Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:24])[C:3]=1[OH:25].O[C@@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O-:30])=[O:29].BrBr>C(Cl)(Cl)Cl>[Br:24][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([Br:23])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:25][C@H:27]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([OH:30])=[O:29]
Reactant: O=C([O-])[C@@H](O)CCc1ccccc1
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](CCc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 9) and (S)-2-hydroxy-4-phenyl-butyrate, ethyl ester (Example 27) according to the procedure of Example 30. White solid: [a]25/D =−12.187° (9.929 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.24 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.52-7.45 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.20 (m, 3H) 5.02 (d, J=6Hz, 1H), 2.99-2.86 (m, 1H), 2.75-2.65 (m, 1H), 2.45 (s, 3H), 2.30-2.20 (m, 2H), 1.61 (s, 3H); MS (+FAB): [M+], 3 bromine isotope pattern, 700 (30%), 702 (100%), 704 (90%), 706 (55%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30, N, 0.00. Found: C, 51.33, H, 3.33, N, 0.29.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:10]2=[CH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1.CN(C)[CH:20]=[O:21]>>[CH2:6]1[C:10]2=[C:11]([CH:20]=[O:21])[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: c1cc2c(cn1)cc1n2CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c2n(c3ccncc13)CCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To dimethylformamide (0.3 ml) was added phosphorus oxychloride (0.33 ml) dropwise at 0° C. The mixture was allowed to stir for 10 min at room temperature. A solution of 2,3-dihydro-1H-3a,6-diaza-cyclopenta[a]indene (0.10 g 0.63 mMol) in 0.1 ml dimethylformamide was added and the mixture was stirred at room temperature for 3 h. The reaction was quenched with ice (ca 5 g) and the pH was adjusted to 9 by addition of 28% sodium hydroxide. The mixture was heated to reflux for 10 min. cooled to room temperature and extracted with ethyl acetate(3×5 ml) The combined organic extracts were dried with sodium sulfate and evaporated to dryness to yield the title compound (0.115 g, 97% Th). For analytical purposes a sample was recrystallised from ethyl acetate to afford slightly yellow crystals. mp 150-151° C. Found C, 70.94; H, 5.56; N, 14.97%; C11H10N2O requires C, 70.95; H, 5.41; N. 15.04%
Reaction SMILES: C=[C:2]([CH2:22][CH3:23])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I([O-])(=O)(=O)=[O:25].[Na+]>CC(C)=O.O.O[Os](O)(O)(O)(=O)=O.[K]>[O:25]=[C:2]([CH2:22][CH3:23])[CH2:3][C:4]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:6][CH2:5]1
Reactant: C=C(CC)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(O)(O)(O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C1(CC(=O)CC)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h

Procedure:
Potassium tetrahydroxydioxidoosmium (0.041 g, 0.111 mmol) was added to a solution of 1-tert-butyl 4-ethyl 4-(2-methylenebutyl)piperidine-1,4-dicarboxylate (1.0 g, 3.07 mmol) in acetone (20 mL) and water (20 mL) and stirred for 10 min. Solid sodium periodate (2.62 g, 12.26 mmol) was added in four portions during 1 hour and the reaction temperature was maintained below 40° C. using an ice-bath. The resulting mixture was stirred for 1 hour at room temperature. At this point LCMS showed incomplete reaction. Another 0.036 eq. of potassium tetrahydroxydioxidoosmium (0.041 g, 0.111 mmol) was added and the mixture was then stirred at rt for 2 hours. LCMS after 2 hours showed completion of the reaction. The suspension was filtered and filtrate was concentrated to remove acetone, and the aqueous layer was extracted with DCM (15 mL×3). The combined organic layers were washed with 10% Na2S2O3 solution (20 ml×2), dried over anhydrous Na2SO4, filtered, then concentrated to get the crude product which was purified by silica gel column chromatography (80 g RediSep Gold column) using (0-35) % EtOAc/Hexanes as mobile phase and the title compound was isolated.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=2)[CH2:9][CH2:10]1
Reactant: CN1CCN(c2cccc(Br)n2)CC1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1

Procedure:
190 mg 1-methyl-4-(6-tributylstannyl-2-pyridyl)-piperazine obtained from 1-(6-bromo-2-pyridyl)-4-methyl piperazine and tributyltin chloride by the same method as in Production Method 46 was reacted in the same manner as in Example 21 with 129 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine obtained in Production Example 39, to give 91 mg of the title compound as a colorless amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2.[OH-].[NH4+].[H][H]>C1COCC1.[Pt]>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:15]/[C:16]1[NH:20][CH:19]=[N:18][C:17]=1[CH3:21])/[C:5](=[O:14])[NH:6]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(N)c21
Reactant: [H][H]
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21

Procedure:
(Z)-4-azido-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-5-nitro-2H-indol-2-one (150 mg, 0.48 mmol) (from Example 44 above) was suspended in THF (40 mL) at r.t. Ammonium hydroxide was added (0.15 mL), followed by a catalytic amount of poisoned platinum on carbon (50 mg, 5% Pt/C.1/2S) (Engelhard Ind.). The reaction mixture was hydrogenated in a Parr bomb under 50 psi of hydrogen for 16 h. The mixture was filtered through a cake of Celite®, and the cake was washed twice with THF. The crude material was purified by flash chromatography on Silica Gel (230-400 mesh, eluted with 1% MeOH/1% ET3N in THF) to afford (Z)-4,5-diamino-1,3-dihydro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one as a dark red solid. (Yield 52 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([CH3:42])=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[N+:37]=2[O-:38])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:36]5[N+:37]([O-:38])=[C:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=6)[C:33]([CH3:42])=[CH:34][CH:35]=5)=[O:40])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)[n+]([O-])c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)[n+]([O-])c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.306 mmol) and 6-(4-fluorophenyl)-5-methylpyridine-2-carboxylic acid 1-oxide (98.9 mg, 0.367 mmol) in N,N-dimethylformamide (1.0 mL) were added HATU (140 mg, 0.368 mmol) and N,N-diisopropylethylamine (105 μL, 0.612 mmol), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give a white solid. The obtained white solid was washed with ethyl acetate to give the title compound (80 mg, 47%) as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[CH:24][CH:25]=[C:2]([CH3:1])[CH:3]=3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1cccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3cccc(C)c3)cc2)cc1
Yield: 19 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(3-methyl-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(3-methyl-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield 19% of theory; m.p. <20° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>>[ClH:23].[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:11]1([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccn2)CCNCC1

Procedure:
Prepare by the method of example 20.10 using 1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acid amide (3 mmol) and HCl in dioxane (40 mmol, 4N) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[Cl:19][C:20]1[C:21]([F:31])=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26].N12CCN(CC1)CC2>C1COCC1>[Cl:19][C:20]1[C:21]([F:31])=[C:22]([S:27]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1F
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)c(Cl)c2F)c(OC)c1
Yield: 53 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (1.00 g, 4.07 mmol) prepared in Example 14a, 3-chloro-2,4-difluorobenzenesulfonyl chloride (1.51 g, 6.11 mmol), 1,4-diazabicyclo[2.2.2]octane (0.69 g, 6.11 mmol) and THF (20 mL), to yield the title compound (0.983 g, 53%) as a colorless amorphous solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[SH:15].Cl[C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1.[OH-].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][N:22]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: Sc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Sc2ccc(Cl)cc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
Potassium t-butoxide (1.1 g) was added to a solution of 2,4-dichlorothiophenol (1.8 g) in N,N-dimethylformamide (DM F) (5 mL). The mixture was stirred at room temperature for 10 minutes and then 6-chloro 2H-pyridazin-3-one (1.31 g) was added. The reaction mixture was stirred at 100° C. for five hours. The mixture was then cooled to room temperature, poured into water (20 mL) and 20% potassium hydroxide (5 mL) was added. The resulting dark solution was extracted with ethyl acetate (2×10 mL). The aqueous layer was collected and the pH was adjusted to 3 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate (3×10 mL). The ethyl acetate layer was collected, dried over anhydrous sodium sulfate, filtered and evaporated to obtain a crude product, which was purified by silica gel chromatography (1:1 ethyl acetate/hexane as eluent) to afford 6-(2,4-dichloro-phenylsulfanyl)-2H-pyridazin-3-one (418 mg, 15%); NMR 6.88 (d, 1H), 7.10 (d, 1H), 7.24 (dd, 1H), 7.48 (d, 11H), 7.52 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]2[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]2[CH2:9]1.[NH2:25][C:26]1[C:27]([C:45](O)=[O:46])=[N:28][C:29]([C:32]2[CH:37]=[C:36]([C:38](=[O:43])[NH:39][CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:34][C:33]=2[F:44])=[CH:30][CH:31]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:25][C:26]1[C:27]([C:45]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]3[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:10]3[CH2:9]2)=[O:46])=[N:28][C:29]([C:32]2[CH:37]=[C:36]([C:38](=[O:43])[NH:39][CH:40]([CH3:42])[CH3:41])[CH:35]=[CH:34][C:33]=2[F:44])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Reactant: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(C(=O)O)n2)c1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CC(C)NC(=O)c1ccc(F)c(-c2ccc(N)c(C(=O)Nc3cnccc3N3CC[C@@H]4OC(=O)N(C(=O)OC(C)(C)C)[C@@H]4C3)n2)c1
Reaction time: 15 h

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in DMF (0.3 M) was added 3-amino-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinic acid (1.2 equiv.), EDC (1.2 equiv.) and HOAt (1.2 equiv.). The solution was stirred for 15 h. To the mixture was added water and the precipitate was filtered. To the filtrate was added EtOAc, and the organic solution was extracted (3 times), dried with Na2SO4, and concentrated to give an orange syrup. The crude was triturated with EtOAc and hexanes mixture and the precipitate was filtered off to give (3aR,7aS)-tert-butyl 5-(3-(3-amino-6-(2-fluoro-5-(isopropylcarbamoyl)phenyl)picolinamido)pyridin-4-yl)-2-oxohexahydro-oxazolo[4,5-c]pyridine-3(2H)-carboxylate. LCMS (m/z): 634.3.
Reaction SMILES: [OH:1][C@:2]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:33])([C@@H:24]([O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:34])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:3](=[O:9])[CH2:4][O:5][C:6](=[O:8])[CH3:7].ClCCl.[C:38](O)(=[O:40])[CH3:39].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(CC(C)C)=O>[C:38]([O:1][C@:2]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:33])([C@@H:24]([O:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:34])[CH:19]=[CH:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:3](=[O:9])[CH2:4][O:5][C:6](=[O:8])[CH3:7])(=[O:40])[CH3:39]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Reactant: CC(=O)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C

Procedure:
A mixture of the 17α-hydroxy-21-acetoxy-11β-trimethylsiloxy-9α-fluoro-pregn-1,4-diene-3,20-dione from Example 26 (20.6 g) dichloromethane (50 ml) and acetic acid (20 ml) was treated with trifluoro-acetic anhydride (20 ml) for a period of 5 hours at 25°. The reaction mixture was diluted with methyl-isobutylketone (200 ml) and extracted with sodium bicarbonate solution (500 ml) and then with water (200 ml). The organic layer was dried over sodium sulfate, and evaporated to dryness under reduced pressure. The residue was amorphous, homogenous in TLC (BPB, silica plates No. 254). Crystalline 17α,21-diacetoxy-11β-trimethylsiloxy-9α-fluoropregna-1,4-diene-3,20 -dione (compound 53) was obtained directly from the residue by trituration with methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-:17].[Na+].C(Cl)(Cl)Cl.Cl>CC(C)=O.O>[CH3:4][C:5]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][CH:15]=2)=[O:7])=[CH:13][CH:12]=1)([C:6]([OH:7])=[O:17])[CH3:15]
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 145.6 %

Procedure:
A mixture of 4-chloro-4′-hydroxybezophenone (116 g, 0.500 mole) and sodium hydroxide (120 g, 3.00 mole) in acetone (1 L) was heated to reflux for 2 hours. The heating was stopped and the heating source was removed. A mixture of chloroform (179 g, 1.50 mole) in acetone (300 mL) was added drop-wise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours and then allowed to cool to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and was acidified (to pH=1) with 1N hydrochloric acid. The precipitate, which formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL toluene each). After filtration and drying under high vacuum, the fenofibric acid (116 g, 73% yield) was obtained as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[C].[Pd].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])=[CH:14][CH:15]=1
Reactant: O=C1CCCCC1=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccccc1Cc1ccc(F)cc1
Temperature: 250 °C
Reaction time: 7 h
Yield: 73 %

Procedure:
In a 100-ml, four-necked flask equipped with a magnetic stirrer, a reflux condenser and a thermometer were placed 22.6 g (0.1 mole, calculated based on a purity of 89%) of the 2-(4-fluorobenzylidene)cyclohexanone produced in Example 6 and 40 ml of diphenyl ether in this order. The flask inside was purged with nitrogen. Thereto was added 2.0 g (10 wt. %, 0.94 mmole as palladium) of 5% palladium carbon (a product of Wako Pure Chemical Industries, Ltd.). The system was made vacuum using an aspirator and then returned to ordinary pressure using nitrogen; this operation was repeated three times. Then, the system was stirred at 250° C. for 7 hours and cooled to room temperature. 100 ml of toluene was added to the system. Filtration was conducted to remove the palladium carbon. The filtrate was extracted with 100 ml of a 10% aqueous sodium hydroxide solution, and this operation was repeated twice. The aqueous layer was washed with 30 ml of toluene. To the resulting aqueous layer was added 35% hydrochloric acid until the aqueous layer became acidic, after which the aqueous layer was extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous sodium chloride solution in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove ethyl acetate, to obtain 14.8 g of a red oil. Yield: 73% The purity of the intended product in the oil was 77% as measured by gas chromatography.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.[H][H]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC(=NCc1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(NCc1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
The process is carried out as in Example 8 but the reaction conditions are modified as follows: 0.636 g (4.8 mmol) of N-benzyl-N-(1-phenylethylidene)amine, 3.2 mg (0.0048 mmol) of [Ir(1,5-cyclooctadiene)Cl]2, 4.5 mg (0.01 mmol) of 1,4-bis(diphenylphosphino)butane (ligand) and 30 mg (0.08 mmol) of tetrabutylammonium iodide, 2 ml of acetic acid, 5 ml of toluene, 40 bar of hydrogen, reaction temperature: 25° C. The reaction time is 2 hours, the conversion is complete.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)OCc1ccc(-c2ccc(COC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2ccc(CO)cc2)cc1
Yield: 80 %

Procedure:
0.1 moles 4,4'bis(acetoxymethyl)biphenyl (prepared by method C above), 0.4 mole sodium hydroxide as 23 percent aqueous solution and 50 mls ethanol were refluxed for 3 hours with stirring. The reaction mixture was filtered and the precipitate washed with water and dried to yield 0.08 moles product=80 percent of theory. m.p. 195°-97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:9](Cl)=[O:10])=[CH:6][S:7][CH:8]=1)[CH3:2].C(Cl)Cl.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH2:21]>C(N(CC)CC)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([OH:23])=[C:20]([CH:22]=1)[NH:21][C:9]([C:5]1[C:4]([O:3][CH2:1][CH3:2])=[CH:8][S:7][CH:6]=1)=[O:10]
Reactant: Nc1cc(Cl)ccc1O
Reactant: CCOc1cscc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cscc1C(=O)Nc1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8.8 g. portion of 4-ethoxy-3-thiophenecarbonyl chloride is dissolved in 100 ml. of methylene chloride and added dropwise to a mixture of 6.6 g. of 5-chloro-2-hydroxyaniline in 100 ml. of methylene chloride and 6.5 ml. of triethylamine. This mixture is stirred at ambient temperature overnight, concentrated to 100 ml. and filtered. The filtrate is allowed to stand overnight and the precipitate which forms is collected, washed with water and dried in vacuo. This combined precipitate is recrystallized from 200 ml. of ethanol, treated with charcoal, filtered through diatomaceous earth and concentrated giving 5'-chloro-4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide as red brown crystals.