Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: COCCN
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(=O)O)c3)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)c1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-benzoic acid (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added 2-methoxyethylamine (0.02 mL, 0.19 mmol), EDCl (20 mg, 0.1 mmol), DMAP (1 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.1 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo and purified by prep-HPLC to afford the desired product (11 mg, 25%). 1H-NMR (CDCl3) δ 8.05 (t, J=1.8 Hz, 1H), 7.77-7.75 (m, 3H), 7.69 (m, 1H), 7.60 (dd, J=8.3, 1.0 Hz, 1H), 7.51 (m, 2H), 7.47 (m,1H), 7.40 (ddd, J=8.2, 1.9, 0.5 Hz, 1H), 6.62 (t, J=4.5 Hz, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Li+:12]>CO>[Li+:12].[CH:1]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCC1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Product: O=C([O-])C1CCCCC1
Yield: 100 %

Procedure:
Under stirring, a solution of cyclohexanecarboxylic acid (10.0 g, 78 mmol) in MeOH (30 mL) was added dropwise over 30 min to 1 M lithium methoxide in MeOH (78 mL, 78 mmol) at 5-10° C. The cooling bath was removed and after 4 h at room temperature, heptane (75 mL) was added slowly. Most of the MeOH was removed at a rotary evaporator. Heptane (100 mL) was added to the thick white suspension which was stirred 2 h at 0° C. The suspension was filtered and the filter cake was washed with heptane and dried in vacuo (<1 mbar) to afford 10.5 g (100%) cyclohexanecarboxylic acid lithium salt. Anal. Calcd for C7H11LiO2 C, 62.70; H, 8.27. Found: C, 62.03; H, 8.11; H2O, 0.67.
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[CH:15]=[C:14]([F:16])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[C@H:5]([OH:17])[C@@H:4]1[OH:18].C1CCCCC=1.C(N(CC)CC)C>C(O)CCC.[Pd]>[F:16][C:14]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:6]1[O:7][C@H:3]([CH3:2])[C@@H:4]([OH:18])[C@H:5]1[OH:17]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1=CCCCC1
Solvent: CCCCO
Product: C[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Temperature: 60 °C
Yield: 68 %

Procedure:
To a suspension of 10 g (0.026 m) of 5′-deoxy-5′-iodo-5-fluoro uridine, obtained as described in Example 2, step A, in 100 ml of n-butanol, 6 ml of cyclohexene (0.06 m) and 14 ml (0.1 m) of triethylamine are added. The mixture is heated to 60° C. in order to achieve a complete solubilization, then 1.5 g of 5% Pd/C are added thereinto. The suspension is heated at 80° C. for 5 hours, filtered at the same temperature by washing with hot n-butanol and concentrated under vacuum until a residue is obtained, which crystallizes with a mixture of 60 ml of ethanol and 40 ml of isopropanol. Thus, 4.5 g of 5′-deoxy-5-fluorouridine are obtained. M.p.=188÷189° C., purity (HPLC)=99.87% and [α]D=18.35° (c=0.42, H2O).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1>[CH3:16][C:14]1([CH3:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:11][C:12](=[O:17])[CH2:13]1
Reactant: CC(C)=CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
AlCl3 (500 g, 3.8 mol) was carefully added to a suspension of 3-methyl-but-2-enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000 mL). The reaction mixture was stirred at 80° C. overnight and poured into ice-water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with water (200 mL×2) and brine (200 mL), dried over Na2SO4 and concentrated to give 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (90 g, 86%).
Reaction SMILES: [N:1]1[C:5](=[C:6]2[N:10]=[N:9][N:8]=[N:7]2)[N:4]=[N:3][N:2]=1.C(=O)([O-])[O-].[NH4+:15].[NH4+].[Cu:17]>O>[N:1]1[C:5](=[C:6]2[N:10]=[N:9][N:8]=[N:7]2)[N:4]=[N:3][N:2]=1.[NH4+:15].[NH4+:1].[Cu+2:17]
Reactant: [Cu]
Agent: N1=NC(=C2N=NN=N2)N=N1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: [Cu+2]
Temperature: 90 °C
Reaction time: 1 h

Procedure:
In this Example, 49.88 grams of bitetrazole were suspended in 100 ml of water. Subsequently, 53.31 grams of copper diammonium carbonate were slowly added to the reaction mixture and the reaction mixture was allowed to off-gas. The resulting reaction mixture was then heated to 90° C. and held at that temperature for approximately 1 hour. A solid was formed that was filtered, washed with water, filtered again and then vacuum oven dried at 80° C. The resulting solid was in a yield of 80.45 grams as compared to the theoretical yield of 79.69 grams. (NOTE: The greater than theoretical yield is believed again attributable to incomplete conversion of the starting materials during processing.) TABLE 2, below, identifies the elemental chemical analysis of the material formed as well as the elemental chemical analysis for a corresponding theoretical composition of CuC2H6N10. The x-ray diffraction pattern obtained for a powder sample of the material of Example 3 is shown in FIG. 3.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: C1=COCCC1
Reactant: COCc1cc(O)cc(O)c1C=O
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a mixture of 2,4-dihydroxy-6-methoxymethyl-benzaldehyde (2.62 g, 14.45 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (2.42 g mL, 28.90 mmol) and pyridium p-toluenesulfonic acid (0.050 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (3.06 g, 80%). 1H NMR (400 MHz, CDCl3) δ 12.30 (s, 1H), 10.10 (s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 5.47 (s, 1H), 4.60 (s, 2H), 3.80 (m, 1H), 3.60 (m, 1H), 3.40 (s, 3H), 2.00-1.50 (m, 6H).
Reaction SMILES: [C:1]([O:9]C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C2=C3C(=CC=C2)C=CC=C3C=1>C(#N)C>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: C1=Cc2cccc3cccc1c23
Solvent: CC#N
Product: O=C(O)c1ccccc1

Procedure:
All reactions were run on a 10 mL scale at room temperature for a total of 5.00 min. The benzoic anhydride and internal standard were added from a stock solution which was 1.0M benzoic anhydride and 25,000 pm acenaphthylene in 100% acetonitrile. A total of 5.0 μL of this stock was used (yielding a 1:2000 dilution) to make each reaction 0.5 mM benzoic anhydride and 25 ppm acenaphthylene. Benzoic acid produced was measured by HPLC (high pressure liquid chromatography) using the acenaphthylene internal standard as a reference.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1,2-Difluoro-4-nitrobenzene (21.6 g) and phenol (14.0 g) were dissolved in 100 mL of DMF and cooled to 0° C. NaH (6.5 g) was added portionwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was taken up in EtOAc and washed with water and brine, and dried over Na2SO4. The solution was concentrated to provide 2-fluoro-4-nitro-1-phenoxybenzene as an oil, which was used in Step B without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 2.5 h

Procedure:
4-Methylbenzenesulfonyl chloride (8.83 g, 46.32 mmol) was added to a solution of tert-butyl (2R)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (5.48 g, 27.24 mmol) in pyridine (25 ml). The reaction mixture was stirred for 2.5 hrs, after which time the reaction was diluted with ethyl acetate (100 ml) and washed with water (100 ml), saturated copper sulphate solution (100 ml), dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate:pentane (20:80) as the eluant to afford the title compound as a clear oil, 9.2 g, (95%).
Reaction SMILES: [C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:14][CH2:13][CH2:12][C@@H:9]1[CH2:10][O:11][S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
To a solution of (R)-Boc-prolinol (500 mg, 2.48 mmol) in pyridine (1.5 mL) was added tosyl chloride (565 mg, 2.96 mmol) in pyridine (1 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 20 min. before allowing it to warm to rt. The mixture was stirred for 8 h at that temperature. The solvent was removed from the resulting suspension, and aq. 1N HCl was added to the crude product and extracted with EtOAc. Organic layer was washed with saturated aq. NaHCO3 followed by water and brine. Organic layer was dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the title product (800 mg, 91%) as a thick oil: MS; m/z 378 (M+Na); 1H NMR (400 MHz, CDCl3); δ 1.38 (m, 9H), 1.79 (m, 2H), 1.93 (m, 2H), 2.44 (s, 3H), 3.26-3.32 (m, 3H), 3.88-3.97 (m, 2H), 4.07-4.14 (m, 2H), 7.34 (br s, 2H), 7.77 (d, 2H, J=8.0 Hz); HPLC (ELSD); 99%.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14](I)=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[Cl:18][C:19]1[S:20][CH:21]=[C:22]([Cl:24])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.CC1OCCC1>CC(N(C)C)=O>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:16])[C:14]([C:21]3[S:20][C:19]([Cl:18])=[N:23][C:22]=3[Cl:24])=[C:10]2[N:9]=[C:8]([CH3:17])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Clc1csc(Cl)n1
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Cl)nc3Cl)c(C)nn12
Temperature: 70 °C
Yield: 87.3 %

Procedure:
7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (10 g, 29.17 mmoles), 2,4-dichlorothiazole (5.2 g, 33.76 mmoles), cesium carbonate (19.9 g, 61.07 mmoles) and 1,10-phenanthroline (1 g, 5.5 mmoles) are charged into a 250 mL 3-necked round bottomed flask, followed by 2-MeTHF (36 mL, 3.6 volumes). The reaction mixture is degassed with nitrogen and then evacuated. Cuprous chloride (0.57 g, 5.7 mmoles), DMAC (10 mL, 1 volume) and 2-MeTHF (4 mL, 0.4 volumes) are added in succession. The reaction mixture is degassed with nitrogen and then evacuated. The contents are refluxed for 20 hr. The reaction mixture is cooled to ˜70° C. and 2-MeTHF (100 mL, 10 volumes) is added. The contents are filtered at ˜70° C. and the residual cake is washed with 2-MeTHF (80 mL, 8 volumes) at about 65-72° C. The filtrate is transferred into a separatory funnel and extracted with water. The organic layer is separated and washed with dilute HCl. The resulting organic layer is treated with Darco G60, filtered hot (60° C.). The filtrate is concentrated at atmospheric pressure to ˜2.8 volumes. 25 mL 2-propanol is added, followed by re-concentration to ˜2.8 volumes. An additional 25 mL 2-propanol is added, followed again by re-concentration to ˜2.8 volumes. Finally, 48 mL 2-propanol is added. The contents are cooled to −7° C., maintained at −7° C. for 1 hr., filtered and rinsed with 20 mL chilled 2-propanol. Product is suction dried and then vacuum dried at 60° C. to afford 9.41 g 7-(1-ethyl-propyl)-3-(2,4-dichloro-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (purity of product by HPLC assay is 95.88%). MS (ES)=369 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21]CC3C=CC=CC=3)=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13]1>C(O)C>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][NH:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13]1
Reactant: Cc1cn(NCCCc2ccncc2F)c2ccc(OCc3ccccc3)cc12
Solvent: CCO
Product: Cc1cn(NCCCc2ccncc2F)c2ccc(O)cc12
Yield: 41.2 %

Procedure:
1-[(3-Fluoro-4-pyridinyl)propylamino]-3-methyl-5-(phenylmethoxy)-1H-indole (15.8 g) was dissolved in absolute ethanol (200 ml) and hydrogenated at 344.74 Kpa (Parr shaker, 50 psi) at 50° C. for seven and one-half hours. Thereafter, the mixture was filtered and the solids were washed with absolute ethanol. The combined filtrates were concentrated and the residue was purified via preparative HPLC (silica, 3:1 dichloromethane/ethyl acetate) to afford an oil (5.0 g) Addition of ethyl acetate solidified the product which was recrystallized from ethyl acetate to give a solid, m.p. 157°-160° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH:15]2[CH2:17][CH2:16]2)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.Cl[Pd]Cl>[Cl:18][C:19]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([CH:8]([CH:15]3[CH2:17][CH2:16]3)[NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Yield: 84.9 %

Procedure:
A mixture of N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (5 g, 15.66 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (as prepared in Example 1, step 1; 4.13 g, 15.66 mmol), sodium carbonate (15.66 mL, 31.3 mmol) and PdCl2 (dppf).CH2Cl2 adduct (0.320 g, 0.392 mmol) in DMF (100 mL) was heated to 100° C. for 25 min. After concentration, the residue was dissolved into CH2Cl2 and filtered through a pad of Na2SO4. The solution was absorbed into celite and concentrated. The residue was purified by flash column (ethyl acetate/heptane, 30%-50%-80%, v/v) and yielded the title compound as a colorless solid (5.0 g). Chiral separation by chiral HPLC (Chiralpak AD-H using Supercritical fluid chromatography. 25% Methanol at 65 grams per minute with supercritical CO2) afforded enantiomer 1 (S)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=3 min), and enantiomer 2 (R)—N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (retention time=4 min). ESI-MS m/z: 376.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ 0.37-0.40 (m, 1H), 0.51-0.55 (m, 1H), 0.57-0.68 (m, 1H), 0.70-0.77 (m, 1H), 1.15-1.27 (m, 3H), 2.70-2.88 (m, 2H), 3.85 (dd, J=5 Hz, 9 Hz, 1H), 4.68 (d, J=5 Hz, 1H), 7.53 (dd, J=1.5 Hz, 8 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.73 (d, J=8 Hz, 1H), 7.80 (t, J=2 Hz, 1H), 8.67 (d, J=2 Hz, 1H), 8.72 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[C:10](=O)[NH:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][NH:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCC2CCC1N2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2C3CCC2CNC3)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
8-Benzyl-3,8-diazabicyclo[3.2.1]octan-2-one (5.87 g, 27.1 mmol) in dry tetrahydrofuran (40 mL) was treated with 1M lithium aluminum hydride in THF (81.4 mL), heated at 60° C. for 2 hours, and then allowed to cool to room temperature and stir overnight. The mixture was cooled to 0° C. and treated in succession with water (4.4 mL), tetrahydrofuran (200 mL), 15% sodium hydroxide solution (4.4 mL), and water (13.3 mL). The mixture was filtered and the filter cake was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z: 203 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([CH2:24][OH:25])=[C:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH:29]([CH3:31])[CH3:30])[C:19]=2[CH2:32][OH:33])=[CH:14][CH:13]=1>CS(C)=O.ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([CH:32]=[O:33])=[C:20]([CH:29]([CH3:31])[CH3:30])[N:21]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:23]=2[CH:24]=[O:25])=[CH:14][CH:13]=1
Reactant: CC(C)c1nc(C(C)C)c(CO)c(-c2ccc(F)cc2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)c1nc(C(C)C)c(C=O)c(-c2ccc(F)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To solution of 16 ml (0.18 mol) oxalyl chloride in 150 ml dry diohloromethans was added, et -78° C., 40 ml dimethyl sulfoxide over a period of 5 minutes. After 10 minutes, 26 g (0,082 mol) of the product of step 3 in 200 ml of 1:3 solution dimethyl sulfoxide/dichloromethane was added dropwise. This reaction mixture was stirred at -78° C. for 20 minutes, before it was quenched with 80 ml triethylamime. The cooling bath was removed and the reaction was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate (500 ml) and 1N hydrochloric acid (200 ml). The organic layer was washed With water (4×100 ml) and brine and dried over magnesium sulfate and filtered. Evaporation of the filtrate in vaouo gave 24.5 g of the Step 4 title product as a viscous oil which was used without further purification.
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].[CH3:29][S:30]([OH:33])(=[O:32])=[O: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].[S:30]([O-:33])(=[O:32])(=[O:31])[CH3:29]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
3.79 g of Donepezil is dissolved in 70 ml of ethyl acetate, and a solution of methanesulfonic acid (0.65 ml) in absolute ethanol (35 ml) is slowly added with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 181.9° C.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][S:4]([OH:7])(=[O:6])=[O:5].NCCNCCNCCNCCN>O>[CH3:3][S:4]([O-:7])(=[O:6])=[O:5].[Zn+2:2].[CH3:3][S:4]([O-:7])(=[O:6])=[O:5]
Reactant: CS(=O)(=O)O
Agent: NCCNCCNCCNCCN
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: CS(=O)(=O)[O-]

Procedure:
A solution of zinc methanesulfonate was prepared from 7 parts zinc oxide, 22.6 parts of a 70% aqueous solution of methanesulfonic acid and 41.4 parts water. To this solution was added 15.5 parts tetraethylenepentamine over a one hour period. A solution of 375.5 parts Example 1 product in 176.7 parts Promor oil was added, and the materials were reacted at 150° C. for two hours under a vacuum of 2 mm of mercury. The product, after dilution with 160.7 parts Promor oil, and filtration, contained 0.40% nitrogen, 0.45% zinc and 0.36% sulfur.
Reaction SMILES: C(=O)([O-])[O-].[Cu+2:5].[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].C(=O)=O>O>[CH3:6][S:7]([O-:10])(=[O:9])=[O:8].[Cu+2:5].[CH3:6][S:7]([O-:10])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Product: CS(=O)(=O)[O-]

Procedure:
190 g copper carbonate was introduced into approximately 0.7 L ion-exchanged water. The solution was stirred and converted into a slurry and methanesulfonic acid was then added in small portions. The copper carbonate underwent dissolution with the production of carbon dioxide and finally underwent complete dissolution to yield an aqueous copper methanesulfonate solution having a copper concentration of 100 g/L. The pH of the obtained aqueous copper methanesulfonate solution was 2.9.