Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([N+:15]([O-])=[O:16])=[CH:14][C:9]=2[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH2:6][C:5]1=[O:24].O1CCCC1.O.O.O.C([O-])(=O)C.[Na+]>CO>[OH:16][NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([CH2:3][O:2][CH3:1])[C:5](=[O:24])[CH2:6][N:7]=[C:8]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]=2[CH:14]=1
Reactant: COCN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCN1C(=O)CN=C(c2ccccc2)c2cc(NO)ccc21

Procedure:
A mixture of 33 g. (0.1 mol) of 1,3-dihydro-1-methoxymethyl-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 1 l. of tetrahydrofuran, 1 l. of methanol. 113 g. (0.5 mol) of stannous chloride dihydrate and 136 g. (1 mol) of sodium acetate trihydrate was stirred at room temperature for 6 hrs. under an atmosphere of nitrogen. The inorganic salts were separated by filtration over celite. The filtrate was evaporated and the residue was partitioned between methylene chloride and 1N sodium hydroxide solution. The methylene chloride layer was washed with water, dried and evaporated. Crystallization of the residue from methylene chloride/ether yielded light yellow product with m.p. 168°-170°. For analysis it was recrystallized from the same solvents, m.p. 168°-171°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)=[O:22]
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Reactant: CC1NC(=O)NN=C1c1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)COc2ccc(C3=NNC(=O)NC3C)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
442 mg of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-5-methyl-1,2,4-triazin-3(2H)-one [prepared as described in step (a) above] were added to a stirred suspension of 85 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of anhydrous dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the ice-cooled suspension were then added 472 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1), and the reaction mixture was stirred at room temperature for 1 hour and then at 100° C. (bath temperature) for a further 1 hour. The dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and then the mixture was diluted with ethyl acetate. It was then washed with water and with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was collected by filtration and then recrystallized from a mixture of chloroform and ethyl acetate, to give 326 mg of the title compound as a white powder melting at 167°-169° C. (with decomposition).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([Br:30])=[C:6]([CH:29]=1)[CH2:7][N:8]1[C@@H:12]([CH3:13])[C@@H:11]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[O:10][C:9]1=[O:28].N(OC(C)(C)C)=O.[CH3:38][S:39]SC>>[F:25][C:24]([F:27])([F:26])[C:16]1[CH:15]=[C:14]([C@H:11]2[O:10][C:9](=[O:28])[N:8]([CH2:7][C:6]3[CH:29]=[C:2]([S:39][CH3:38])[CH:3]=[CH:4][C:5]=3[Br:30])[C@H:12]2[CH3:13])[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: CSSC
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(N)ccc1Br
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (4S,5R)-3-(5-amino-2-bromobenzyl)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (457 mg, 0.92 mmol) in methyl disulfide (4 mL) was added tert-butyl nitrite (182 μL, d=0.867, 1.38 mmol). The resulting mixture was stirred at 80° C. for 1 h. An aliquot indicated completion of the reaction. The titled compound was obtained as a glassy material after preparative TLC plates eluted by 25% EtOAc in hexanes. LC-MS: 529.71 (M+1)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H][H]>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccc(O)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCC[C@H]1CC[C@H](C2CCC(=O)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A soluton of 500 g of 4-(4-n-propylcyclohexyl)-phenol in 5 l of toluene is hydrogenated at a hydrogen pressure of 5 bar and 120° C. in the presence of 50 g of palladium on activated carbon (5% by weight). The reaction mixture is filtered and freed from water by azeotropic distillation. It is then treated with 110 g of pyridine sulfone (pyridine-sulfur trioxide complex), stirred at 50° C. for 1 hour and filtered using basic alumina. After removal of the solvent, 433 g (86% yield) of the trans-4-(4-n-propylcyclohexyl)cyclohexanone remain as a colourless solidified melt having a purity of 99.5% (GC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([NH2:16])[CH:9]([NH2:15])[CH2:10][O:11][CH2:12][O:13][CH3:14])=[CH:4][CH:3]=1.CO[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#N)[CH:29]=1)=[NH:27].C(OCC)(=O)C>CO>[C:26]([C:28]1[CH:29]=[C:30]([C:34]2[NH:15][CH:9]([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:31]=[CH:32][CH:33]=1)#[N:27]
Reactant: COCOCC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCOCC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.8 %

Procedure:
1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine(218 mg) was dissolved in methanol(3 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (266 mg), and the mixture was stirred at room temperature for 17 hrs. To the reaction mixture was added an additional amount of 3-cyanobenzeneimidic acid methyl ester (266 mg), and the reaction mixture was stirred at room temperature for 6 hrs. To the reaction mixture was added ethyl acetate (50 ml), and the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and then the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=2:1) to give 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (146 mg) as colorless oil. The protected compound (115 mg) was dissolved in the mixture solution of 2N hydrochloric acid (1.5 mL) and tetrahydrofuran (1.5 ml), and the solution was stirred at 50° C. for 3 days. After cooling the mixture to the room temperature by standing it at room temperature and neutralizing with saturated sodium hydrogen carbonate aqueous solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo to give the title compound (105 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].CN1CCOCC1.Cl.C(N(CC)CCCN=C=NCC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1ccon1
Agent: CCN=C=NCCCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccon1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A mixture of 3-isoxazolecarboxylic acid (4.2 g), 4-dimethylaminopyridine (5.1 g), N,O-dimethylhydroxylamine hydrochloride (4.0 g), N-methylmorpholine (4.2 g) and 1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.5 g) in dichloromethane (175 ml) were stirred at ambient temperature overnight. The reaction mixture was then washed with 2N hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml), brine, dried over magnesium sulphate and evaporated to give the product as a dark orange oil (3.7 g).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (1.3 ml, dissolved in 11 ml of absolute ethanol and 50 ml of dipropyl ether) is slowly added to a solution of Donepezil (3.79 g) in absolute ethanol (38 ml) with stirring at room temperature. The mixed solution is stirred at room temperature and the solid precipitated is filtered and dried 55° C. under vacuum to give the title compound. Melting point: 177.4° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:20]=[C:19](F)[C:18]([F:22])=[CH:17][C:9]=1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][OH:32])[CH:27]=[N:28][C:29]=1[Cl:30]>CS(C)=O>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][O:32][C:19]2[C:18]([F:22])=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:8]([F:7])[CH:20]=2)[CH:27]=[N:28][C:29]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)c1cc(F)c(F)cc1F
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(F)c(OCc2cnc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
Potassium carbonate (535 mg, 3.88 mmol) was added to a solution of tert-butyl 2,4,5-trifluorobenzoate (Preparation 10, 275 mg, 1.29 mmol) and (5,6-dichloropyridin-3-yl)methanol (241 mg, 1.36 mmol) in DMSO (5 mL). The reaction mixture was stirred at RT for 18 hours. After cooling the reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (2×100 mL) and dried over MgSO4, filtered and concentrated in vacuo to give 490 mg of the title compound in a quantitative yield. The crude compound was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:10]=[CH:11]2)=[CH:6][CH:5]=1.CS(Cl)(=O)=O.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: C[C@@H]1CCCN1
Reactant: N#Cc1ccc(-c2cc3ccc(CCO)cc3cn2)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ncc2c1

Procedure:
The product from Example 74B, methanesulfonyl chloride, and (2R)-2-methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1>>[CH3:22][O:21][CH2:20][O:19][C:11]1[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=[C:9]([S:8][CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[CH:10]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: COc1ccc(CCl)cn1
Product: COCOc1cc(SCc2ccc(OC)nc2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 3-chloromethyl-6-methoxypyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].O.Cl>C(O)C.O1CCCC1>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(OCOC)c12
Yield: 64.6 %

Procedure:
470 mg of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate was dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran, to which 350 mg of potassium hydroxide and 2 ml of water were added, followed by refluxing for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to obtain 280 mg of the titled compound as pale yellow crystals.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Si](C)(C)O)(C)(C)C.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH2:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reactant: [H][H]
Agent: [Pt]
Agent: CC(C)(C)[Si](C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)cnc2ccccc12
Reaction time: 1.5 h

Procedure:
The mixture of [4-(tert-butyldimethylsilanyloxy)butyl](3-nitro-quinolin-4-yl)amine and tert-butyldimethylsilanol (110 g) from the previous step was dissolved in toluene (880 mL) and placed in a Parr hydrogenation vessel along with 5% platinum on carbon catalyst (3.0 g). The vessel was pressurized to 50 psi (3.4×105 Pa) hydrogen and shaken on the Parr apparatus for 1.5 hours, occasionally adding additional hydrogen to maintain a pressure of 50 psi (3.4×105 Pa). After 3 hours, the reaction mixture was filtered through CELITE filter agent and concentrated under reduced pressure to provide N4-[4-(tert-butyldimethylsilanyloxy)butyl]quinoline-3,4-diamine as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:25][CH:26]([OH:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O.Cl>CS(C)=O>[C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[CH2:25][C:26](=[O:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CN(CC(O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(CN(CC(=O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
[Step 2] To a solution (10 ml) of 2-benzoyl-4-bromo-N-(2-hydroxy-3-phenylpropyl)-N-(4-methanesulfonylbenzyl)benzamide (1.0 g) in DMSO was added triethylamine (2 ml), and pyridine sulfur trioxide complex (1.1 g) was added at room temperature. The mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:2) to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.72 g). [Step 3] To a solution (6 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.3 g) in ethanol was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.15 g), and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:18][C:19](=[O:21])[CH3:20]>O>[CH2:18]([O:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:19]([CH3:20])=[O:21]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)COc1ccc(Cl)cc1C(=O)O

Procedure:
To a solution of 5.16 g. (0.3 mole) of 5-chlorosalicylic acid in 60 ml. of ethanol and 40 ml. of water containing 1.2 g. (0.03 mole) of sodium hydroxide is added 2.8 g. (0.03 mole) of chloroacetone and the solution heated to reflux for 5 hours. The resulting solution is cooled in an ice bath and the precipitated product filtered, dried and recrystallized from ether, 800 mg., m.p. 90°-91° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C:10]3[CH:11]=[C:12]([CH3:22])[CH:13]=[CH:14][C:15]=3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1.CC(C)=O>C([O-])(O)=O.[Na+].O1CCOCC1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:10]3[CH:11]=[C:12]([CH3:22])[CH2:13][CH2:14][C@H:15]3[C:16]([CH3:21])([CH3:20])[O:17][C:18]=2[CH:19]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)c1ccc(C)cc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Reaction time: 0.17 h

Procedure:
One hundred mg of human IgG were dissolved in 7 ml of 0.2M NaHCO3, pH 9.6, and 108 mg of a cannabinol derivative having the formula ##STR5## in 2 ml of dioxane were added. Nine additional ml of dioxane were added, and the mixture was mixed intermittently for 4 hours at 4° C., after which 180 ml of cold acetone were added. The mixture was centrifuged for 10 minutes at 2,000×g, and the pellet was washed once with 20 ml of cold acetone. Following centrifugation for 10 minutes at 2,000×g, the pellet was resuspended in 10 ml of phosphate buffered saline (PBS). Dialysis was carried out for 3 days at 4° C. against 2 changes per day of 1000-ml volumes of PBS, to produce a THC-human IgG conjugate.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:26]([N:24]([CH3:25])[C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2N(C)C(C)C)Cc2ccccc2C1
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(C)c1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 16 h
Yield: 97.6 %

Procedure:
A 100 mL round bottom flask which contains 2-{[2-(isopropyl-methyl-amino)-pyridine-3-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester (341, 220 mg, 0.58 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (61 mg, 1.46 mmol). After 16 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 4 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.2 g, 98%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]([CH2:3][OH:2])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(C)(=O)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(CO)C1
Reaction time: 2.5 h
Yield: 38.7 %

Procedure:
To a solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester (8.4 g, crude) in DMF (50 mL) was added K2CO3 (7.5 g) and iodomethane (8.5 mL) The mixture was stirred overnight at R.T. An aqueous work-up followed by purification on silica gave 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.267 g). A solution of 4-methanesulfonyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (3.2 g) in dry THF (20 mL) was added via cannular to a mixture of lithium aluminium hydride (0.75 g) in THF (30 mL) at 0° C. and under N2 atmosphere. The resultant mixture was then warmed to R.T. and stirred for 2.5 h. The reaction was carefully quenched with aqueous ammonium chloride (5 mL) then filtered over Celite. An aqueous work-up followed by purification on silica gave 3-hydroxymethyl-4-methanesulfonyl-piperazine-1-carboxylic acid tert-butyl ester (1.13 g).
Reaction SMILES: [C:1](OCCC[Si](OC)(OC)OC)(=O)[C:2]([CH3:4])=[CH2:3].CO[C:19]1[CH:25]=[CH:24][C:22](O)=[CH:21][CH:20]=1>>[CH2:21]1[CH:1]2[CH:2]3[CH:4]=[CH:22][CH:24]([CH:25]2[CH:19]=[CH:20]1)[CH2:3]3
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 87.5 °C
Reaction time: 33 h
Yield: 70 %

Procedure:
59.1 g (0.20 mol) 3-methacryloyloxypropyltrimethoxy silane and some hydroquinone monomethyl ether (MEHQ) are placed in a sulphonation flask which is connected via a distillation bridge to a cracking apparatus. After flushing with argon, cyclopentadiene is fed into the reaction vessel, with simultaneous stirring and warming to 85 to 90° C. After 33 hours the reaction has finished and formed dicyclopentadiene is distilled off at 0.05 mbar. Following subsequent fractional distillation in a high vacuum, the norbornene silane (1) (bp: 98°-100° C./7.0 mPa) is obtained as a colourless liquid in 70% yield.