Azzindani/Open_Reaction_Data huggingface dataset:
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][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1C(=CC=O)c1ccccc1OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)/C=C/C=C(c1ccccc1OC)c1ccccc1OC
Yield: 75.7 %

Procedure:
In the manner described in Example 99, 3,3-bis(2-methoxyphenyl)-2-propenal (7.1 g) was reacted with (carbomethoxymethylene) triphenylphosphorane (9.7 g) in carbon tetrachloride (60 ml) and dichloromethane (20 mL) for 3 days at room temperature and then overnight at reflux. The crude ester isolated in the normal manner was crystallized from 2-propanol-hexane to yield 6.5 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid methyl ester, mp 100°-102° C. A portion was recrystallized from the same solvents to furnish the analytical sample, mp 101°-102° C. Anal. Calcd for C20H20O4 : C, 74.06: H, 6.21. Found: C, 73.83; H, 6.23.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=3)[CH2:12][O:11]2)=[CH:6][CH:5]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl.CS(C)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[C:18]2[C:13](=[CH:14][C:15]([C:19]#[N:20])=[CH:16][CH:17]=2)[CH2:12][O:11]1
Reactant: CN(C)CCCCl
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
60% Sodium hydride (0.92 g) was dispersed in THF (30 ml). To the obtained suspension was added dropwise a solution of 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.80 g) in THF (10 ml) at 40-50° C. The mixture was stirred at the same temperature for 30 min, and a solution of 3-dimethylaminopropyl chloride (3.2 g) in toluene (20 ml) was added dropwise, which was followed by stirring for 10 min. Then, dimethyl sulfoxide (30 ml) was further added dropwise and the mixture was stirred at 65-70° C. for 3 hr. The reaction mixture was poured into ice water (200 ml) and extracted 3 times with toluene (60 ml). The organic layer was extracted twice with 20% aqueous acetic acid (60 ml). The aqueous layer was neutralized, extracted twice with toluene (60 ml) and washed with water. Anhydrous potassium carbonate (2 g) and silica gel (2 g) were added and the mixture was stirred and filtered. The solvent was evaporated to give 1-(3′-dimethylaminopropyl)-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (citalopram base) as a viscous oil (3.37 g, 51.6%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH3:2].CS(C)=O.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:31][CH2:30][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3ccc(C(=O)O)cc3nc21
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3ccc(C(=O)O)cc3nc21

Procedure:
A mixture of 1-ethyl-4-chloro-7-carboxy-1H-pyrazolo[3,4-b]quinoline (0.9 g, 3.3 mmol), DMSO (9 ml) and cyclohexanemethyl amine (0.86 ml, 6.6 mmol) was heated at 120°-130° C. for 6 hours. The reaction mixture was poured into water, acidified with acetic acid and the solid which formed was collected by filtration, dissolved in 5% NaOH and extracted with CH2Cl2 (2×50 ml). The aqueous layer was acidified with acetic acid and the solid which formed was collected by filtration and washed with water. The solid was purified by column chromatography on silica gel eluting with 30% methanol/10% acetic acid/60% CH2Cl2 to afford 1-ethyl-7-carboxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[BH-:16](O[C:26]([CH3:28])=O)(OC(C)=O)OC(C)=O.[Na+:29].C(Cl)Cl>CO>[BH4-:16].[Na+:29].[CH2:8]([NH:15][CH:28]1[CH2:26][N:15]2[C:6]3[C:1]([CH:7]=[C:8]2[CH2:9][CH2:10]1)=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccccc1
Reactant: NCc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: [BH4-]
Product: c1ccc(CNC2CCc3cc4ccccc4n3C2)cc1

Procedure:
Hydrogenation of the obtained (E)-ethyl 3-(1-(2-(tert-butoxy)-2-oxoethyl)-1H-indol-2-yl)acrylate derivatives (4) over a catalyst such as Pd—C 10% or PtO2 in an aprotic solvent such as EA followed by reaction with KOtBu in an aprotic solvent such as THF gives the corresponding tert-butyl 7-oxo-6,7,8,9-tetrahydropyrido[1,2-a]indole-6-carboxylate derivatives (5). Decarboxylation by reaction with silica gel in an aprotic solvent such as toluene and subsequent reductive aminations with, first, benzylamine in the presence of a reducing agent such NaBH(OAc)3 in an aprotic solvent such as DCM, and with, second, an appropriate aldehyde (as precursor of R3) in the presence of a reducing agent such NaBH4 in a protic solvent such as MeOH gives the corresponding N-benzyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-7-amine derivatives (6). Friedel-Craft acylation with oxalyl chloride in an aprotic solvent such as DCM, followed by esterification with MeOH and subsequent reduction with triethylsilane in the presence of TFA gives the corresponding methyl 2-(7-(benzylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (7). Debenzylation by hydrogenation over a catalyst such as Pd—C 10% in a protic solvent such as EtOH or by reaction with 1-chloroethyl chloroformate and MeOH in an aprotic solvent such as DCM gives the respective N-substituted methyl 2-(7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate derivatives (8). Reaction with an appropriate heteroaryl halide like R4—Cl in the presence of a base such as K2CO3 in an aprotic solvent such as DMA followed by saponification with a base such as NaOH furnished the compounds of formula (I) (Method A).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:11]3[CH2:12][CH2:13][C:14](=[O:19])[C:15]=3[CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: O=C1CCc2c(O)cccc21
Reactant: Clc1cncc(Cl)n1
Solvent: CCOC(C)=O
Product: O=C1CCc2c(Oc3cncc(Cl)n3)cccc21
Yield: 90 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (314 mg). Yield: 90%. 1H NMR (250 MHz, DMSO-d6) δ 2.70 (t, 2H, H3, J=5.7 Hz), 2.94 (t, 2H, H2, J=5.7 Hz), 7.55-7.64 (m, 3H, Harom), 8.57 (s, 1H, HPz 5), 8.66 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:11].[C:12](=O)([O-])[O-].[K+].[K+].COS([O:23][CH3:24])(=O)=O>CC(C)=O>[CH3:12][O:11][C:3]1[C:2]([CH3:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:23][CH3:24])=[O:7]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(C)c1OC
Yield: 90.4 %

Procedure:
To a mixture of 3-methyl-salicylic acid (1.32 mol)and anhydrous potassium carbonate (3.6 mol)dissolved in 3.5 L of dry acetone in a 5L round bottle flask, dimethylsulfate (2.2 mol) was added in several times. The mixture was refluxed overnight, and the reaction was monitored by TLC. After filtration of the reaction mixture, the solvents of the filtrate were evaporated and 215 g of a pale yellow thick oil was obtained as the raw product. Yield 91%. 1H NMR (500 MHz, CDCl3, 25° C.) δ: 2.263 (s, 3H, CH3), 3.782 (s, 3H, OCH3), 3.854 (s, 3H, OCH3), 6.984 (t, J=7.5, 1H, ArH), 7.276 (d, J=7.5, 1H, ArH), 7.582 (d, J=7.5, 1H, ArH); 13C NMR (500 MHz, CDCl3, 25° C.) δ: 15.72, 51.81, 61.17, 123.26, 124.36, 128.86, 132.46, 134.88, 158.16, 166.61.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:13]([OH:15])=[O:14])[OH:12].CCCCCCC.C(OCC)(=O)C>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:13]([OH:15])=[O:14])[OH:12]
Reactant: O=C(O)C1(O)CCSc2ccc(Cl)cc21
Solvent: O=CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)[C@@]1(O)CCSc2ccc(Cl)cc21

Procedure:
The enantiomers of 6-chloro-4-hydroxythiochromane-4-yl-carboxylic acid (1.4 g, 5.7 mmol; from step (iii) above) were separated using chiral chromatography (Kromasil TBB; heptane: ethyl acetate: formic acid) yielding 0.500 g (71%) of the slower moving sub-title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C([N:31]([CH2:35]C)[CH:32]([CH3:34])[CH3:33])(C)C.ClC(Cl)(Cl)C[O:40]C(Cl)=O.C1(N)CC1>O1CCCC1.CN(C)C=O>[CH:32]1([NH:31][C:35]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:40])[CH2:33][CH2:34]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Agent: NC1CC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)NC5CC5)cn4c3)c2)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 13.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) and N,N-diisopropylethylamine (286 μL, 1.67 mmol) in tetrahydrofuran (5 mL) was added 2,2,2-trichloroethylchlorocarbonate (130 μL, 0.944 mmol), and the mixture was stirred at room temperature for 50 min. N,N-Dimethylformamide (5 mL) and cyclopropaneamine (290 μL, 4.19 mmol) were added to the reaction mixture, and the mixture was stirred at 80° C. for 11 hr. The reaction mixture was concentrated under reduced pressure, diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0%→100% ethyl acetate-hexane) to give the title compound (51.0 mg, 14%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6]Br)[CH3:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[Na+].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:8])[CH2:5][CH2:6][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.5 %

Procedure:
Ethyl-3-bromoproprionate (3.20 ml; 25 mmol) was added to a mixture of morpholine (2.20 ml; 25 mmol) and Na2CO3 (2.78 g; 26 mmol) in 4.5 ml of EtOH at RT. The mixture was stirred for 30 min at RT and 4 h at reflux. After cooling to RT and filtering, the filtrate was concentrated and the residue was dissolved in H2O. The pH was adjusted to ~1.5 with saturated KHSO4 and the acidic mixture was washed with Et2O. Solid K2CO3 was added to the aqueous layer until a pH of ~9 was reached. The basic mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated to afford 4.75 g (100+%; contained trace solvent) of ethyl-3-morpholinoproprionate as a colorless liquid. A solution of this ester (935 mg; 5 mmol) in 20 ml of Et2O was added to a suspension of LiAlH4 (400 mg; 10 mmol) in 80 ml of Et2O at 0° C. After stirring for 30 min at 0° C., the reaction was quenched by the careful addition of 0.42 ml of H2O followed by 0.42 ml of 15% NaOH and 1.26 ml of H2O. MgSO4 was added and the suspension was filtered and concentrated to afford 531 mg (73%) of Compound 201a as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][S:16]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
tert-Butyl 4-aminopiperidine-1-carboxylate (0.10 g, 0.50 mol) was combined with methanesulfonyl chloride (0.043 mL, 0.56 mol) and triethylamine (0.21 mL, 1.5 mmol) in methylene chloride (2 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give tert-butyl 4-[(methylsulfonyl)amino]piperidine-1-carboxylate, LCMS [M+Na]+: m/z=301.0. The later was treated with 4.57 M hydrogen chloride in 1,4-dioxane (1 mL, 4 mmol) at room temperature for 1 hour. The mixture was concentrated to give the desired HCl salt, which was used directly in the next step. LCMS calculated for C6H15N2O2S (M+H)+: m/z=179.1; Found: 179.1.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[O:14][CH:15]=[CH:16][CH:17]=1>>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: Brc1ccco1
Product: c1ccc(-c2cn(-c3ccco3)cn2)cc1
Yield: 7.4 %

Procedure:
The procedure described above in Example 29 for Formula IIc-iii was followed, starting from 4-phenyl-1H-imidazole (250 mg, 1.73 mmol) and 2-bromofuran, to prepare the desired 1-(furan-2-yl)-4-phenyl-1H-imidazole (27 mg, 0.13 mmol, yield 7.4%) as a brownish solid. The HPLC purity of the final product was 99.8%. LC-MS [M+H] 211 (C13H10N2O+H expected 211.08). The 1H-NMR spectra was in accordance with the chemical structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>CC(C)=O>[CH3:2][CH2:1][NH:3][C:4](=[O:5])[NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])=[CH:12][C:10]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCNC(=O)Nc1nc2cc(OS(=O)(=O)c3cccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A stirred solution of 1-ethyl-3-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (35 mg, example 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetone (3 ml) was treated with triethylamine (25 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester (14 mg) as a off-white solid Mass spectrum: 367 [M+H]+; retention time=7.88 minutes.
Reaction SMILES: C(OCC)(=O)C.C(OC([NH:17][C:18]([NH:30][CH2:31]/[CH:32]=[CH:33]/[C:34]1[CH:94]=[CH:93][C:37]([CH2:38][C:39]2[C:40]([CH3:92])=[CH:41][C:42]([O:84]CC3C=CC=CC=3)=[C:43]([C@@H:45]3[O:74][C@H:73]([CH2:75][O:76]CC4C=CC=CC=4)[C@@H:64]([O:65]CC4C=CC=CC=4)[C@H:55]([O:56]CC4C=CC=CC=4)[C@H:46]3[O:47]CC3C=CC=CC=3)[CH:44]=2)=[CH:36][CH:35]=1)=[N:19]C(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:19][C:18]([NH:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:94]=[CH:93][C:37]([CH2:38][C:39]2[C:40]([CH3:92])=[CH:41][C:42]([OH:84])=[C:43]([C@@H:45]3[O:74][C@H:73]([CH2:75][OH:76])[C@@H:64]([OH:65])[C@H:55]([OH:56])[C@H:46]3[OH:47])[CH:44]=2)=[CH:36][CH:35]=1)=[NH:17]
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCNC(=N)N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a methanol (2.6 mL)-ethyl acetate (1.3 mL) mixture solution of (1S)-1-[5-[4-[(1E)-3-[[benzyloxy carbonyl amino(benzyloxycarbonylimino)methyl]amino]prop-1-en-1-yl]benzyl]-2-(benzyloxy)-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-benzyl-D-glucitol (154 mg, 0.131 mmol) was added 20% palladium hydroxide (160 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was dissolved in methanol (1.5 mL). And 20% palladium hydroxide (63 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. The reaction solution was filtered through celite, and evaporated under reduced pressure to obtain a residue. Thus obtained residue was purified with silica gel column chromatography (ethyl acetate:ethanol:water=10:2:1 then 5:2:1, and then ethanol:water=10:1) to obtain the title compound (38 mg, 63%) as a colorless powder. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([OH:20])[C:18]=1[Br:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (3.69 g, 10.94 mmol) and potassium carbonate (3.03 g, 21.98 mmol) in DMF (27 mL) was added methyl iodide (0.753 mL, 12.04 mmol). The mixture was stirred overnight after which time it was diluted with water and extracted with ethyl acetate (4×). The combined extracts were washed with water (8×), brine, dried over magnesium sulfate and concentrated to provide methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate as a white solid (3.72 g). MS (M+1)=351.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.59 (m, 7H), 5.24 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: C([C:4]1[CH:8]=[CH:7][S:6]C=1)(=O)C.[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.N1CCOC[CH2:20]1.[S]>CC(=O)CC>[NH2:18][C:17]1[S:6][C:7]([CH3:20])=[C:8]([CH3:4])[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: N#CCC(=O)c1ccsc1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccsc1
Agent: [S]
Solvent: CCC(C)=O
Product: Cc1sc(N)c(C(=O)c2ccsc2)c1C
Yield: 38 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 38%; IR (KBr) cm−1: 3337, 3229, 3107, 1576, 1427, 1265, 1162, 855, 736, 719; 1H NMR (CDCl3):δ1.71 (s, 3H), 2.15 (s, 3H), 6.17 (bs, 2H), 7.30 (d, J=2.2 Hz, 2H), 7.63 (t, 1H, J=2 Hz); yellow solid, mp: 122-123° C. (petroleum ether).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])[NH2:8])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:19][C:20]([SH:23])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:19][C:20]1[S:23][N:8]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:9]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 4-methylbenzimidamide hydrochloride (1.55 g, 9.08 mmol) and Et3N (4.6 g, 6.33 ml, 45.4 mmol) in DCM (30 mL) was cooled with a NaCl/ice-bath to −10° C. Perchloromethyl mercaptan (1.86 g, 1.09 ml, 9.99 mmol) in DCM (10 mL) was added during 40 min. The resulting yellow suspension was stirred for 20 min at 0° C. and 2 h at RT. Water (40 mL) and aq. 2N NaOH (10 mL) was added. The organic layer was separated and extracted with brine (50 mL). The aqueous layers were extracted with DCM (2×40 mL). The combined organic layers were dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by silica chromatography (Flash 50 g Si-cartridge using AcOEt: Heptane 1:19 to 1:9.) to yield 5-chloro-3-p-tolyl-1,2,4-thiadiazole (1.63 g, 7.74 mmol, 85% yield) as light yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[CH:17].[NH2:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:24])=[CH:21][C:20]=1[O:35][CH3:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>CO>[CH3:36][O:35][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:19]=1[NH:18][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]#[CH:17])=[CH:11][N:12]=1)[C:23]([NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)=[O:24]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: C#CCN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: C#CCN1CCC(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 150 °C

Procedure:
9-chloro-2-methyl-6-prop-2-ynyl-2,6,8,10-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-3-one (Intermediate 154; 53 mg, 0.21 mmol), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 66 mg, 0.25 mmol) p-toluenesulphonic acid monohydrate acid (80 mg, 0.42 mmol) and isopropanol (4 mL) were combined in a 10 mL microwave reactor tube and heated in by microwave irradiation at 150° C. for 80 minutes. The sample was transferred to an SCX (10 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as an off white gum (4 mg, 3%).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:25]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[CH2:22][CH:21]([CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:28][CH2:29]3)[C:19](=[O:20])[C:14]2=[CH:15][C:16]=1[O:17][CH3:18].[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
Fumaric acid (1.16 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: 168.5° C.