Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]([CH3:7])=[O:6])=O.C(N(CC)CC)C.C(O)C=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:5]([O:4][CH2:2][CH:1]=[C:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH:27]=[CH:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1)(=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=CCO)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC=C1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.24 ml of acetanhydride, 0.36 ml of triethylamine and 50 mg of 4-dimethylaminopyridine are added to 400 mg of the pregna-1,4,17(20)-triene-21-ol-3-one produced in accordance with Example 1 in 10 ml of absolute methylene chloride, followed by stirring for 30 minutes at 0° C. A thin-layer chromatogram shows that the reaction is quantitative after this period. The reaction solution is successively washed with ice-cold dilute HCl, NaHCO3 solution and finally with water. The CH2Cl2 phase is dried over Na2SO4, the drying agent is filtered off and the residue is concentrated to dryness. The residue is substantially pure product in a yield of more than 90%. 1H-NMR (80 MHz, COCl3 ; δ-value):
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
To a solution of 5-chloro-2-nitroaniline (50 g, 289.74 mmol) in AcOH (200 ml) was added NIS (63 g, 280.02 mmol) with stirring overnight at room temperature. Then the solids were collected by filtration and washed with water (50 ml). The solid was dried in an oven under reduced pressure to afford 5-chloro-4-iodo-2-nitroaniline as a yellow solid (70 g, 81%). Next, to a solution of 5-chloro-4-iodo-2-nitroaniline (15 g, 50.26 mmol) in dioxane (200 ml) and water (20 ml) was added (4-chlorophenyl)boronic acid (15.7 g, 100.40 mmol), K3PO4 (21.2 g, 99.87 mmol) and Pd(PPh3)4 (3 g, 2.60 mmol) with stirring for 6 h at 95° C. maintained with an inert atmosphere of nitrogen. Then the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 5%˜10% ethyl acetate in petroleum ether to afford 5-chloro-4-(4-chlorophenyl)-2-nitroaniline as a yellow solid (9 g, 63%). To a solution of 5-chloro-4-(4-chlorophenyl)-2-nitroaniline (12 g, 42.39 mmol) in ethanol (150 ml) was added hydrogen chloride (conc, 10 ml) to this was followed by the addition of Zn powder (16.6 g, 253.34 mmol) in portions at room temperature. The resulting solution was stirred for 4 h at 85° C. Then the resulting mixture was concentrated under vacuum, dissolved in water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine as an off-white solid (8.7 g, 81%). Finally, a solution of 4-chloro-5-(4-chlorophenyl)benzene-1,2-diamine (7 g, 27.65 mmol) in heptafluorobutanoic acid (70 ml) was stirred for 1.5 h at 120° C. Then the mixture was poured into water (200 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to afford 5-chloro-6-(4-chlorophenyl)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as an off-white solid (7.3977 g, 62%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)Oc1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1cccc2cccnc12)C(=O)O
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.4 mmol) in EtOH (1 ml) was added a solution of NaOH (24 mg, 0.6 mmol) in H2O (0.5 ml) at 27° C. The mixture was stirred for 30 min at 27° C. The mixture was then concentrated and the residue treated with water (5 mL) and extracted with ethyl acetate (2×5 mL). The water layer was then treated with 2N HCl until pH 3 before being extracted with ethyl acetate (2×5 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title product (70 mg, 80.5%) as a white solid which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][C:16]2[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]([CH3:12])[C:10]=2[CH:11]=1.[CH:27](=O)[CH2:28]C>>[CH2:27]([N:15]([C:3]1[C:2]([CH3:1])=[CH:11][C:10]2[C:9]([CH3:12])=[CH:8][CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=2[CH:4]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)[CH3:28]
Reactant: CCC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Yield: 43 %

Procedure:
Following General Procedure D, ethyl 4-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-ylamino)benzoate (Compound 39, 0.085 g, 0.24 mmol) was reacted with propionaldehyde (180 μL, 2.4 mmol) to give 0.039 g (41%) of the title compound as a clear oil.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](N)=[N:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N([O-])=[O:21].[Na+]>O.C(O)(=O)C>[CH2:2]([N:9]1[C:17]2[C:16](=[O:18])[NH:15][C:14](=[O:21])[NH:13][C:12]=2[N:11]=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
35.9 g (0.13 mol) of 7-benzylguanine hydrochloride from stage a) were dissolved in a mixture of 90 ml of water and 807 ml of glacial acetic acid and heated to 100° C. After cooling to 50° C., a solution of 35.88 g (0.52 mol) of sodium nitrite in 90 ml of water was added in one portion. After 16 hours at room temperature, the resulting precipitate was filtered off with suction, washed with water on the suction filter and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([C:14]#[N:15])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:14]#[N:15])([C:10]([O:12][CH3:13])=[O:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C#N)Cc1cccc(Cl)c1
Reactant: COC(=O)CBr
Product: COC(=O)CC(C#N)(Cc1cccc(Cl)c1)C(=O)OC

Procedure:
In the same manner as Example 1-(b), 26.5 g of methyl 3-(3-chlorophenyl)-2-cyanopropionate was reacted with methyl bromoacetate to obtain methyl 4-(3-chlorophenyl)-3-cyano-3-methoxycarbonylbutyrate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:30][CH2:29][C:7]2([O:11][CH2:10][C:9]([C:12]3[C:13]([O:27][CH3:28])=[N:14][CH:15]=[C:16]([N:18]4[C:22]([C:23]([F:26])([F:25])[F:24])=[N:21][N:20]=[N:19]4)[CH:17]=3)=[CH:8]2)[CH:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:30][CH2:29][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[C:13]([O:27][CH3:28])=[N:14][CH:15]=[C:16]([N:18]4[C:22]([C:23]([F:24])([F:25])[F:26])=[N:21][N:20]=[N:19]4)[CH:17]=3)[CH2:8]2)[C@@H:6]1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:4]
Reactant: COC(=O)C1CCC2(C=C(c3cc(-n4nnnc4C(F)(F)F)cnc3OC)CO2)C1c1ccc(F)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(-n4nnnc4C(F)(F)F)cnc3OC)CO2)[C@@H]1c1ccc(F)cc1

Procedure:
The title compound was prepared by hydrogenation with H2 in methanol over 20% palladium hydroxide of 6-(4-fluorophenyl)-3-[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-pyridin-3-yl]-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester by the method given in Example 6, Step G. H NMR (400 MHz, CDCl3): δ 7.435(d, J=3 Hz,1H);7.20-7.28(m, 2H); 6.78-6.85(m, 2H); 6.503(d, J=3 Hz, 1H); 4.12(t, J=7 Hz 1H); 3.67 (m, 1H); 3.55(s,3H); 3.53(s, 3H); 3.27-3.45(m, 1H); 3.15-3.20(m,1H); 3.10(t, J=8 Hz, 1H); 2.25-3.33(m, 2H); 2.15-2.24(m, 1H); 1.85-2.0(m, 2H); 1.69(dd, J=13 Hz, J=9 Hz, 1H). Mass spectrum: 522 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:26]([F:29])([F:28])[F:27])[C:6]=1[CH3:30].[OH-].[Na+]>CO.C1COCC1>[CH2:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]2[CH3:30])=[C:16]([C:26]([F:28])([F:29])[F:27])[CH:17]=1)(=[O:23])=[O:22])[CH3:25]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of [1-(4-ethanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.6 g, 1.32 mmol) in methanol/THF (8 ml of a 1:1 mixture) is added 1M NaOH (3 ml). After stirring at room temperature for 1.5 hours, the solvent is removed in vacuo and the residue is dissolved in water (3 ml). The solution is acidified to pH1 using 6M HCl and the resulting suspension is filtered and dried to yield the titled product. (MH+ 441)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C(Cl)(Cl)Cl>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[S:11][C:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Reactant: O=C(O)c1cccnc1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc2sc(-c3cccnc3)nc2c1
Yield: 44 %

Procedure:
2-Amino-4-nitrobenzenethiol,17 g, 0.10 mole, and nicotinic acid, 18.7 g, 0.15 mole, are heated 2 hours at reflux in 250 cc of CHCl3 containing 100 g of PPE. The solution is concentrated in vacuo, and the residue slurried in H2O. The pH is adjusted to 11 with 50% NaOH solution. The precipitate is filtered, washed with H2O and dried in vacuo to yield 11.2 g of tan solid m.p. 196°-198°, 44% of theory.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>C(Cl)Cl>[C:18]1([CH2:24][CH2:25][CH2:26][NH:27][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCc1ccccc1
Reactant: NC(=O)c1ccc(OC2CCC(=O)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(OC2CCC(NCCCc3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 83.4 %

Procedure:
Combine 4-(4-oxo-cyclohexyloxy)-benzamide (20 mg, 0.085 mmol), 3-phenyl-propylamine (11 mg, 0.085 mmol), triacetoxyborohydride (23 mg, 0.111 mmol) and acetic acid (5 μL, 0.085 mmol) in CH2Cl2 (1 mL). Let stir overnight. Purify by SCX column (ammonia in methanol 2.0M). Triturate the residue with EtOAc/hexanes 1/1 to provide a white powder (25 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NCCN1CCOCC1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCCN3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL) was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 4-(2-aminoethyl) morpholine (15 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (17 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C27H38ClN5O5S [M+] 579.2, found 580.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.99-1.11 (m, 2H, CH2), 1.37-1.85 (m, 8H, 4×CH2), 2.05-2.18 (m, 1H, CH), 2.25-2.37 (m, 6H, 3×NCH2), 2.57 (t, J=6.4 Hz, 2H, COCH2), 3.18 (s, 3H, SO2CH3), 3.21 (q, J=5.4 Hz, 2H, CONCH2), 3.47 (t, J=7.5 Hz, 1H, CH), 3.50-3.58 (m, 4H, 2×OCH2), 4.23 (t, J=6.4 Hz, 2H, NCH2), 5.94 (brm, 1, NH), 6.50 (d, J=2.3 Hz, 1H, Ar), 7.22 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.51 (d, Jm=1.7 Hz, 1H, Ar), 7.84 (s, 1H, NH), 8.00 (d, Jo=8.2 Hz, 1H, Ar).
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:36])(=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]>CC(C)=O.O>[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-:36])(=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of succinic acid (0.59 g) in acetone (35 ml) and water (5 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: 169.2° C.
Reaction SMILES: [OH:1][N:2]=[CH:3]/[C:4](/[CH3:18])=[CH:5]/[C@@H:6]1[C@@H:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7]1([CH3:17])[CH3:16].I[CH2:20][CH2:21][CH3:22].[OH-].[Na+].Cl>CN(C)C=O>[CH3:16][C:7]1([CH3:17])[C@H:6](/[CH:5]=[C:4](\[CH3:18])/[CH:3]=[N:2][O:1][CH2:20][CH2:21][CH3:22])[C@H:8]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C/C(C=NO)=C\[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.58 g of t-butyl (1R)-trans-3-[(E)-3-hydroxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate, 2.0 g of 1-iodopropane and 10 ml of anhydrous dimethylformamide (hereinafter, abbreviated as DMF) was added 0.10 g of sodium hydroxide (60% dispersion in mineral oil) and the mixture was stirred at room temperature overnight. Thereafter, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.56 g of t-butyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-propoxyimino-1-propenyl]cyclopropanecarboxylate:
Reaction SMILES: [C@H:1]12[CH2:17][C@H:4]([N:5](C(OCC3C=CC=CC=3)=O)[CH2:6]1)[CH2:3][S:2]2(=[O:19])=[O:18].[BrH:20]>>[BrH:20].[C@H:1]12[CH2:17][C@H:4]([NH:5][CH2:6]1)[CH2:3][S:2]2(=[O:19])=[O:18]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2C[C@H]1CS2(=O)=O
Agent: Br
Product: O=S1(=O)C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
(1S,4S)-benzyl 2-thia-5-azabicyclo[2.2.1]heptane-5-carboxylate 2,2-dioxide (1.4 g, 4.98 mmol) was treated with hydrobromic acid (33% in acetic acid) (20 mL, 116 mmol) and stirred at rt. After 18 h, a white precipitate was filtered, washed with glacial acetic acid (5 mL), and dried under reduced pressure to give (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, hydrobromide (1.01 g, 85% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (br. s., 2H), 4.60 (br. s., 1H), 4.15 (br. s., 1H), 3.67-3.51 (m, 2H), 3.49-3.32 (m, 2H), 2.34 (d, J=13.2 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 57.7, 56.7, 55.3, 44.2, 33.5.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CS(O[CH2:21][CH:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])(=O)=O>C1(C)C=CC=CC=1>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([CH2:21][CH:22]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CC(COS(C)(=O)=O)OS(C)(=O)=O
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(CC(C)OS(C)(=O)=O)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 18.4 %

Procedure:
1.0 g of a 80% mineral oil dispersion of sodium hydride is added in small portions, at room temperature, to a mixture of 6.0 g (30 mmoles) of N-(2,6-dimethylphenyl)-methanesulfonamide and 100 ml of dry toluene, and the resulting mixture is heated to 100° C. within 0.5 hours. 7.0 g (30 mmoles) of 1,2-bis(methanesulfonyloxy)-propane are added to the mixture at 100°-105° C. within one hour, and the reaction mixture is stirred at the same temperature for 5 hours. The mixture is cooled, washed thrice with 20 ml of water, twice with 25 ml of 1 n aqueous sodium hydroxide solution and then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The resulting oily substance, weighing 5.9 g, is triturated with diethyl ether to obtain 4.4 g (44%) of a crude, solid product, m.p.: 70°-80° C. The crude product is recrystallized twice from isopropanol to obtain 1.85 g (18.5%) of 1-[N-(2,6-dimethylphenyl)-methanesulfonamido]-2-methanesulfonyloxy-propane, m.p.: 117°-120° C. This compound is identical with the product obtained according to Method (A).
Reaction SMILES: [OH-].[K+].O.O.NN.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH:26]=1>C(O)COCCO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:13][C:12]=2[CH:26]=1
Reactant: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(Cc2cc3cc(Br)ccc3o2)cc1
Yield: 82.5 %

Procedure:
5.07 g of potassium hydroxide was added to 30 ml of diethylene glycol, and the mixture was stirred at room temperature during which 5.5 g of 80% hydrazine dihydrate.2H2O and 5.0 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran were further added. The thus prepared mixture was refluxed under heating. After cooling, the resulting reaction solution was adjusted to pH 4-5, extracted with benzene, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/isopropanol mixture as an elution solvent, thereby obtaining 3.95 g of 5-bromo-2-(4-methoxybenzyl)benzofuran as a brown oily material.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][OH:36])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][O:36][S:43]([C:40]2[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=2)(=[O:45])=[O:44])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the compound (4) (25.1 g, 51.2 mmol) in anhydrous pyridine (250 ml) were added p-toluenesulfonyl chloride (14.6 g, 1.5 equivalents) and 4-dimethylaminopyridine (626 mg, 0.1 equivalents), and the reaction liquid was stirred at room temperature for 16 hours. After the sufficient progress of the reaction was confirmed, water (10 ml) was added to stop the reaction, and the reaction liquid was concentrated under reduced pressure. The residue was suspended in a minor amount of ethyl acetate, poured to 0.5 M hydrochloric acid (200 ml), and extracted with ethyl acetate (3×200 ml). The organic layers were combined, washed with a saturated sodium hydrogen carbonate solution (2×100 ml) and saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was crystallized twice from heated ethanol to obtain the title compound (5) in the form of colorless needle crystals (25.0 g). The filtrate was concentrated, purified with silica gel chromatography (hexane-ethyl acetate, 5:1→4:1→3:1) to obtain the compound (5) (4.00 g). {29.0 g (45.0 mmol) in total, 87.9%}.