Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:29](=[O:31])[CH3:30]>C1COCC1>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)cc2)C1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)CCO2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-bromophenyl)morpholine-4-carboxylate (750 mg, 2.19 mmol, CAS 1131220-82-0) in THF (6 ml) was cooled to −78° C., treated dropwise with n-butyllithium (2.05 ml, 3.29 mmol, 1.6 M solution in hexane) and stirred 1 h at −78° C. N-Methoxy-N-methylacetamide (226 mg, 2.19 mmol) was added and the mixture was stirred for 1 h at −78° C., and then allowed to warm up to −5° C. The reaction mixture was quenched by addition of saturated ammonium chloride solution (4 ml) and water (4 ml) and the resulting mixture was partitioned between water and ethyl acetate.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][C@@H:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].[C:19](=[S:21])=[S:20].[CH3:22]I>C(O)C>[CH3:22][S:20][C:19]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:21]
Reactant: CI
Reactant: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Yield: 59 %

Procedure:
In the same manner as described in Example 2, (i), (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (42.25 g), KOH (23.38 g), carbon disulfide (12.1 ml), methyl iodide (16.3 ml) and 50% ethanol (600 ml) are reacted. The product is crystallized from chloroform to give the title compound (50.2 g, 59%), m.p. 111°-113° C., NMR (CDCl3, δ): 2.68 (s, 3H, N--CSSCH3), Mass (m/e): 306 (M+), 258 (M+ --CH3SH).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:28])[C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[CH:13][O:14]2)=[CH:9][CH:8]=1)(=O)=O.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[O:28]=[C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])=[CH:8][CH:9]=2)[O:14][CH:13]=[C:12]1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Nc1ccc(-c2coc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2=O)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc2c(=O)c(-c3ccc(NS(C)(=O)=O)cc3)coc2c1
Temperature: 85 °C

Procedure:
3-(4-(methylsulfonamido)phenyl)-4-oxo-4H-chromen-7-yl trifluoromethanesulfonate (2.5 g, 5.39 mmol), trimethylsilylacetylene (0.92 ml, 1.2 eq), PdCl2(PPh3)2 (175 mg, 0.05 eq), copper iodide (28.8 mg 0.03 eq), triphenylphosphine (40 mg 0.03 eq) and triethylamine (3.12 ml, 4.0 eq) were combined in dry tetrahydrofuran (10 ml) and heated in microwave for 30 minutes at 85° C. The reaction mixture was partitioned between ethyl acetate and water, the organic phase dried with magnesium sulfate, and solvent removed under reduced pressure. The crude product was heated in acetonitrile, cooled down and the solids were filtered off. This procedure was repeated twice in order to afford N-(4-(4-oxo-7-((trimethylsilyl)ethynyl)-4H-chromen-3-yl)phenyl)methanesulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])C.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12]>C1C=CC=CC=1>[C:4]1([CH:9]([CH3:10])[CH3:11])[CH:3]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:1][CH2:12][CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCc1ccccc1CC
Reactant: CCc1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1ccccc1
Product: CCCc1ccccc1

Procedure:
Additional synergies can be realized from integrating the process of this invention with a downstream transalkylation process as illustrated in FIG. 2. Thus, concentrated reactor effluent stream 52 containing crude ethylbenzene, about 20-80 wt. % benzene, and higher-boiling polyalkylated aromatics may be directed to a second benzene recovery column 110 to separate a crude ethylbenzene product stream 70 from a benzene stream 72. The crude ethylbenzene stream 70, including components such as cumene, n-propylbenzene, and other alkylaromatics heavier than ethylbenzene, plus other heavy material, is sent to a third fractionation column 120 in which an ethylbenzene product 74 is distilled overhead. A crude polyethylbenzene stream 76 is recovered from the bottom of column 120 and directed to a fourth fractionation column 130. In column 130, polyethylbenzenes, including diethylbenzene, cumene, n-propylbenzene, and other alkylaromatics heavier than ethylbenzene, are separated from heavy residue material 78, removed as overhead stream 80, and combined with at least a portion of benzene vapor stream 72 coming from column 110 to form a mixed stream 82. Mixed stream 82 is then fed to a secondary transalkylation reactor 140 operating in the vapor phase. In this secondary, transalkylation reactor, in the presence of a suitable catalyst and under proper reactor conditions, the transalkylation of diethylbenzene to ethylbenzene is promoted as well as the dealkylation of higher alkylbenzenes, such as cumene, and n-propylbenzene, to form benzene and light gases. Transalkylation product stream 84 from reactor 140, comprising ethylbenzene, benzene, light gases, and unreacted components, is :fed to a stabilizer/absorber unit 150. Vapor stream 59 coming from the partial condenser associated with column 14 may also be fed to stabilizer 150 to recover the aromatic components. The light gases 86 recovered from the stabilizer may be combusted as fuel. The stabilizer bottoms stream 88 may be returned to benzene recovery column 110, for example, for further recovery of benzene and ethylbenzene as described above.
Reaction SMILES: [CH2:1]([OH:7])[C@H:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:7][CH2:1][C@@H:2]2[CH2:3][CH2:4][CH2:5][O:6]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OC[C@@H]1CCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tetrahydrofurfuryl alcohol (Codexis, 1.6 g, 15.2 mmol) in 5 mL of CH2Cl2 and 5 mL of pyridine was added p-toluenesulfonyl chloride (4.3 g, 22.8 mmol) in portions over 15 minutes. The mixture stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. MS (DCI/NH3) m/z 257 (M+H)+, 274 (M+NH4)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[CH:6]=[CH:7]/[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=O)=[O:9].Cl.[NH2:20][OH:21].[OH-].[Na+].Cl>CO.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:18])[NH:20][OH:21])=[O:9]
Reactant: O=C([O-])CCCCCNC(=O)/C=C/c1ccco1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(C=Cc1ccco1)NCCCCCC(=O)NO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
To a solution of 6-{[(E)-3-(2-furyl)-2-propenoyl]amino}hexanoate (0.200 g, 0.75 mmol) in methanol (2 ml) a solution of hydroxylamine hydrochloride (0.210 g, 3.02 mmol) in methanol (3 ml) and NaOH (242 mg, 6.04 mmol) in H2O (1 ml) were added. The mixture was stirred for 30 min at room temperature and acidified with 1N HCl to pH 3 of the reaction medium. The mixture was extracted with ethyl acetate (3×25 ml), the organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated and the residue (0.172 g) was crystallized from acetonitrile (5 ml) to give the title compound (0.117 g, 58%). M.p. 151-152.5° C. 1H-NMR (DMSO-d6, HMDSO), δ: 1.15-1.62 (m, 6H); 1.94 (t, J=7.2 Hz, 2H); 3.14-3.22 (m, 2H); 6.40 (d, J=15.5 Hz, 1H); 6.57 (dd, J=1.6 and 3.2 Hz, 1H); 6.74 (d, J=3.2 Hz, 1H); 7.21 (d, J=15.5 Hz, 1H); 7.75 (s, 1H); 8.11 (t, J=5.6 Hz, 1H); 8.67 (d, J=1.6 Hz, 1H); 10.34 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 1% (column size 4.6×150 mm; mobile phase acetonitrile+0.1% H3PO4, gradient from 25 to 100%; detector UV 270 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C13H18N2O4, %: C, 58.64; H, 6.81; N, 10.52. Found, %: C, 58.64; H, 6.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([F:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)F)c(F)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (104 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (156 mg, 0.57 mmol, Amine-7, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[N+:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl)([O-:27])=[O:26]>C1C=CC=CC=1.C(#N)C>[C:15]([C:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N+:25]([O-:27])=[O:26])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CC(Cc1ccccc1[N+](=O)[O-])(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
A 500 ml. Morton flask equipped with a condenser, stirrer, and dropping funnel was flame dried and charged with NaH (11.9 g - 61% dispersion in mineral oil; 0.3 mole) and 150 ml. of 10% DMF in benzene. Triethyl 1,1,2-ethanetricarboxylate (73.9 g; 0.3 mole) was then added with vigorous stirring over a one hour period. After stirring at room temperature for 0.5 hour, there was then added as rapidly as possible o-nitrobenzyl chloride (51.5 g; 0.3 mole). The resulting reaction mixture was heated at reflux for 23 hours. After cooling, insoluble material was removed by filtration (supercel). Water was added to the filtrate followed by aqueous HCl to acidify the aqueous layer. Extraction with ether followed. The combined ethereal extracts were then washed twice with water, once with brine, dried over Na2SO4, filtered and rendered free of solvent in vacuo. The viscous oil so obtained was dissolved in acetonitrile and washed with n-pentane to remove the mineral oil. Removal of the acetonitrile afforded the crude product. The IR (infrared) and NMR (nuclear magnetic resonance) spectra were consistent with the structure and this material was used directly in the next step without further purification.
Reaction SMILES: [OH:1]S([O-])(=O)=O.[K+].[F:7][C:8]([F:17])([F:16])[CH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]#[N:15].S([O-])([O-])=O.[Na+].[Na+].[OH2:24]>CO>[F:17][C:8]([F:7])([F:16])[CH2:9][CH2:10][CH2:11][S:12]([CH2:13][C:14]#[N:15])(=[O:1])=[O:24]
Reactant: N#CCSCCCC(F)(F)F
Reactant: O
Reactant: O=S(=O)([O-])O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: N#CCS(=O)(=O)CCCC(F)(F)F
Reaction time: 8 h

Procedure:
To a suspension of 67.50 g of a double salt 2KHSO5.KHSO4.K2SO4 (Oxone, registered trade mark) in 100 ml of water was added dropwise a solution of 17.82 g of (4,4,4-trifluorobutylthio)acetonitrile in 100 ml of methanol at room temperature over 60 minutes under a nitrogen atmosphere, and the mixture was stirred overnight. To the reaction mixture was added 50 ml of an aqueous 10% sodium sulfite solution, followed by extraction with 200 ml of ethyl acetate twice. Organic layers were combined, washed with 50 ml of an aqueous 10% sodium sulfite solution and 50 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under rescued pressure. The residue was subjected to silica gel column chromatography to obtain 22.34 g of (4,4,4-trifluorobutyl sulfonyl)acetonitrile represented by the formula:
Reaction SMILES: C(OC(=O)[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:25]=1.[C:55]([O-:58])([O-])=[O:56].[K+].[K+].[OH-].[Na+]>C(O)C>[C:24]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:14])([O:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:55]([OH:58])=[O:56])=[CH:12][CH:11]=3)[N:34]=2)[CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4cccc(-c5ccccc5)c4)oc3C)cc2)C(=O)O)cc1

Procedure:
A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex 35, Part D), toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 2, Part F) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-Biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionic acid.
Reaction SMILES: [I:1]I.[CH2:3]([O:10][C@H:11]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@H:13]([CH2:34][Hg]Cl)[C@@H:12]1[OH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(Cl)Cl>[CH2:3]([O:10][C@H:11]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:14][C@H:13]([CH2:34][I:1])[C@@H:12]1[OH:37])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1C[Hg]Cl
Solvent: ClCCl
Product: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Reaction time: 16 h
Yield: 80.7 %

Procedure:
A solution of iodine (3.36 g, 13.2 mmol, 1.2 equiv) in DCM (168 mL) was added to a solution of (((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-hydroxytetrahydro-2H-pyran-2-yl)methyl)mercury(II) chloride (7.5 g, 11.0 mmol, 1.0 equiv) in dry DCM (26 mL) under nitrogen atmosphere. The mixture was stirred for 16 hours and then the reaction was quenched with aqueous sodium thiosulfate solution (20 g in 50 mL water). The mixture was stirred until colorless, the layers were separated, and the organic layer was washed with saturated sodium chloride solution (75 mL) and then water (75 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material thus obtained was then purified by silica gel chromatography, eluting with 15% EtOAc in petroleum ether, to give (2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-ol as a colorless oil (5.1 g, 81%). 1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 15H), 4.65-4.49 (m, 6H), 4.12 (td, J=5.5, 2.9 Hz, 1H), 4.02 (ddd, J=8.3, 5.8, 2.5 Hz, 1H), 3.85 (dd, J=10.1, 6.0 Hz, 2H), 3.74 (dt, J=10.4, 5.1 Hz, 2H), 3.63 (t, J=3.8 Hz, 1H), 3.40 (dd, J=10.3, 5.8 Hz, 1H), 3.29 (dd, J=10.5, 8.5 Hz, 1H), 3.11 (d, J=9.2 Hz, 1H). ESI (M+23) 597.0; calc for C28H31IO5 574.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([OH:13])=[CH:10]2)=[CH:5][CH:4]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[N:14]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[OH:13])=[O:15]
Reactant: O=N[O-]
Reactant: COc1ccc2ccc(O)cc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccc(O)c(N=O)c2c1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
110.2 g (0.633 mol) of 7-methoxy-β-naphthol were nitrosated in a mixture of 650 ml of glacial acetic acid and 65 ml of water at 0° C. in the course of two hours using a solution of 45.0 g (0.65 mol) of sodium nitrite in 340 ml of water. Stirring was continued for a further two hours and in this time the temperature of the reaction mixture was allowed to rise to 22° C. Then the volume was made up to 1.6 l with water and the precipitated product was filtered off by suction. After drying, 120.3 g (93.5%) of 1-nitroso-7-methoxy-β-naphthol were obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=O.[OH-].[Na+].Cl>O.C(O)C>[F:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8](=[N:2][OH:3])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: NO
Reactant: O=C(c1cccc(F)c1)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=C(c1cccc(F)c1)c1cccc(F)c1
Temperature: 20 °C
Yield: 96.7 %

Procedure:
3-3′-Difluorobenzophenone oxime may be prepared according to the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm3 of water is poured dropwise into a solution of 5.0 g of 3,3′-difluorobenzophenone in 10 cm3 of ethanol, and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under reflux for 10 minutes, is cooled to 20° C. and then acidified with 7.5 cm3 of 4 N hydrochloric acid. Once triturated, the oily precipitate obtained becomes a white solid which is filtered, washed with water and then dried at 35° C. under reduced pressure (2.7 kPa). 5.17 g of 3,3′-difluorobenzophenone oxime are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:10][OH:11])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2].ClN1C(=O)CCC1=O.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]([C:33]([F:36])([F:35])[F:34])=[CH2:32])[CH:27]=[C:28]([Cl:30])[CH:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2([C:33]([F:36])([F:34])[F:35])[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=3)[CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1
Reactant: CCc1ccc(C=NO)cc1[N+](=O)[O-]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
In dimethylformamide (40 mL), 2-ethyl-5-hydroxyiminomethylnitrobenzene (4.30 g) and N-chlorosuccinimide (2.97 g) were dissolved, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, and thereto was added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (3.5 g), followed by triethylamine (1.7 g), and then the mixture was stirred for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylnitrobenzene (5.74 g).
Reaction SMILES: C(OC(N1CC[N:11]([CH2:14][C:15]2[C:16](=[O:38])[N:17]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=3)[CH:20]=2)CC1)=O)(C)(C)C.FC1C=CC(CN2C(=O)C(COS(C)(=O)=O)=CC(C3C=CC(OC)=C(F)C=3)=N2)=CC=1>>[NH2:11][CH2:14][C:15]1[C:16](=[O:38])[N:17]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:20]=1
Reactant: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Agent: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Product: COc1ccc(-c2cc(CN)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 50.4 %

Procedure:
Following the procedure of Example 24 (1), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 24 (2) to yield the title compound as a pale brown crystalline powder (yield: 50.4%).
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:49](Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[CH:23][CH:24]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)NCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.65 g), potassium carbonate (0.533 g) and dimethylformamide (6 ml) is added benzyl bromide (0.33 g). The mixture is stirred at room temperature for one hour, then diluted with ethyl acetate. The solution is washed with water, dried, and evaporated. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-5-benzyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (0.49 g).