Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][CH3:24])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:5][CH2:4]1)[CH3:2].[O:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([C:3]1([CH2:1][CH3:2])[CH2:8][CH2:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[N:17]2[CH2:18][CH2:19][N:20]([CH2:31][CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH2:21][CH2:22]2)=[CH:5][CH2:4]1)[CH3:24]
Reactant: O=CC1CCOCC1
Reactant: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCNCC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC1(CC)CC=C(c2ccc(OC)cc2N2CCN(CC3CCOCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]piperazine (90 mg, 0.27 mmol) prepared in Example (6f) in tetrahydrofuran (10 mL) were added tetrahydropyran-4-carbaldehyde (37 mg, 0.32 mmol), sodium triacetoxyborohydride (87 mg, 0.41 mmol) and acetic acid (32 mg, 0.57 mmol) in that order, and the mixture was stirred at room temperature for 1 hour and 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 50 mg of 1-[2-(4,4-diethylcyclohex-1-enyl)-5-methoxyphenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][C:29]1([CH3:38])[CH2:34][NH:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][O:30]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:33]2[CH2:34][C:29]([CH3:28])([CH3:38])[O:30][CH2:31][C@H:32]2[C:35]([OH:37])=[O:36])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC1(C)CN[C@H](C(=O)O)CO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CC(C)(C)OC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 60.7 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.26 g, 0.51 mmol) was reacted with (S)-6,6-dimethylmorpholine-3-carboxylic acid hydrochloride (0.1 g, 0.51 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.18 g, 63%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:23])[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH:27]2[O:31][CH2:30][CH2:29][O:28]2)[CH2:14][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC1OCCO1)C(=O)N1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in oil, 1.4 g) in anhydrous dimethylformamide (50 ml) was added dropwise, under nitrogen, a solution of 4-benzyl-1-[(ethoxycarbonyl)acetyl]-piperazine (8.5 g, 29.3 mmol) in anhydrous dimethylformamide (50 ml) over 25 minutes at room temperature. After a further 30 minutes at room temperature, 2-(2-bromoethyl)-1,3-dioxolane (3.6 ml, 30.7 mmol) was added dropwise over 3 minutes and the resulting yellow solution was stirred for 24 hours. Water (400 ml) was added and products were extracted with diethyl ether (3×300 ml). The combined ethereal phases were washed with brine (1×150 ml), dried (MgSO4) and concentrated. Flash chromatography of the residue (silica gel, diethyl ether--ethanol, 95:5) afforded 8 g of the title compound (70%) as a colourless oil, δ (360 MHz, CDCl3), 1.25 (3H, t, J=7.1Hz), 1.56-1.78 (2H, m), 2.06 (2H, q, J=7.4Hz), 2.44 (4H, br s), 3.46-3.96 (11H, m), 4.16 (2H, q, J=7.1Hz), 4.86 (1H, t, J=4.6Hz), 7.24-7.36 (5H, m); m/e (ES) 391 (M+1)+.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:28])[NH:16][C:17]2[S:18][C:19]3[N:20]=[CH:21][N:22]=[C:23]([O:26][CH3:27])[C:24]=3[N:25]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[CH3:27][O:26][C:23]1[C:24]2[N:25]=[C:17]([NH:16][C:15]([N:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[O:28])[S:18][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nc12
Agent: Cl
Solvent: ClCCl
Product: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride gas was bubbled through a solution of 4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester (5.20 g, 13 mmol) in methylene chloride (70 mL) for 10 min at 0° C. A white precipitate formed. The resulting slurry was stirred at 25° C. for 2 h. At this time, the mixture was concentrated in vacuo and dried under high vacuum to afford piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide hydrochloride (4.61 g) as a white solid; LRMS for C11H14N6O2S (M+H)+ at m/z=295. This solid was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)=[C:13]([C:27]([O:29][CH3:30])=[O:28])[C:12]2(O)[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH:14]([C:18]1[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=1)[C:13]([C:27]([O:29][CH3:30])=[O:28])=[C:12]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccc(OCc3ccccc3)cc2C1(O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C1=C(c2ccc(OC)cc2)c2cc(OCc3ccccc3)ccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of methyl (3RS)-5-benzyloxy-3-hydroxy-3-(4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)indene-2carboxylate (crude material prepared above) in CH2Cl2 (75 ml) under an argon atmosphere at 0° C. was added triethylsilane (3.9 ml, 23.6 mmol), followed by boron trifluoride etherate (14.7 ml, 120 mmol). The reaction mixture was stirred for 10 min at 0° C., at which time the mixture was partitioned between 3M HCl and EtOAc. The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 25-45% Et2 O/hexanes. The title compound (8.41 g, 83% for two steps) was isolated as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:4]
Reactant: NCCN1CCNC1=O
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCN1CCNC1=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), 1-(2-aminoethyl)imidazolidin-2-one (22.46 mg, 0.087 mmol), 4-methylmorpholine (23.45 mg, 0.232 mmol), and HATU (28.7 mg, 0.075 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-(2-(2-oxoimidazolidin-1-yl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13.2 mg, 0.024 mmol, 42.0% yield): LCMS=543.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.54-7.73 (7 H, m), 5.11 (1 H, s), 3.32-3.49 (6 H, m), 3.21-3.29 (2 H, m); HPLC peak RT=2.4 min (Method E).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[C:8]3[CH2:12][C:11]([C:6]=2[CH:5]=1)=[CH:10][CH:9]=3)([O-])=O>[Ni].[Pd].CO>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[CH:8]3[CH2:12][CH:11]([C:6]=2[CH:5]=1)[CH2:10][CH2:9]3
Reactant: O=[N+]([O-])c1ccc2c(c1)C1=CC=C2C1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C1CCC2C1

Procedure:
In the synthesis shown in Scheme 1, a 3-nitrobenzene, generated from a 6-nitro-anthranilic acid (A), is reacted with a cyclic 1,4-diene (B), such as 5-isopropyl-cyclopentadiene, to form a 5-nitro-benzonorbornadiene (C) in a Diels-Alder reaction. Under standard catalytic reduction conditions (for example, using Raney nickel or palladium on carbon in a solvent such as methanol), both the 5-nitro group and the 2,3-double bond of the 5-nitro-benzonorbornadiene (C) are reduced to form the 5-amino-benzonorbornene (D). Reaction of the 5-amino-benzonorbornene (D) with a heterocyclyl-carboxylic acid or heterocyclyl-carboxylic acid derivative (E), where Q may be hydroxyl, fluoro, chloro or bromo, in a solvent such as dichloromethane gives a fungicidal heterocyclyl-carboxylic acid benzonorbornen-5-yl-amide (F). An example of (D) is 5-amino-9-isopropyl-benzonorbornene, which is a precursor of an amide of, for example, 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([CH3:8])[CH2:6]O)=[N+:2]=[N-:3].N1C(C)=CC=CC=1C.[O-:17][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19].[N:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2>C(Cl)Cl.CC#N>[O-:20][S:18]([C:21]([F:24])([F:23])[F:22])(=[O:19])=[O:17].[N:1]([CH2:4][C@@H:5]([CH3:8])[CH2:6][N+:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2)=[N+:2]=[N-:3]
Reactant: C1CN2CCN1CC2
Reactant: C[C@@H](CO)CN=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@H](CN=[N+]=[N-])C[N+]12CCN(CC1)CC2
Reaction time: 0.67 h
Yield: 100.5 %

Procedure:
(R)-(-)-3-azido-2-methylpropanol (0.64 g, 5.56 mmol) was dissolved in CH2Cl2 (40 mL). 2,6-lutidine (1.9 mL, 16.3 mmol) was added at -20° C. followed by adding trifalic anhydride (1.4 mL, 8.32 mmol). The mixture was kept in -20° C. for 40 min, diluted with CH2Cl2, washed with water, 0.1 N HCl aqueous solution, water and brine, dried over Na2SO4 and concentrated to give the trifalte (1.33 g). The triflate (0.7 g, 2.83 mmol) was reacted with 1,4-diazabicyclo[2.2.2]octane (0.31 g, 2.77 mmol) in CH3CN for 3 hrs. The solvent was removed and the residue was dried under vacuum to give the product (1.0 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:20]2)[S:17][CH:18]=1)=[O:13])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:20][CH:21]([S:23][C:24]3[C@H:25]([CH3:48])[C@@H:26]4[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:27]4[C:28]=3[C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[CH2:22]2)[S:17][CH:18]=1)=[O:13]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cs4)C3)[C@H](C)[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCO)cs4)C3)[C@H](C)[C@H]12
Yield: 75.7 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl]azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (605.3 mg, 0.84 mmol) in tetrahydrofuran (30 ml) were added acetic acid (0.15 ml, 2.6 mmol) and a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran (2.5 ml, 2.5 mmol) in an ice bath and the mixture was stirred for 1 hour at room temperature. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by: chromatography on a silica gel column using toluene: acetonitrile (2:3) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-{1-[4-(2-hydroxyethylcarbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (383.7 mg, yield 75%) as a pale yellow solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]([Br:27])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>O>[CH2:20]([O:19][C:18]1[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=[C:16]([Br:27])[CH:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Yield: 92 %

Procedure:
A 1 L round-bottom flask was charged with 1-benzoyl-3-(3-(benzyloxy)-5-bromopyridin-2-yl)thiourea (17.9 g, 40.5 mmol) and 3M sodium hydroxide (3.3 mL, 9.9 mmol), and the reaction mixture was refluxed overnight. The reaction mixture was then cooled, poured into water, and filtered to provide 1-(3-(benzyloxy)-5-bromopyridin-2-yl)thiourea (12.6 g, 92.2% yield) as a yellow solid. 1H NMR (CDCl3) δ 10.60 (bs, 1H), 8.59 (bs, 1H), 7.87 (d, 1H), 7.40 (m, 5H), 7.30 (d, 1H), 6.90 (m, 1H), 5.15 (s, 2H). Mass spectrum (apci) m/z=340.0 (M+H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[C:11]1[CH:18]=[CH:17][C:14](C=O)=[CH:13][CH:12]=1.C[Si](C)(C)C1C=CC(Cl)=CC=1>>[C:1]([C:11]1[CH:18]=[CH:17][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Agent: C[Si](C)(C)c1ccc(Cl)cc1
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Various benzophenone derivatives were prepared in accordance with the same procedure as in Example 1 excepting that 0.2 mole of a benzaldehyde derivative was used instead of 4-dimethylaminobenzaldehyde and 0.2 mole of a halobenzene derivative was used instead of 4-trimethylsilylchlorobenzene. The particulars are set out as follows.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Yield: 21.1 %

Procedure:
In a 5 liter 3-necked round-bottomed flask were placed 5-chloroisophthalic acid dimethyl ester (146.4 g) and methanol (2.5 liters). To the resulting solution was added (dropwise) a solution of potassium hydroxide (42.8 g) in methanol (500 ml) with vigourous stirring under nitrogen. The resulting mixture was refluxed 2 hours, cooled down and the solvent was then eliminated in the rotavap. The residue was taken up in water (800 ml), the pH brought to 8 and the resulting solution washed with ethyl ether. The aqueous solution was made acidic with aqueous hydrochloric acid and extracted with ethyl acetate (3×400 ml). The combined organic layers were dried (magnesium sulfate) and the solvent was then eliminated in the rotavap. The solid residue was stirred in 1.3 liters of chloroform overnight and filtered. The solvent was then evaporated yielding 5-chloroisophthalic acid monomethyl ester as a white solid (29 g).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]([C:10](=[O:14])[CH:11]=[CH:12][CH3:13])=[C:3]1[CH3:15].C(O)(=[O:18])C>O>[CH3:15][C:3]1[C:2](=[O:18])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4]=1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13]
Reactant: CC=CC(=O)C1=C(C)C(Br)CCC1(C)C
Reactant: CC(=O)O
Solvent: O
Product: CC=CC(=O)C1=C(C)C(=O)CCC1(C)C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
125 g of crude 3-bromo-2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-1-ene [prepared under letter a] were added dropwise to a mixture of 100 g (1 Mole) CrO3, 100 ml acetic acid and 100 ml of water, kept at 20°-25°. After addition of the reactants the reaction mixture was heated under stirring at 40° for 30 min., and finally diluted with 1 l of water. After neutralization of the reactin mixture by means of a 10 % aqueous solution of NaOH, the obtained mixture was submitted to a steam distillation. 3 l of the thus obtained distillate were then extracted with ether (3 × 500 ml), the organic layer was washed with water, dryed over Na2SO4 and finally concentrated under reduced pressure. There were thus obtained 68.2 g (73 %) of a semi-cristalline product, b.p. 71°-116°/o.01 Torr, which was finally cristallized in hexane to afford 51.3 g (55 %) of pure 2,6,6-trimethyl-1-(but-2-enoyl)-cyclohex-1-en-3-one, m.p. 68°-69°.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3([CH2:24][CH2:25][OH:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41].[OH-].[K+]>O1CCCC1.O.CO>[OH:26][CH2:25][CH2:24][C:16]1([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=3)[C:40]([C:36]3[O:35][CH:39]=[CH:38][CH:37]=3)=[O:41])[CH2:9][CH2:10]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CCC3(CCO)CCCCCCC3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCO)CCCCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclooctyl]ethanol (synthesized in Example 73) (0.53 g) in tetrahydrofuran (7 mL) were added triethylamine (0.79 mL) and 2-furoyl chloride (0.35 mL) successively. The solution was stirred at room temperature for 1 hour. To the reaction solution was added methanol (7 mL) and a 3N aqueous potassium hydroxide solution (4.7 mL), and it was stirred at room temperature for 15 hours. Water was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, methanol-chloroform (5:95)] to give the title compound (0.55 g).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17](C)([C:23]([O-])=O)[C:18]([O:20]CC)=[O:19])=[CH:13][CH:12]=1)=[O:10]>[OH-].[Na+].C(O)C.O>[S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)C(C)(C(=O)[O-])c1ccc(C(=O)c2cc3ccsc3s2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(C(=O)c2cc3ccsc3s2)cc1
Yield: 74.7 %

Procedure:
Ethyl 2-{4-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}-2-methyl-malonate (16.23 g) is suspended in a mixture of 5% (w/v) aqueous sodium hydroxide solution (90 cc) and ethanol (90 cc), and the suspension is heated at the boiling point for 3 hours. After cooling, the reaction mixture is diluted with distilled water (1000 cc), and then extracted three times with diethyl ether (total 600 cc). The aqueous phase is filtered off, acidified to pH 1 by the addition of a 5N aqueous hydrochloric acid solution and extracted three times with diethyl ether (total 600 cc). The combined ether solutions are washed three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate, decolourizing charcoal (1 g) is added, and the solutions are filtered and evaporated. Crude 2-{4-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionic acid (9.9 g), melting at 150° C., is thus obtained.