c1O

Procedure:
The titled compound was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and N-benzyl cyanomethylsulfonamide under the similar conditions as described for EXAMPLE 12 (part B).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.C(OP(Cl)(OCC)=O)C.[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([CH3:44])([CH3:43])[CH2:40][C:41]#[CH:42])([CH3:33])([CH3:32])[CH3:31].[F:45][C:46]([F:54])([F:53])[C:47]([C:49]([F:52])([F:51])[F:50])=[O:48]>C1COCC1>[C:30]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([CH3:44])([CH3:43])[CH2:40][C:41]#[C:42][C:47]([C:49]([F:52])([F:51])[F:50])([OH:48])[C:46]([F:54])([F:53])[F:45])([CH3:31])([CH3:32])[CH3:33]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C#CCC(C)(C)CCCCOC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(CC#CC(O)(C(F)(F)F)C(F)(F)F)CCCCOC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 27.62 g of diisopropyl amine in 28 ml of THF was added at −78° 171 ml of n-BuLi (1.6 M in hexane) the solution was warmed to 0° for 30 min and cooled to −78°. The LDA-solution was treated at −78° with a solution of 59.38 g of the crude 10-tert-butoxy-1,1,1-trofluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-yn-2-ol in 20 ml of THF over 40 min and stirring was continued at −78° for 1 h. The yellow solution was treated at −78° with 47.11 g of diethylchlorophosphate over 30 min, the mixture was warmed to 22° over 2 h and stirring was continued at 22° for 2 h. The suspension was added at −78° dropwise to a solution of LDA, prepared with 52.62 g diisopropyl amine, 325 ml of n-BuLi (1.6 M in hexane) and 60 ml of THF as described above, over 20 min and stirring was continued at −78° for 2 h. The suspension containing the anion of 8-tert-butoxy-4,4-dimethyl-oct-1-yne was treated at −78° with 60.0 g of hexafluoroacetone over 10 min and stirring was continued at −78° for 30 min. The suspension was washed with 300 ml of sat. aqueous NH4Cl and sat. aqueous NaCl, the organic layer was dried over MgSO4 and evaporated to give 107.9 g of crude product. The material was crystallized from 160 ml of hexane at −20° to give 43.00 g of the pure title compound as a white solid, m.p. 66-67°. The mother liquor was purified by chromatography on silica with hexane/AcOEt 19:1 to give 21.1 g of the pure title compound. IR(nujol): 3157m (OH), 2242m (C,C-triple bond); MS(EI): 361/20 (M−CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCCC(O)(c2cccc(Cl)c2)C1
Agent: [S]
Product: Cc1cccc(-c2cccc(Cl)c2)c1
Reaction time: 60 h
Yield: 76.3 %

Procedure:
A mixture of 1-(3-chlorophenyl)-3-methylcyclohexan-1-ol (25.0 g, 0.11 mole) and sulfur (7.1 g, 0.22 mole) was heated at 250° for 4.5 hours. The reaction mixture then stood at room temperature for approximately 60 hours, and then it was distilled under reduced pressure to give 19.5 grams of distillate; bp, 150°-165°/10 mm. The distillate was chromatographed on silica gel, elution with hexane. The eluent was evaporated under reduced pressure to give 3'-chloro-3-methyl[1,1'-biphenyl] (17.0 g) as an oil. The nmr and the ir spectra of the oil were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C=O)C.S(Cl)([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Cl:20])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2,6-dichlorophenylacetic acid (4.16 g, 20.3 mmol, 1.1 eq), DMF (0.4 mL), and CH2Cl2 (40 mL) under a nitrogen atmosphere was treated with thionyl chloride (1.88 mL, 25.8 mmol, 1.4 equiv.). The resulting mixture was stirred at rt for 20 h. The mixture was concentrated afford (2,6-dichloro-phenyl)-acetyl chloride as a yellow syrup. A solution of the acid chloride in DMA (10 mL) was added to a solution of 6-chloro-N4-(4-trifluoromethyl-phenyl)-pyrimidine-4,5-diamine hydrochloride (6.0 g, 18.5 mmol, 1.0 eq) in DMA (20 mL) under a nitrogen atmosphere. After 2 h, isopropanol (50 mL) was added. The resulting solid precipitate was collected by filtration, rinsed with EtOH, and dried under vacuum at 50° C. for 18 h to give the title compound as a white solid (5.6 g, 64%). 1H NMR (d6-DMSO): 9.93 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 7.92 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.7 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.33 (t, J=7.7 Hz, 1H), 4.24 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:28])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]3=[C:16]([O:25][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[C:26](=[O:27])[NH2:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)c3ccccc3cc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c2ccccc2cc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 53.7 %

Procedure:
40% Methanolic Triton B (0.378 mL, 0.832 mM) was added to a solution of 5-benzyl-11-hydroxy-5H-benzo[b]carbazole-1-carboxylic acid amide, (0.235 g, 0.64 mM) in 5 mL DMF at room temperature. After 2 minutes, methyl bromoacetate (0.125 mL, 0.202 g, 1.28 mM) was added and the resultant mixture stirred at room temperature for 2 h. Cesium carbonate (0.105 g, 0.32 mM) was then added as a solid, and the mixture allowed to stir at room temperature for an additional 1 h. The mixture was diluted with ethyl acetate, washed with H2O, 1N HCl, saturated aqueous NaHCO3 solution, and saturated brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue-was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 0.151 g (53%) of the title compound (5-benzyl-1-carbamoyl-5H-benzo[b]carbazol-11-yloxy)-acetic acid, methyl ester as a brown foam (MP 120–125° C., MW 438.49).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CC(C)CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)CC(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with isovaleryl chloride (7.8 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl.[OH-].[Na+]>CCO.CO.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:20]=3[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3c([N+](=O)[O-])cccc3o2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: Nc1cccc2oc(N3CCN(C(=O)OCc4ccccc4)CC3)nc12
Yield: 24 %

Procedure:
A mixture of 4-(4-nitrobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester, from Example 7 (35.7 mmol theory), SnCl2 (40.25 g, 178.4 mmol), and concentrated HCl solution (4.46 mL) in EtOH was heated at 70° C. overnight, cooled, diluted with 20% MeOH in CH2Cl2, neutralized with NaOH to pH 8-10 and extracted with CHCl3. The extracts were combined, dried over Na2SO4, concentrated, and purified by chromatography with 1-5% MeOH in CH2Cl2 to provide the title compound (3.0 g, 24% overall yield from 4-nitro-3H-benzoxazole-2-thione), characterized by NMR and mass spectral analyses.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[I:11].[OH-].[Na+]>C(O)(=O)C.O>[I:11][C:4]1[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: CCCc1nc(I)c(CO)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc(I)c(C=O)[nH]1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of 35.8 g of 5-hydroxymethyl-4-iodo-2-n-propylimidazole in 325 mL of glacial acetic acid at 20° C. was added dropwise over 1 h 290 mL of 1.0N aqueous ceric ammonium nitrate solution. The resulting mixture was stirred at 20° C. for 1 h. The reaction mixture then was diluted with water, adjusted to pH 5-6 employing aqueous sodium hydroxide solution, and extracted with chloroform. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude solid was recrystallized from 1-chlorobutane to furnish 29.9 g of product as a light yellow solid; mp 141°-142° C. NMR (CDCl3) δ 11.51 (br s, 1H); 9.43 (s, 1H); 2.81 (t, 2H); 1.81 (sext. 2H); 0.97 (t, 3H). ##STR74##
Reaction SMILES: C[O:2][C:3]([C:5]1([NH2:16])[CH2:15][CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:4].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1>>[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:16][C:5]2([C:3]([OH:2])=[O:4])[CH2:15][CH2:14][CH2:13][C:8]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:7][CH2:6]2)=[O:24])=[CH:21][C:20]=1[O:28][CH2:29][CH2:30][C:31]1[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: COC(=O)C1(N)CCCC2(CC1)OCCO2
Product: COc1ccc(C(=O)NC2(C(=O)O)CCCC3(CC2)OCCO3)cc1OCCc1cccc(C)c1

Procedure:
The title compound was prepared from the compound of step 3 and 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to steps 3 and 4 of example 1.
Reaction SMILES: CN(C)[C:3](=[CH:9][CH:10]=[C:11]([CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5].Cl.C([OH:25])C>>[OH:25][C:3](=[CH:9][CH:10]=[C:11]([CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]([O:6][CH2:7][CH3:8])=[S:5]
Reactant: CCCCC(=CC=C(C(=S)OCC)N(C)C)C(=O)OCC
Reactant: CCO
Agent: Cl
Product: CCCCC(=CC=C(O)C(=S)OCC)C(=O)OCC
Temperature: 20 °C

Procedure:
The procedure is as in Example 2, starting with diethyl 2-dimethylamino-5-n-butylthio-2,4-hexadienedioate (10 g), 12N aqueous hydrochloric acid solution (63 cc) and ethanol (100 cc). The mixture is maintained for 1 hour at a temperature of approximately 20° C. After purification by chromatography on a silica column with dichloromethane as eluent, diethyl 2-hydroxy-5-n-butylthio-2,4-hexadienedioate (5.6 g), m.p. 37° C., is obtained. Diethyl 2-dimethylamino-5-n-butylthio-2,4-hexadienedioate may be prepared in the following manner:
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN1CCOCC1.ClC(OCC(C)C)=O.N[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>CN(C=O)C.CCOCC>[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])[CH3:33].[OH:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:1]
Reactant: NCC(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The D-biotin (1 g, 4.1 mmol) is solubilized in 45 ml of anhydrous DMF in the hot state. The mixture is cooled to 0° C. under argon, and then N-methylmorpholine (590 μl, 5.33 mmol) and isobutyl chloroformate (840 μl, 6.60 mmol) are successively added. The mixture is kept stirred for 30 min, and then 2-aminoacetophenone (824 mg, 6.10 mmol) is added. The solution is maintained stirred at room temperature for 3 h 30 min, and then evaporated to dryness. The residue is taken up in 50 ml of water. The precipitate obtained is filtered, washed with water and then with 50 ml of MeOH in the hot state. The precipitate obtained is filtered and washed with water. Recrystallization is carried out by dissolving the product in MeOH in the hot state and reprecipitating by addition of water. The precipitate is filtered, washed with water, and then with ether to give 1.1 g (2.95 mmol, 72%) of crude product 1c.
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=1.C(OCC)(=O)C.I[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: OCC#Cc1ccc(Br)cc1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC/C=C(/c1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium methoxide (23 mg, 0.43 mmol) was added to 1 M solution of lithium aluminum hydride in tetrahydrofuran (9 mL, 9.0 mmol). The mixture was cooled to 0° C. and a solution of 3-(4-bromophenyl)prop-2-yn-1-ol (1.9 g, 9.0 mmol) in tetrahydrofuran (15 mL) was slowly added. The reaction was stirred for at 0° C. for 3 h; ethyl acetate (2.7 mL, 9.0 mmol) was added and the mixture was stirred for 10 min without cooling. 4-Iodobenzotrifluoride (2.33 g, 8.6 mmol), anhydrous zinc chloride (0.74 g, 5.4 mmol), tris(dibenzylideneacetone)-dipalladium chloroform complex (0.19 g, 0.18 mmol) and tri(2-furyl)phosphine (0.17 g, 0.73 mmol) were added, the mixture was evacuated and kept under nitrogen. The mixture was heated at 65° C. for 16 h. Methanol (4.5 mL) was added and the mixture was stirred for additional 1 h. The reaction mixture was diluted with ether (300 mL) and saturated aqueous solution of ammonium chloride (2.5 mL) was added. The mixture was filtered through a pad of silica gel, evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 80:20) affording (E)-3-(4-bromophenyl)-3-(4-trifluoromethylphenyl)-prop-2-en-1-ol.