Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6].Cl.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([CH3:37])[C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:30])[CH:23]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2OCCCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2OCCCC)c1
Temperature: 68 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
1.24 mL (1.24 mmol) of aqueous 1 M sodium hydroxide solution are added to a solution of 0.4 g (0.83 mmol) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylate in 10 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 5 hours. After cooling, the reaction is worked up by addition of 3 mL (3 mmol) of aqueous 1 M hydrochloric acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The product is recrystallized from a pentane/acetone mixture to give 0.3 g (76%) of (Z)-3-[2-butoxy-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2-methoxyacrylic acid in the form of a cream-colored solid with a melting point of 61° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.O.NN>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(CC(C)C)CC2)ccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(N2CCN(CC(C)C)CC2)ccc1N
Yield: 82.5 %

Procedure:
A solution of 1-[3-(methyloxy)-4-nitrophenyl]-4-(2-methylpropyl)piperazine (1.7 g, 5.82 mmol), FeCl3 (0.280 g, 1.75 mmol), activated carbon (2.0 g), and hydrazine hydrate (2.23 mL, 70 mmol) was heated in methanol (50 mL) for 3 hours. The mixture was filtered over celite and concentrated to give 2-(methyloxy)-4-[4-(2-methylpropyl)-1-piperazinyl]aniline as a white solid (1.24 g, 4.80 mmol, 83% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.22 Hz, 6 H), 1.85 (s, 1 H), 2.20 (s, 2 H), 2.61 H), 3.10 (s, 4 H), 3.54 (s, 2 H), 3.83 (s, 3 H), 6.43 (m, 1 H), 6.52 (d, J=1.83 Hz, 1 H), 6.64 (d, J=8.42 Hz, 1 H).
Reaction SMILES: [O:1]=[C:2]([CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC1C=CC=CC=1)[C:3]([OH:5])=[O:4].C(Cl)C1C=CC=CC=1>C(#N)C>[C:14]1([CH2:6][C:2](=[O:1])[C:3]([OH:5])=[O:4])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)C(=O)C(Cc1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: ClCc1ccccc1
Product: O=C(O)C(=O)Cc1ccccc1
Yield: 66 %

Procedure:
By the same operation as in Example 61 except that 6 ml of acetonitrile was used as the solvent, 2-oxo-3,4-diphenylbutanoic acid formed in a yield of 66 % by the reaction of 0.49 g (3 mmoles) of phenylpyruvic acid with 0.5 ml of benzyl chloride, as determined by NMR spectral analysis.
Reaction SMILES: CI.[CH:3]1[C:8]2=[C:9]3[C:17](=[CH:18][CH:19]=[C:7]2[CH:6]=[CH:5][CH:4]=1)[C:16]1C(=[CH:12][CH:13]=[C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]2=1)C3.[CH3:24][C:25]([CH3:28])([O-])[CH3:26].[K+].CS(C)=O>O>[CH3:24][C:25]1([CH3:28])[C:9]2[C:17](=[CH:18][CH:19]=[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:8]3=2)[C:16]2[C:26]1=[CH:12][CH:13]=[C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]1=2
Reactant: c1ccc2c3c(ccc2c1)-c1c(ccc2ccccc12)C3
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: CC1(C)c2ccc3ccccc3c2-c2ccc3ccccc3c21
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Methyl iodide 13.45 g (94.74 mmol) was dropwise added to a mixed solution of 8.41 g (31.58 mmol) of 13H-dibenzo[a,g]fluorene, 15.95 g (142.11 mmol) of potassium t-butoxide and 100 ml of dimethylsulfoxide at 20° C. in 20 minutes, and the solution was stirred for 8 hours. After left standing overnight, 13.45 g (94.74 mmol) of methyl iodide was further dropwise added and stirred for 11 hours. Water was dropwise added to the reaction mixture, and the solution was extracted twice with dichloromethane. After separating the solution, the organic phase was concentrated and refined by flash chromatograph (silica gel: hexane/dichloromethane=5/1) to obtain 4.66 g (yield: 50.1%) of 13,13-dimethyl-13H-dibenzo[a,g]fluorene.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:4]1.[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br.[I-].[Na+]>CN(C=O)C.C1COCC1.O>[Cl:19][C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4]1
Reactant: Clc1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)CCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)CCc1cn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 0.38 g) was added to the mixed solution of ethyl 3-(indol-3-yl)propionate (1.8 g) in DMF (20 ml) and THF (20 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 10 minutes, to which were added 2,4-dichlorobenzyl bromide (1.8 g) and sodium iodide (0.3 g). The reaction mixture was stirred at room temperature for 3 hours and then poured into water, and the mixture was extracted with IPE. The organic layer was washed with water, then dried and concentrated. The residue was dissolved in ethanol (30 ml), which was stirred at 50° C. for 2 hours in the presence of water (10 ml) and sodium hydroxide (1 g). The reaction mixture was concentrated, made acidic, and then extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-IPE to obtain the entitled compound (2.4 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=[N:19]O)[CH3:18])[CH:9]=1.[H][H]>[Pd].CCO.CC(O)=O>[NH2:19][CH:17]([C:10]1[CH:9]=[C:8]([N:7]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:1])[CH3:30])[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=1)[CH3:18]
Reactant: CC(=NO)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Yield: 104.7 %

Procedure:
A solution of 1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)pyrazolo[1,5-a]pyrimidin-5-yl]ethanone oxime (4.50 g, 8.77 mmol) in 4:1 EtOH/AcOH (90 mL) under nitrogen in a Parr bottle was treated with 10% Pd on carbon (933 mg, 0.877 mmol), and the mixture was shaken on the Parr apparatus under 45 psi hydrogen for 23 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure, azeotroping with toluene at 40-45° C. to remove most AcOH. The oily residue was taken up in EtOAc (˜100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give the title compound, 5-(1-aminoethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (4.02 g, 91% purity, 95% yield) as an oil: MS (ESI+) for C20H39N5O2Si2 m/z 438 (M+H)+.
Reaction SMILES: C(N)C1C=CC=CC=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31](OC)=[O:32])[C:24]2=[O:38])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][N:37]=3)[C:31]([NH:16][CH2:15][C:11]3[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=3)=[O:32])[C:24]2=[O:38])=[CH:39][CH:40]=1
Reactant: NCc1cccnc1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Solvent: NCc1ccccc1
Product: O=C(NCc1cccnc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 39 %

Procedure:
Following the procedure as described in Example 15, making variations as required to replace benzylamine with pyridin-3-ylmethanamine to react with methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-(pyridin-3-ylmethyl)isonicotinamide was obtained as a colorless solid in 39% yield: mp 153-155° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.29 (br, 1H), 8.60 (s, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.44-8.42 (m, 1H), 8.37 (d, J=5.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.35-7.31 (m, 4H), 7.18-7.13 (m, 2H), 4.46 (d, J=6.0 Hz, 2H), 4.39 (s, 2H), 3.93 (t, J=7.5 Hz, 2H), 3.38-3.34 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 156.8, 153.5, 149.3, 148.7, 148.5, 143.2, 135.7, 135.1, 133.6, 133.6, 130.4, 130.3, 124.0, 116.0, 115.7, 115.2, 110.4, 46.6, 41.6, 41.2, 41.0; MS (ES+) m/z 406.2 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[CH:10]=[CH:31]/[C:32]([O:34][CH3:35])=[O:33])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2[nH]ccc2c1
Yield: 96.4 %

Procedure:
A solution of 1H-indole-5-carbaldehyde (0.217 g, 1.5 mmol) and methyl (triphenylphosphoranylidene)acetate (0.535 g. 1.6 mmol) in DCM (4 mL) was stirred in a flask under reflux overnight, then the solvent was removed under reduced pressure. Purification by silica gel column chromatography, with a mixture of DCM/Hexane 8:2 as eluent system, gave 0.291 g of methyl (2E)-3-(1H-indol-5-yl)acrylate (97% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]=O.[NH2:19][C:20]1[N:21]([CH3:32])[N:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:25])[CH:24]=1>>[NH2:19][C:20]1[N:21]([CH3:32])[N:22]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:23](=[O:25])[C:24]=1[CH2:17][N:14]1[CH2:15][CH2:16][N:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)[CH2:12][CH2:13]1
Reactant: C=O
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: Cn1c(N)cc(=O)n1-c1ccccc1
Product: Cn1c(N)c(CN2CCN(c3cccc4c3OCCO4)CC2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(1,4-benzodioxan-5-yl)piperazine (2.45 g), 37-40% aqueous formaldehyde solution (0.8 ml) and industrial methylated spirit (30 ml) was stirred at ambient temperature under nitrogen for 18 hours, then a slurry of 3-amino-2-methyl-1-phenyl-3-pyrazolin-5-one (1.95 g) in industrial methylated spirit (55 ml) was added in one portion. The stirred mixture was heated under reflux for 5 hours, then allowed to stand at ambient temperature for 18 hours. The resulting solid was collected by filtration, and the filtrate was concentrated in vacuo to 40 ml then cooled in ice to give a second crop of white solid which was collected by filtration. The combined solids were suspended in industrial methylated spirit (80 ml), and the mixture was heated to reflux temperature. Undissolved solid was removed by filtration of the hot mixture, then the filtrate was concentrated to 40 ml, cooled in ice, and the resulting solid was collected by filtration. The two crops of solid were combined and dried in vacuo at 65° C. to give 3-amino-4-[4-(1,4-benzodioxan-5-yl)piperazin-1-ylmethyl]-2-methyl-1-phenyl-3-pyrazolin-5-one 0.75 hydrate as a white solid (2.45 g), m.p. 222-224° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH:25]1([O:24][C:18]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
The mixture of 2-(2-cyclobutoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (8) (250 mg, 0.64 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and the solution acidified with conc. HCl until pH˜3 to yield a precipitate. The precipitate is filtered to give a pure product (9) as white solid (190 mg, 81%).
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[C:26](O)(=[O:28])[CH3:27]>>[C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C@H:7]2[CH2:8][CH2:9][C@H:4]([NH:3][C:26](=[O:28])[CH3:27])[CH2:5][CH2:6]2)[CH2:13][CH2:14]1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccccc3)CC2)CC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccccc3)CC2)CC1

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-phenyl-methanone dihydrochloride (138 mg) and acetic acid (23 mg) by procedure C. Yield: 85 mg (66%). White solid. 357.3 ([M+H]+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([S:15]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH2:30]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:25]=3)[NH:20][N:19]=2)(=[O:17])=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>CN(C=O)C>[N:1]([CH2:30][CH2:29][CH2:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[S:15]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=[O:16])=[O:17])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
Sodium azide (0.425 g, 6.54 mmol) was added to a solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (1.16 g, 2.16 mmol) in DMF (20 mL). The reaction mixture was stirred at 80° C. for 15 hours in a sealed tube. After cooling to ambient temperature, it was poured into excess water and extracted with ethyl acetate. The organic phase was washed with 10% ammonium chloride/water solution, water and brine. It was dried with anhydrous magnesium sulfate, filtered, concentrated and dried at 73° C. in vacuo for 45 minutes to yield 5-(3-azido-propoxy)-3-(naphthalene-1-sulfonyl)-1H-indazole as an amber gum (0.770 g, 87.7%); Mass Spectrum (−EI, [M−H]−) m/z 406. 1HNMR (400 MHz, DMSO-d6): δ14.05 (br, 1H), 8.64-8.68 (m, 1H), 8.53 (dd, 1H, J=7.42 Hz and 1.16 Hz), 8.25-8.28 (m, 1H), 8.01-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.26 (d, 1H, J=2.08 Hz), 7.08 (dd, 1H, J=9.16 Hz and 2.32 Hz), 4.06 (t, 2H, J=6.14 Hz), 3.49-3.52 (m, 2H), 1.96-1.99 ppm (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][OH:5].[CH3:9][Si]([Cl:13])(C)C>CO>[ClH:13].[CH3:9][O:7][C:6](=[O:8])[CH:2]([NH2:1])[CH2:3][CH2:4][OH:5]
Reactant: NC(CCO)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C(N)CCO
Product: Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A suspension of DL-homoserine (1.00 g, 8.39 mmol) in methanol (40 mL) was placed in an ice bath. Trimethylsilyl chloride (2.34 mL, 18.5 mmol) was added dropwise via syringe. The reaction mixture gradually became homogenous and was further stirred at rt for 14 h, concentrated by rotary evaporation, and further dried under high vacuum. The crude oil thus obtained was used for the next step without further purification. 1H NMR (300 MHz, CD3OD) δ 2.00-2.24 (m, 2H), 3.70-3.80 (m, 2H), 3.85 (s, 3H), 4.12-4.22 (m, 1H). m/z (ESI) 134 [C5H11NO3+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[OH:11]
Reactant: BrBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (16.0 g, 100 mmol) in acetic acid (20 mL) was added into a mixture of 4-methoxy-2-nitrophenol (16.9 g, 100 mmol, sodium acetate (16.4 g, 200 mmol) and acetic acid (100 mL). The mixture was stirred for 30 min at room temperature, and then at 70° C. for 2 h and poured into water (1.5 l) containing concentrated sulfuric acid (10 mL). The precipitated solid filtered and crystallized from (chloroform/hexane) to give a brownish solid, m.p. 116-118° C.; MS m/e 246 (M−H)+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]1[CH2:9][NH:8][CH2:7]1)(=[O:4])=[O:3].[CH3:10][CH:11]([CH2:13][CH2:14][CH2:15][C@H:16]([C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([CH2:33][CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C:27](=O)[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH3:17])[CH3:12].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.O>[CH3:1][S:2]([O:5][CH:6]1[CH2:9][N:8]([C@H:27]2[CH2:28][CH2:29][C@@:30]3([CH3:31])[C@@H:25]([CH2:24][CH2:23][C@@H:22]4[C@@H:32]3[CH2:33][CH2:34][C@@:35]3([CH3:36])[C@H:21]4[CH2:20][CH2:19][C@@H:18]3[C@H:16]([CH3:17])[CH2:15][CH2:14][CH2:13][CH:11]([CH3:10])[CH3:12])[CH2:26]2)[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC1CNC1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](N5CC(OS(C)(=O)=O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 3.50 g of the mesylate salt of 3-methanesulfonyloxyazetidine (m.p. 111.5°-113° C. dec.) and 5.46 g of 5α-cholestan-3-one in 100 ml of anhydrous methanol maintained at room temperature under a nitrogen atmosphere add 1.74 g sodium cyanoborohydride portionwise over a 20 minute period. Stir for 30 minutes at room temperature, pour into 600 ml water, add to the mixture 100 ml 1.1 M aqueous sodium bicarbonate and extract three times with ethyl ether. Combine the ether extracts, dry over 3 A molecular sieves and remove solvent in vacuo to give a mixture of α- and β-mesylates. Chromatography of this mixture on 150 g Stahl-type silica using ethyl acetate affords the pure title product (slower-moving component), m.p., 135.5° C. dec., [α]D26 =+12.1° (CHCl3, 0.4%).
Reaction SMILES: C12(C3C=CC(OC[C:17]4[O:18][C:19]5[CH:25]=[C:24]([C:26]([OH:28])=O)[CH:23]=[CH:22][C:20]=5[N:21]=4)=CC=3)CC3CC(CC(C3)C1)C2.[CH2:31]([NH2:37])[C:32]1[O:36][CH:35]=[CH:34][CH:33]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[O:36]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:31][NH:37][C:26]([C:24]1[CH:23]=[CH:22][C:20]2[N:21]=[CH:17][O:18][C:19]=2[CH:25]=1)=[O:28]
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccc2nc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)oc2c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NCc1ccco1)c1ccc2ncoc2c1
Temperature: 25 °C
Yield: 32.5 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (30.1 mg, 0.08 mmol), furfuryl amine (11.0 mg, 0.12 mmol, 0.01 ml), EDC (21.7 mg, 0.12 mmol) and HOBt (15.4 mg, 0.12 mmol) in DMF 3.0 mL was added DIPEA (14.2 mg, 0.12 mmol, 0.02 ml). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=6:3:1) to give 2-adamantan-1-yl-phenoxymethyl)-benzoxazole-6-carboxylic acid (furan-2-ylmethyl)-amide as a white solid (6.3 mg, 17.4% yield).
Reaction SMILES: [Cl-:1].[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[CH2:7][CH:8]([OH:14])[CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11].CS(C)=O.[O:20]=[C:21]1[NH:29][CH:28]=[N:27][C:26]2[N:25]([CH2:30][CH2:31][C:32](OC3C=CC([N+]([O-])=O)=CC=3)=[O:33])[CH:24]=[N:23][C:22]1=2.CO>CC(C)=O>[Cl-:1].[O:20]=[C:21]1[NH:29][CH:28]=[N:27][C:26]2[N:25]([CH2:30][CH2:31][C:32]([NH:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[CH2:7][CH:8]([OH:14])[CH2:9][N+:10]([CH3:13])([CH3:12])[CH3:11])=[O:33])[CH:24]=[N:23][C:22]1=2
Reactant: C[N+](C)(C)CC(O)CC(=O)NCCN
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CC(C)=O
Solvent: CO
Product: C[N+](C)(C)CC(O)CC(=O)NCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Reaction time: 1 h
Yield: 33 %

Procedure:
248 mg (1.0344 mmol) of 4-[(2-aminoethyl)amino]-2-hydroxy-4-oxo-N,N,N-trimethyl-1-butanaminium chloride was placed into a 10 ml round bottom flask with magnetic stirring bar. Then 2 ml of dimethylsulfoxide was added and the solution was gently heated to help dissolve the amine. 340 mg (1.034 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was added to the stirring solution. The solution was stirred for a period of one hour and 3 ml of methanol was added. Then 3 ml of acetone was added and the solution was filtered. The solid was washed several times with acetone and allowed to dry. This yielded 105 mg of 4-[[2-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]ethyl]amino]-2-hydroxy-4-oxo-N,N,N-trimethyl-1-butanaminium chloride (AIT-0090) as a white solid. m.p. approximately 260-265 (dec) Yield: 33%.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:29][CH2:28]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21]>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Para-toluenesulfonic acid (1.902 g, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 170.8° C.