Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[N:17]=[N:18][N:19]([C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[N:20]=2)=[CH:6][CH:5]=1.Cl.O>CO>[CH3:29][C:21]([N:19]1[N:18]=[N:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=2)=[N:20]1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: COC(OC)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(C=O)cc2)n1
Yield: 97.3 %

Procedure:
A solution of 4-dimethoxymethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl (2.9 g, 7.0 mmol) and 15 mL of 4M hydrochloric acid in 50 mL of methanol was stirred at room temperature for 18 hours. The mixture was diluted with 200 mL of diethyl acetate and poured into 300 mL of water. The ethyl acetate layer was washed 3 times with water, dried over magnesium sulfate and concentrated giving a white, waxy solid (2.51 g). A portion of the solid (1.53 g) was crystallized from diethyl ether and isolated. Drying gave 2'-[2-(1-methyl-1-phenylethyl)biphenyl-2H-tetrazolebiphenyl-4-carbaldehyde (1.2 g, 3.2 mmol), m.p. 98.5°-97° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][C:11]2C=CC=[CH:13][CH:12]=2)[N:4]=1.[NH4+:17].[Cl-]>N>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][C:13]#[N:17])[N:4]=1
Reactant: Nc1cccc(SCc2ccccc2)n1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Product: N#CCCCSc1cccc(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A solution of 2-amino-6-benzylthiopyridine hydrochloride (47.2 g.) in liquid NH3 (700 ml.) was stirred while Na (17.0 g.) was added in small portions. When the addition was complete NH4Cl (21.9 g.) was added and then the mixture was evaporated to dryness. The residue was dissolved in a mixture of EtOH (100 ml.) and H2O (100 ml.) and the mixture treated with 4-bromobutyronitrile (23 ml.) and stirred at room temperature for 18 hours. Ths solution was evaporated to dryness and the residue was partitioned between 2N aqueous HCl and ether. The aqueous phase was basified with 10N aqueous NaOH and extracted with EtOAc. The extract was dried over Na2SO4 and evaporated to dryness to give 4-(2-aminopyrid-6-ylthio)butyronitrile (36.1 g.) which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)COc1ccc(N)cc1
Yield: 97.6 %

Procedure:
A solution of 30.8 g of methyl 4-nitrophenoxyacetate [prepared as described in step (a) above] in 500 ml of methanol was shaken in an atmosphere of hydrogen and in the presence of 5.0 g of 10 w/w palladium-on-charcoal for 6 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure, to give 25.8 g of the title compound having an Rf value=0.79 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][C:26](OCC)=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)C>Cl>[CH:17]1([CH:22]=[CH:23][CH:24]([CH3:31])[CH2:25][CH:26]=[O:27])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CC(C)C=CC1CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCO
Solvent: CCCCCC
Product: CC(C=CC1CCCC1)CC=O
Temperature: 0 °C
Yield: 69 %

Procedure:
Diisobutylaluminum hydride (95 ml of 1.0 M solution in hexane) was added into a hexane (200 ml) solution of ethyl 5-cyclopentyl-3-methylpent-4-enoate (used in example 1; 20.0 g; 95 mmol), at −65° C. After 3 hours stirring at the same temperature, ethanol (3 ml) was added, and the reaction mixture was poured into an ice-cold NH4Cl solution (200 ml) and diluted with 2 N HCl (100 ml). The organic layer was separated, washed with brine (3×200 ml), dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (hexane/MTBE 15:1) to give 10.9 g (69% yield) of 5-cyclopentyl-3-methylpent-4-enal.
Reaction SMILES: [C:1]([NH:4][C:5]1([C:12]#[N:13])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2].[C:14](O)(=[O:16])[CH3:15]>C(OC(=O)C)(=O)C.[Pt]=O>[C:1]([NH:4][C:5]1([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:10][CH:9]2[CH2:11][CH:6]1[CH2:7][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)NC1(C#N)CC2CCC1C2
Agent: O=[Pt]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1(NC(C)=O)CC2CCC1C2

Procedure:
The procedure is as in Example 3, but starting from 2-acetylamino-2-cyano-bicyclo[2.2.1]heptane (7.14 g), in the form of the exo racemate in acetic acid (250 cc) and acetic anhydride (7.5 cc), in the presence of Adams platinum oxide (0.7 g); taking up the residue from the evaporation in water and ethanol (80/20 by volume) (100 cc), 2-acetylamino-2-acetylaminomethyl-bicyclo[2.2.1]heptane (8.7 g) is thus obtained in the form of fine white crystals which melt at 208° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Cl:12])[CH:3]=1.Cl.[CH3:14][C:15]1[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[C:15]([CH3:14])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([Cl:12])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)c(Br)cc1Cl
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Yield: 95.6 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-chloro-5-fluorobenzoyl chloride (1 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (843 mg) described in Preparation Example 64, the title compound (1.5 g) was obtained.
Reaction SMILES: [F:1][C:2]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)([F:4])[F:3].C(Cl)(=O)C(Cl)=O.C(=O)=O.CO.CS([O-])(=O)=O.[O:27]=[C:28]1[C@@H:33]2[CH2:34][C@@H:30]([CH2:31][NH2+:32]2)[O:29]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CN(C)C=O.C(N(CC)CC)C.O1CCCC1>[F:1][C:2]([F:4])([F:3])[C:5]1([C:8]([N:32]2[CH2:31][C@@H:30]3[CH2:34][C@H:33]2[C:28](=[O:27])[O:29]3)=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: O=C1O[C@@H]2C[NH2+][C@H]1C2
Agent: CS(=O)(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1O[C@H]2C[C@@H]1N(C(=O)C1(C(F)(F)F)CC1)C2
Temperature: 2 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Trifluoromethyl-cyclopropanecarboxylic acid (167.0 g, 1084 mmol) was suspended in toluene (500 mL) and then dimethylformamide (3.6 mL, 47 mmol) was added. The mixture was cooled to 2° C. (ice bath) and a solution of oxalyl chloride (90 mL, 1037 mmol) in toluene (167 mL) was added dropwise (within 25 min). The mixture was then stirred for additional 30 min, followed by 4 h at room temperature. Subsequently, it was cooled to 0° C. again (dry ice/methanol bath) and (1S,4S)-3-oxo-2-oxa-5-azonia-bicyclo[2.2.1]heptane methanesulfonate (200 g, 956 mmol), tetrahydrofuran (330 mL) and triethylamine (500 mL, 3.59 mol) were slowly added, keeping the reaction temperature below 5° C. Especially after addition of 50% of triethylamine, the reaction becomes strongly exothermic and efficient cooling is essential. The mixture was stirred for 20 h at room temperature, before it was poured onto an aqueous citric acid solution (10% in water, 1.6 L) and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (500 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product (245 g, brown oil) was dissolved in dichloromethane (330 mL) before ethyl acetate (130 mL) and heptane (660 mL) were added and dichloromethane was carefully distilled off in vacuo. The product started to crystallize. The suspension was cooled to 2° C. (ice bath) and stirred for 1 h, before it was filtered. The precipitate was washed with ethyl acetate/heptane 1:9 (v/v, 300 mL) and dried in vacuo to afford the title compound as a light brown powder (219 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 1.17-1.25 (m, 1H), 1.30 (dd, J=5.3 Hz, 8.3 Hz, 1H), 1.37-1.46 (m, 2H), 2.13 and 2.37 (AB, JAB=10.7 Hz, each 1H), 3.63 and 3.73 (AB, JAB=12.1 Hz, each 1H), 4.99 (s, 1H), 5.21 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1I.[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:20](OC)=[O:21])=[C:15](B(O)O)[CH:16]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:3]=1[C:13]1[CH:12]=[C:11]([F:10])[CH:16]=[CH:15][C:14]=1[C:20](=[O:21])[NH:8]2
Reactant: Nc1nccc(Cl)c1I
Reactant: COC(=O)c1ccc(F)cc1B(O)O
Product: O=c1[nH]c2nccc(Cl)c2c2cc(F)ccc12
Yield: 21.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 1 using 4-chloro-3-iodopyridin-2-amine (1.20 g, 4.72 mmol) and 5-fluoro-2-methoxycarbonylphenylboronic acid (1.03 g, 5.19 mmol) to provide 410 (250 mg, 21% yield) as a solid. LC-MS (M+H=249, obsd.=249).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[O:10][C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH:7]=1.[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29]Br)=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[F:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:31])[CH2:29][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]3[O:10][C:11]([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)=[CH:12][N:13]=3)[CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Cc1ccc(N)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(NCC(=O)c2ccc(F)cc2)cc1Nc1ncc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(5-Amino-2-methyl-phenylamino)-oxazol-5-yl]-benzonitrile (60 mg, 0.207 mmol) in dimethylacetamide (3 mL) was added 4-fluorophenacyl bromide (45 mg, 0.207 mmol), NaHCO3 (18 mg, 0.207 mmol). The mixture was stirred at room temperature for 2 h. After removal of the solvent, the residue was treated with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated. 4-(2-{5-[2-(4-Fluoro-phenyl)-2-oxo-ethylamino]-2-methyl-phenyl amino}-oxazol-5-yl)-benzonitrile was obtained after silica gel column chromatography (dichloromethane/ethanol: 9812) (38 mg, 43%) as beige solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>S(Cl)(Cl)=O>[NH:17]1[C:16]([NH:15][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:11]=2)=[O:14])=[N:20][N:19]=[N:18]1
Reactant: Nc1nnn[nH]1
Reactant: CCCCOc1cccc(C(=O)O)n1
Solvent: O=S(Cl)Cl
Product: CCCCOc1cccc(C(=O)Nc2nnn[nH]2)n1
Yield: 61 %

Procedure:
0.94 g of 6-n-butoxy-2-pyridinecarboxylic acid, 10 ml of thionyl chloride and 0.48 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is recrystallized from a mixture of dimethylformamide, water and ethanol, whereby 0.77 g of N-(5-tetrazolyl)-6-n-butoxy-2-pyridinecarboxamide is obtained.
Reaction SMILES: [Br:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([C:8](=[O:16])[NH:9][C:10]3=[O:15])[C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.[CH2:19](I)[CH3:20]>>[Br:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([C:8](=[O:16])[N:9]([CH2:19][CH3:20])[C:10]3=[O:15])[C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COc1ccc(Br)c2c1C1C(=O)NC(=O)C1CC2
Product: CCN1C(=O)C2CCc3c(Br)ccc(OC)c3C2C1=O

Procedure:
Using the procedure of example 64, but starting with 6-bromo-3a,4,5,9b-tetrahydro-9-methoxy-1H-benz[e]isoindole-1,3-(2H)-dione and ethyl iodide instead of methyl iodide afforded the desired compound; M+ 337; mp 170°-4°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH:16]=[CH2:17])[CH:5]=1.[O:18]([C:25]1[C:30]([CH:31]=[CH:32][C:33](O)=[O:34])=[CH:29][CH:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:16]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([F:10])[C:7]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][NH:2][C:33](=[O:34])[CH:32]=[CH:31][C:30]1[C:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:26][C:27]([C:36]([F:37])([F:38])[F:39])=[CH:28][CH:29]=1)#[CH:17]
Reactant: C=Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccccc1
Agent: Cl
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Oc2ccccc2)cc(F)c1NS(C)(=O)=O
Yield: 75 %

Procedure:
N-(4-Aminomethyl-2-ethenyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (35 mg, 0.13 mmol) was reacted with 3-(2-phenoxy-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (17 mg) to give the title compound (22 mg, 75%) after purification by column chromatography (Hex/EtOAc=1/1).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)C.[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[O:7]([C:8]1[C:9]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cccnc2-c2ccc(F)nc2)SC[C@H]1O

Procedure:
By carrying out the operation analogously to example 239, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=14%).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[N+:16]([O-])=O)[CH:2]([CH3:4])[CH3:3].[H][H]>[Pd].CO>[CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[NH2:16])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)COC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)COC(=O)c1ccc(N)cc1N
Yield: 81.6 %

Procedure:
A 500 ml Parr Shaker was charged with 80.0 g of isobutyl-2,4-dinitrobenzoate, 200 ml methanol, and 3.0 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 50 psi hydrogen pressure while maintaining the temperature below 50° C. Hydrogen uptake cease after 4 hrs. The mixture was cooled, filtered and the methanol removed under reduced pressure. The remaining solid was washed with toluene, filtered and dried to give 50.7 g of isobutyl-2,4-diaminobenzoate, a light tan solid, mp 89° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][CH:6]1[C:11]([CH3:13])([CH3:12])[CH:10](O)[CH2:9][CH2:8][NH:7]1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH:6]3[C:11]([CH3:13])([CH3:12])[CH:10]([C:15]=2[CH:16]=[CH:17][CH:18]=1)[CH2:9][CH2:8][NH:7]3
Reactant: COc1ccccc1CC1NCCC(O)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c1CC1NCCC2C1(C)C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-ol (0.80 g) in polyphosphoric acid (10 mL) is stirred at 120° C. overnight. After cooling the solution to ca. 80° C., water (300 mL) is added and the mixture is stirred vigorously for another 10 min. Then, the mixture is cooled in an ice bath, more water is added, and the mixture is basified using 10 M aqueous NaOH. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure to yield the title product that is used without further purification.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].I>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: I
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a mixture of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 65° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. The reaction mixture was diluted with chloroform, washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure and the residue was recrystallized from ligroin to give 11.2 g (77.8%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose, melting at 133°-136° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].[NH2:22][C@@H:23]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:24]([OH:43])[CH2:25][N:26]1[C@H:35]([C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27]1.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.CC1CCC(O)C/C/1=C/C=C1\CCCC2(C)C(C(/C=C/C(C(C)C)C)C)CCC\12>O1CCCC1.C(OCC)(=O)C>[C:39]([NH:38][C:36]([C@@H:35]1[CH2:34][C@H:33]2[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:27][N:26]1[CH2:25][C@@H:24]([OH:43])[C@@H:23]([NH:22][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1CCC(O)C/C1=C/C=C1\CCCC2(C)C1CCC2C(C)/C=C/C(C)C(C)C
Agent: O=c1c2ccccc2nnn1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of 287 mg of N-(2-quinolylcarbonyl)-L-asparagine and 401 mg of 2-[3(S)-amino-2(R)-hydroxy-4 -phenylbutyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide in 3 ml of tetrahydrofuran was cooled to-10° C. and 163 mg of 3-hydroxy-1,2,3-benzotriazin-4(3H)-one and 220 mg of dicyclohexylcarbodiimide were added. The mixture was stirred at-10° C. for 2 hours and at 20° C. for 16 hours, then diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using 4% (by volume) methanol in dichloromethane for the elution to give 537 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid: MS: m/e 671 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:37])(=[O:36])[CH:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:37])(=[O:36])[CH:30]([CH2:32][C:33]([O-:35])=[O:34])[OH:31]
Reactant: O=C(O)CC(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
1.901 g of Donepezil is dissolved in 15 ml of ethyl acetate. A solution (4 ml) of malic acid (0.679 g) in absolute ethanol is added slowly and drop-wisely and the resulted solution is stirred. The solid precipitated is filtered with suction to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2([CH3:28])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:28][C:18]1([N:15]2[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19]1
Reactant: CCOC(=O)N1CCC(C)(N2CCC(O)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)N1CCC(C)(N2CCC(=O)CC2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (617 mg, 4.86 mmol) was taken into a oven dried round bottom flak and cooled to −78° C. under nitrogen atmosphere. Then dimethyl sulfoxide (767 mg, 9.72 mmol) in anhydrous dichloromethane (5 mL) was added dropwise. After 10 minutes, a solution of ethyl 3-(4-hydroxy-1-piperidyl)-3-methyl-pyrrolidine-1-carboxylate (830 mg, 3.24 mmol) in dichloromethane (10 mL) was cannulated into the flask and stirred at −78° C. for another 10 minutes. Triethylamine (1.31 g, 12.96 mmol) was then added and stirred at −78° C. for 30 minutes, allowed to warm to 0° C. over 30 minutes and was quenched with saturated solution of ammonium chloride (10 mL). The product was extracted into dichloromethane (2×50 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford the title compound as a yellow oil (810 mg, 90%). 1H NMR (CDCl3, 400 MHz): δ 4.18 (m, 2H), 3.88 (m, 1H), 3.62-3.35 (m, 3H), 2.92 (m, 1H), 2.85 (brs, 2H), 2.75 (brs, 1H), 2.48-2.39 (m, 4H), 2.05-1.89 (m, 1H), 1.41 (m, 1H), 1.26 (t, 3H), 1.08 (s, 3H) MS (M+1): 255.12.
Reaction SMILES: [O-2].[Ca+2].[O-2].[Al+3].[O-2].[O-2].[Al+3].[CH2:8]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[NH2:16])[CH3:9]>[Pd]>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:9]
Reactant: CCC1CCCCC1N
Agent: [Pd]
Agent: [Al+3]
Agent: [Ca+2]
Product: CCc1ccccc1N
Yield: 95 %

Procedure:
The procedure described in Example 27 is followed, using a reaction temperature of 250° C. and a catalyst which contains 0.5% by weight of palladium on a mixture of 19.4% by weight of calcium oxide and 80.6% by weight of aluminum oxide, and starting from 2-ethylcyclohexylamine. o-Ethylaniline (boiling point=210° C.) is obtained in a yield of 95% of the theory.