Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]=3[C:10]([C:20]#[N:21])=[C:9]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1C[O:33]CC1>>[O:33]=[C:18]1[C:19]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[C:10]([C:20]#[N:21])[C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2=O
Temperature: 2.5 °C

Procedure:
A solution of 1-phenyl-3-(piperidin-1-yl)-9H-fluorene-4-carbonitrile (350 mg) in THF was added sodium hydride (34 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Yellow solid; mp 166-168° (C; ESIMS 365 (M++1); IR (KBr) 2219 (CN), 1705 cm−1 (CO); 13C NMR (75.53 MHz, CDCl3): δ 22.68, 24.67, 51.55, 95.24, 115.94, 118.11, 120.97, 121.16, 122.41, 126.70, 127.64, 129.33, 133.10, 133.94, 135.61, 139.20, 145.60, 149.61, 158.96, 188.36.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1cccc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a cooled (0° C.) solution of 4-(3-nitro-phenyl)-morpholine (43)(4.16 g, 20 mmol) in methanol (50 ml) was added Pd/C (10% loading, 460 mg). The mixture was stirred at room temperature under an H2 (1 atm) for 16 hrs. The mixture was then filtered through a Celite™ pad, the filtrate dried using MgSO4, filtered and concentrated in vacuo to give the title compound (3.39 g, 95.2%) as an orange solid that was suitably clean to be used without any further purification. m/z (LC-MS, ESP): 179 [M+H]+, R/T=1.69 mins.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.P(=O)(O)(O)O.O=[CH:29][C:30](=[CH2:32])[CH3:31].O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[CH:31][C:30]([CH3:32])=[CH:29]2
Reactant: C=C(C)C=O
Reactant: Nc1cc(F)ccc1Br
Agent: N
Agent: O=P(O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Solvent: O
Product: Cc1cnc2c(Br)ccc(F)c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
2-Bromo-5-fluoro-aniline (2.50 g, 95 mass % article, 12.5 mmol), m-nitrobenzenesulfonic acid (1.33 g, 6.53 mmol), 10.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (34.8 mg, 0.125 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2.32 g of methacrolein (98 mass % article, 32.5 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 730 mg of 8-bromo-5-fluoro-3-methyl-quinoline as a yellow white solid (yield: 24.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[OH:17])=[O:5])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]=[O:16])[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2c(C=O)ccc(O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2c(C=O)ccc(OCc3ccccc3)c2[nH]1

Procedure:
2.33 g of 4-formyl-7-hydroxyindole-2-carboxylic acid ethyl ester is combined with 1.8 ml of benzyl bromide, 1 g of potassium carbonate, and 100 ml of acetone and heated under reflux for 4 hours. The reaction mixture is then evaporated to dryness, combined with water, and extracted with ethyl acetate. The organic phase is washed twice with saturated sodium bicarbonate solution, dried over sodium sulfate, concentrated, and recrystallized from ethyl acetate/hexane, thus obtaining 1.8 g of 7-benzyloxy-4-formylindole-2-carboxylic acid ethyl ester, mp 131°-132° C.
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[C:11](=[CH:14]N(C)C)[CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[NH:28])[NH2:27].C(O)C.[ClH:32]>CO.C(OCC)(=O)C>[ClH:32].[ClH:32].[CH3:24][O:25][C:26]1[N:27]=[CH:14][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:28]=1
Reactant: COC(=N)N
Reactant: CCCN1CCC[C@@H]2CC(=O)C(=CN(C)C)C[C@H]21
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCC[C@H]2Cc3nc(OC)ncc3C[C@@H]21

Procedure:
Following the procedure of Example 1, a reaction mixture was prepared from trans-(±)-1-n-propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline and O-methylisourea hydrogen sulfate in 20 ml. of anhydrous ethanol. The reaction mixture was heated to reflux temperature overnight and was then evaporated to dryness. The resulting residue was dissolved in chloroform. The chloroform solution was chromatographed over florisil using chloroform containing increasing amounts (0-15%) of methanol as the eluant. Fraction 5 was shown by tlc to contain trans-(±)-2-methoxy-6-n-propyl-5,5a,6,7,8,9,9a,10-octahydropyrimido[4,5-g]quinoline formed in the above reaction. The solvent was removed in vacuo leaving a residual yellow oil. The yellow oil was dissolved in methanol and the methanolic solution saturated with gaseous hydrogen chloride. Ethyl acetate was added to the hot methanol solution to the point of incipient precipitation. Upon cooling, yellow crystals of trans-(±)-2-methoxy-6-n-propyl-5,5a,6,7,8,9,9a,10octahydropyrimido[4,5-g]quinoline dihydrochloride formed which were collected by filtration. The product had a molecular ion at 261.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5]([OH:7])=[O:6].C1CCC(NC2CCCCC2)CC1.S(=O)(=O)(O)O.[F:34][C:35]1[C:40](O)=[C:39]([F:42])[C:38]([F:43])=[C:37]([F:44])[C:36]=1[F:45].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.O1CCOCC1.CCOCC>[F:34][C:35]1[C:40]([O:6][C:5](=[O:7])[C@H:4]([CH2:3][CH2:2][CH3:1])[NH:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[C:39]([F:42])[C:38]([F:43])=[C:37]([F:44])[C:36]=1[F:45]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8.0 g (20 mmoles) of BOC--Nva--OH.DCHA are added to a mixture of 60 ml of ether and 20 ml of 2 n aqueous sulfuric acid, and the mixture is shaken until dissolution is complete. The etheral solution is separated, washed with 20 ml of 2 n aqueous sulfuric acid and water, dried, and evaporated in vacuo. The oily residue and 3.70 g (20 mmoles) of pentafluorophenol are dissolved in 25 ml of ethyl acetate, the solution is cooled to 0° C., 3.92 g (19 mmoles) of DCC are added, and the reaction is conducted for one hour. Thereafter the suspension is filtered, the filtrate is evaporated in vacuo, and the oily residue is dissolved in 50 ml of n-hexane. The solution is washed with 5×20 ml of 5% aqueous sodium bicarbonate solution and 2×20 ml of water and evaporated in vacuo. The oily residue solidified upon cooling. 6.21 g (81%) of BOC--Nva--OPFP are obtained; m.p.: 60°-62° C., Rf3 =0.70, [α]D :-32.3° C. (c=1.0, in dioxane).
Reaction SMILES: [F-].[Cs+].[F:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([OH:14])=[C:6](I)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)CCC>CN(C)C=O.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([OH:14])=[C:6]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)[CH:5]=1
Reactant: Oc1cc(C(F)(F)F)c(F)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(C(F)(F)F)c(F)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Cesium fluoride (790 mg, 5.2 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol), and copper(I) iodide (100 mg, 0.52 mmol) were added to a solution of 4-fluoro-2-iodo-5-(trifluoromethyl)phenol (Preparation 10, 800 mg, 2.6 mmol) and 4-(tributylstannyl)pyridazine (1.1 g, 2.9 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was heated at 45° C. under an atmosphere of argon. After 1 hour, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and water, and filtered through diatomaceous earth. The solids were washed with additional ethyl acetate. The layers were separated, and the organic layer washed with water, aqueous lithium chloride and brine, then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane, concentrated onto diatomaceous earth, and purified by automated silica gel flash chromatography (100% dichloromethane to 10% methanol in dichloromethane gradient elution) to afford the title compound as an orange solid (598 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].Br[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2O)C=CC=1>CN1CCN(C)C1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: OCc1cccc(O)c1
Reactant: Fc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: OCc1cccc(Oc2ccc(F)cc2)c1
Temperature: 150 °C
Reaction time: 48 h
Yield: 0 %

Procedure:
3-Hydroxybenzyl alcohol (3.0 g, 24.6 mmol) was dissolved in 1,3-dimethyl-2-imidazolidinone (50 mL). 4-Bromofluorobenzene (6.5 g, 36.9 mmol), potassium carbonate (2.0 g, 14.8 mmol), 8-quinolinol (71 mg, 0.5 mmol), and copper chloride(I) (49 mg, 0.5 mmol) were added thereto, and then the mixture was stirred at 150° C. for 2 days. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=90:10 to 80:20) to give the title compound (0.98 mg, yield 18%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.[CH3:15][CH:16]1[CH2:21][C:20](=[O:22])[O:19][C:17]1=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]2[CH:7]=[C:8]([C:20](=[O:22])[CH2:21][CH:16]([CH3:15])[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: CC1CC(=O)OC1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 37.7 g (0.2 mole) of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro naphthalene and 22.82 g (0.2 mole) of methylsuccinic anhydride in 250 cm3 of anhydrous 1,2-dichloroethane, there are added, by portions, over a period of about 1 hour, 53.3 g (0.4 mole) of anhydrous aluminum chloride in a manner to maintain the temperature lower than or equal to 30° C. After stirring for 3 hours at ambient temperature, the reaction mixture is poured into 200 cm3 of ice water. The organic phase is decanted. The aqueous phase is again extracted twice with 100 cm3 of dichloromethane. The dichloroethane and dichloromethane phases are combined, washed with water, dried on sodium sulfate and concentrated under reduced pressure. The residue is taken up in 300 cm3 of hexane, filtered, successively washed three times with 200 cm3 of toluene and then recrystallized in isopropyl ether. After drying, 20.7 g of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- 2-naphthyl)-4-oxo-2-methyl butyric acid in the form of a white solid whose melting point is 165° C. are obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:9][C:8]=1[N+:24]([O-])=O)=O>C(O)(=O)C.C(OCC)(=O)C.O.[Fe]>[NH:24]1[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([N:13]3[C:14](=[O:23])[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=4[C:21]3=[O:22])[CH:9]=2)[NH:6][CH2:5][C:3]1=[O:2]
Reactant: COC(=O)CNc1ccc(N2C(=O)C3=C(CCCC3)C2=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1CNc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reaction time: 3 h
Yield: 76.3 %

Procedure:
2-(4-Methoxycarbonylmethylamino-3-nitrophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (2.06 g) was dissolved in a mixture of acetic acid (20 ml) and ethyl acetate (20 ml), and the resultant solution was dropwise added to a mixture of 5% aqueous acetic acid (10 ml) and iron powder (4 g) at 70° to 80° C., followed by stirring at the same temperature for 3 hours. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, dried and concentrated to give 2-(3,4-dihydro-2(1H)-quinoxalinon-7-yl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.3 g). m.p., 208°-209° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].C(#N)C.[CH3:15][O:16][C:17]([C:19]1[C@H:20]2[CH2:28][C@@H:27]3[O:29][C@:26]3([CH3:30])[C@@H:21]2[CH:22]([OH:25])[O:23][CH:24]=1)=[O:18]>CO>[CH3:15][O:16][C:17]([C:19]1[C@H:20]2[CH2:28][C@@H:27]3[O:29][C@:26]3([CH3:30])[C@@H:21]2[C@H:22]([O:25][C:10](=[O:11])[NH:9][CH3:8])[O:23][CH:24]=1)=[O:18]
Reactant: COC(=O)C1=COC(O)[C@@H]2[C@@H]1C[C@@H]1O[C@@]12C
Reactant: CN=C=O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
0.15 ml of triethylamine and 60 μl of methylisocyanate were added to an acetonitrile solution containing 200 mg of a known (4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-hydroxy-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester followed by stirring for 1 hour at room temperature. After adding 1 ml of methanol to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain colorless needles from the hexane-ether eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-1-methylcarbamoyloxy-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester (55 mg, yield : 22%). The physicochemical properties of this compound are described in Table 1, Compound No. 3).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:7][C:6]([C:19]3[S:23][C:22]([NH2:24])=[N:21][CH:20]=3)=[N:5][C:4]=2[CH2:3]1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:24][C:22]1[S:23][C:19]([C:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])[C:9]3[CH2:10][CH2:11][N:2]([CH3:1])[CH2:3][C:4]=3[N:5]=2)=[CH:20][N:21]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)s2)nc2c1CCN(C)C2
Product: CCNC(=O)Nc1ncc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C)C3)s1
Yield: 11 %

Procedure:
The product from step 1 was treated as described for example 85 with ethyl isocyanate. The mixture was concentrated in vacuo and the material purified by prep HPLC at high and low pH, yielding the title compound (15.5 mg, 0.037 mmol, 11% over 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(CC(=O)C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(c2noc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.8 %

Procedure:
A mixture of 3.9 g of 5-fluoro-3-(4-piperidyl)-1,2-benzisoxazole, 3.8 g of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.7 g of sodium carbonate, a few crystals of potassium iodide and 140 ml of 2-methyl-4-pentanone was stirred and was heated under reflux under nitrogen for 8 hrs. After stirring at ambient temperature for 12 hrs, the mixture was filtered and the filter cake was stirred with 200 ml of water. The solid was collected and dried. Recrystallization from methanol-dimethylformamide-water gave 2.5 g (35.8%) of product. The product was combined with 1.0 g of that from another run to yield a total of 3.5 g of product, mp 202°-204°.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[C:15]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:16]=[C:15]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(-n2cccn2)cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2cccn2)cc1O
Temperature: 50 °C
Yield: 57.2 %

Procedure:
To 0.395 g of the material from Step B, above, dissolved in 10 mL THF, is added a catalytic amount of 10% Pd/C and excess ammonium formate. The reaction is heated to 50° C. for 45 minutes. Upon cooling, celite is added. The reaction is then gravity filtered and concentrated in vacuo. The residue is redissolved in ethyl acetate and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 0.152 g of the final title compound (57.1%).
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([OH:15])=O.C[NH:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1>>[N:24]1([C:21]2[N:20]=[CH:19][C:18]([NH:17][C:13]([C:3]3[N:4]=[C:5]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[O:6][C:2]=3[Cl:1])=[O:15])=[CH:23][CH:22]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1Cl
Reactant: CNc1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)oc1Cl

Procedure:
With a procedure similar to example 1 above, 5-chloro-2-phenyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 5-chloro-2-phenyl-oxazole-4-carboxylic acid and methyl-(6-morpholin-4-yl-pyridin-3-yl)-amine. LCMS calcd for C19H17ClN4O3 (m/e) 384, obsd 385 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)([OH:12])[CH2:10][CH3:11].[C:20]1([CH2:26][CH2:27][CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([OH:12])[CH2:10][CH3:11]
Reactant: BrCCCc1ccccc1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccccc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(O)(c1ccc(OCCCc2ccccc2)cc1)c1ccccc1OC

Procedure:
6.45 g. of 1-(2-methoxyphenyl)-1-(4-hydroxyphenyl)-propan-1-ol, 5.5 g. of 3-phenylpropyl bromide, 6.5 g. of anhydrous potassium carbonate, 0.5 g. of potassium iodide and 65 ml. of dry acetone are slightly boiled for 15 hours, with stirring. After cooling, acetone is distilled off under reduced pressure, to the residue water is added and it is extracted with benzene. The organic phase is washed to neutral with water, a 5% aqueous sodium hydroxide solution and again water. After drying over anhydrous magnesium sulfate the solution is evaporated in vacuo. The residue is crystallized from n-hexane to yield 7.8 g. of the named compound, melting at 75°-76° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8](=[O:17])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:18]1([Mg])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:18]1[CH:19]=[CH:20][C:21]([C:8]([OH:17])([CH:2]2[CH:1]3[CH:6]=[CH:5][CH:4]([CH2:7]3)[CH2:3]2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: O=C(CCN1CCCCC1)C1CC2C=CC1C2
Reactant: [Mg]c1ccccc1
Product: OC(CCN1CCCCC1)(c1ccccc1)C1CC2C=CC1C2

Procedure:
It has been possible to achieve this object by a method for producing biperiden by reacting 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with an exo/endo ratio of at least 2.5:1 with a phenylmagnesium compound to give a biperiden (Ia)-containing mixture of isomers of 1-(bicyclo-[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I), characterized in that the isolation of biperiden (Ia) from the mixture of isomers comprises the following steps:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(N[C@@H](C)c2cccc(F)c2)c2cccc(N)c2)cc1
Yield: 93.3 %

Procedure:
In a similar manner to that described in Example (1b), a solution N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-N-[(S)-1-(3-fluorophenyl)ethyl)amine (2.70 g) [prepared as described in step (a) above] in methanol (100 ml), nickel chloride hexahydrate (3.37 g) and sodium borohydride (1.13 g) were reacted, to afford the title compound (2.32 g) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1.C1(C)C(O)=CC=CC=1.BrC1C=C(C=CC=1)C=O>>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[O:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1Oc1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: Cc1ccccc1O
Agent: O=Cc1cccc(Br)c1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3ccccc3C)c2)cc1

Procedure:
The title compound was synthesized in the same manner as in Example 277 from methyl 3-(4-hydroxyphenyl)propanoate and [3-(2-methylphenoxy)phenyl]methanol (synthesized in the same manner as in Reference Example 201 from o-cresol and 3-bromobenzaldehyde (mixture with side product)) (preparative HPLC (gradient cycle A) was used for purification). colorless oil (yield 28%).