Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19](O)[C:16]=1[CH:17]=[O:18]>CC(C)=O>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:6][CH3:7])[C:16]=1[CH:17]=[O:18]
Reactant: Cc1cc(C)c(C=O)c(O)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C)cc(C)c1C=O
Reaction time: 48 h
Yield: 88.5 %

Procedure:
Dimethylsulfate (16.4 g; 130 mmole) and potassium carbonate (20.7 g; 150 mmole) were added to a solution of 2,4-dimethyl-6-hydroxybenzaldehyde (20.0 g; 130 mmole) in acetone (200 ml). The mixture was heated under reflux with stirring for 48 hours and then evaporated to dryness. The residue was dissolved in dichloromethane and washed successively with water, aqueous sodium hydroxide (1M) and water, and then was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2,4-dimethyl-6-methoxybenzaldehyde (18.9 g; 89.0%). The product was obtained as a brown oil and was characterized by its proton magnetic resonance spectrum, the details of which are recorded in Table 2 below.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]=[N+]=[N-])=[CH:10][CH:9]=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[N:4]=1)[CH3:2]>CO.[Pd]>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH2:16])=[CH:12][CH:13]=2)[C:6]2[CH:19]=[CH:20][CH:21]=[CH:22][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1ccc(CCN=[N+]=[N-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc2ccccc2n1-c1ccc(CCN)cc1
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 2-[4-(2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl azide (990 mg, 3.4 mmol) in methanol (20 mL) was added 10% Pd—C (100 mg). The resulting mixture was stirred for 4 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol/triethylamine (100:5:1) to afford 855 mg (94%) of the title compound as white solids: 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.76 (2H, q, J=7.5 Hz), 2.89 (2H, t, J=6.5 Hz), 3.06 (2H, t, J=6.5 Hz), 7.45-7.06 (7H, m),7.80-7.74 (1H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:27]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)=[O:27])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: OO
Reactant: Nc1c(Br)cc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br
Product: Nc1c(Br)cc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,5-dibromo-4-amino-phenylmercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:15]>>[C:1]1([CH:7]=[C:8]([S:10]([NH2:15])(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CC(=Cc1ccccc1)S(=O)(=O)Cl
Agent: [OH-]
Product: CC(=Cc1ccccc1)S(N)(=O)=O

Procedure:
The 1-phenylpropene-2-sulfonyl chloride is added to 200 ml. of concentrated ammonium hydroxide. After 1 hour the crystalline precipitate which has formed is filtered off, and washed sequentially with water and hexane. The crude product so obtained is partitioned between 150 ml. of 1N sodium hydroxide and 50 ml. of ether, giving two clear phases. The ether phase is removed and washed with 50 ml. of water, and then the water wash is added to the original aqueous phase. This combined solution is acidified using concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off, and after drying this affords 10.9g. of 1-phenylpropene-2-sulfonamide, m.p. 138°-139.5°C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4](I)[CH:3]=1.CN.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]([CH:32]=[O:33])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:32]([NH:30][CH3:29])=[O:33])[CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1I
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
Through a solution of tert-butyl 4-fluoro-2-iodobenzylcarbamate (1.00 g, 2.85 mmol) in dry DMF (20 mL), in an oven dried glass insert in a high pressure bomb reactor flushed with nitrogen, was bubbled methylamine gas at 0° C. until the solution was saturated and excess methylamine was condensed into the reaction (approximately 30 equivalents of methylamine). Diisopropylethylamine (0.99 mL, 5.70 mmol), palladium acetate (64 mg, 0.29 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (158 mg, -0.29 mmol) were added to the saturated solution. The glass insert was then placed in the pressure vessel and the vessel was purged once with carbon monoxide gas. The vessel was recharged with carbon monoxide gas to pressure of 300 psi, placed into an oil bath, and heated to 90° C. for four hours. The vessel was cooled, the gas was released slowly and the resulting mixture was partitioned between water and ethyl acetate. The layers were separated and the organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a brown liquid. The residue was purified by flash column chromatography (ISCO column, 110 g silica gel) eluting with a 10-50% acetone/hexane gradient over 35 minutes to afford the desired product as a brown crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].[F:12][C:13]([F:35])([F:34])[C:14]1[CH:15]=[C:16]2[CH:22]=[C:21]([C:23](O)=[O:24])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:17]2=[N:18][CH:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:11][C:23]([C:21]2[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:17]3=[N:18][CH:19]=[C:14]([C:13]([F:12])([F:35])[F:34])[CH:15]=[C:16]3[CH:22]=2)=[O:24])[CH:5]=[N:6][C:7]=1[N:8]([CH3:9])[CH3:10]
Reactant: CN(C)c1ncc(N)cc1F
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Product: CN(C)c1ncc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)cc1F
Yield: 385.6 %

Procedure:
Compound No. 35 was prepared by a method similar to that described in Stage 1.4 by reacting 0.4 g (1.18 mmol) of 5-fluoro-6-(N,N-dimethylamino)-3-aminopyridine (WO2004/110986), with 0.4 g (0.18 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid obtained in Stage 1.3. We thus obtain 0.33 g of the expected product in the form of a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH3:17])=[O:15].[CH2:18](O)[CH:19]=C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:4][CH:3]1[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Reactant: C=CCO
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O
Yield: 90 %

Procedure:
A solution of 1-tert-butyl 3-methyl 4-oxopyrrolidine-1,3-dicarboxylate (48.65 g, 0.20 mol), allyl alcohol (300 mL), and dibutyltin oxide (5.0 g, 20 mmol) in anhydrous toluene (800 mL) was refluxed for 20 h under a Dean-Stark trap with portionwise removal of solvent (total of 200 mL) over the first 6 hours, followed by addition of more allyl alcohol (75 mL) at the end of the first 6 hours. The reaction mixture was concentrated, dissolved in minimal methylene chloride, and loaded onto a silica gel column (700 mL volume) and eluted with methylene chloride, 10%, then 15%, then 20% ethyl acetate/methylene chloride to afford 3-allyl 1-tert-butyl 4-oxopyrrolidine-1,3-dicarboxylate (48.6 g, 90%) as a pale pink oil (NMR and MS as above). This compound (48.47 g, 0.18 mol) was dissolved in anhydrous tetrahydrofuran (200 mL) and added to a stirred solution of Pd(PPh3)4 (4.16 g, 3.6 mmol) in anhydrous tetrahydrofuran (400 mL) under nitrogen, stirred for 4 h, and concentrated. The residue was dissolved in heptane and loaded onto a silica gel column (1000 mL volume) and eluted with 60:35:5 heptane/methylene chloride/ethyl acetate to afford tert-butyl 3-allyl-4-oxopyrrolidine-1-carboxylate (27.93, 69%) as a pale yellow oil (NMR and MS as above).
Reaction SMILES: C([O:8][NH:9][C:10]([CH:12]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:13]([NH:15][C@@H:16]([CH2:36][C:37]1[N:38]=[CH:39][NH:40][CH:41]=1)[C:17]([NH:19][C@@H:20]([CH:30]1CCCCC1)[C@@H:21]([OH:29])[CH2:22][C@@H:23]([CH:26]([CH3:28])[CH3:27])[CH:24]=[CH2:25])=[O:18])=[O:14])=[O:11])C1C=CC=CC=1>[Pd].CO>[CH:43]1([CH2:30][C@H:20]([NH:19][C:17](=[O:18])[C@@H:16]([NH:15][C:13](=[O:14])[CH:12]([C:10](=[O:11])[NH:9][OH:8])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:36][C:37]2[N:38]=[CH:39][NH:40][CH:41]=2)[C@@H:21]([OH:29])[CH2:22][C@H:23]([CH2:24][CH3:25])[CH:26]([CH3:28])[CH3:27])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: C=C[C@@H](C[C@H](O)[C@@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)NOCc1ccccc1)C1CCCCC1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)C(=O)NO)C(C)C

Procedure:
150 mg of (S)-α-[(RS)-α-[(benzyloxy)carbamoyl]-hydrocinnamamido]-N-[(1S,2S,4S)-1-cyclohexyl-2-hydroxy 4-isopropyl-5-hexenyl]imidazole-4-propionamide were hydrogenated in the presence of 5% palladium on carbon in methanol for 3 hours. After completion of hydrogen uptake, the catalyst was filtered and the filtrate was evaporated. Recrystallization of the residue from methanol/methylene chloride/ether yielded (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-4-ethyl-2-hydroxy-5-methylhexyl]-α-[(RS)-α-(hydroxycarbamoyl)hydrocinnamamido]imidazole-4-propionamide as white crystals of melting point 123°.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>ClCCl>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][O:11][S:22]([CH3:21])(=[O:24])=[O:23])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-glycinol (25.0 g, 155 mmol) and N,N-diisopropylethylamine (32.4 mL, 186 mmol) in anhydrous dichloromethane (70 mL) was added methanesulfonyl chloride (19.5 mL, 171 mmol) dropwise under ice-water cooling. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the product was extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was removed in vacuo to give methanesulfonic acid 2-(tert-butoxycarbonylamino)ethyl ester as a crude oil (37 g, 99.7% yield) which was used for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[Cl:23])[NH:14]2)=[CH:10][CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1nccc(Cl)c1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc(Cl)c1-c1cc2ccc(N)cc2[nH]1
Yield: 89.6 %

Procedure:
A solution of [2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-yl]-carbamic acid tert-butyl ester (160 mg, 0.43) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL) at 25° C. The solution was heated to reflux for 3 hours. Concentrate the solution in vacuo to afford crude 2-(4-chloro-2-methoxy-pyridin-3-yl)-1H-indol-6-ylamine (105 mg, 90%) as light yellow oil. The crude product was used directly for next step. MH+ 273.9.
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([OH:25])[CH2:20][CH2:21][CH2:22][C:23]#[CH:24].N1C=CN=C1>C(Cl)Cl>[Si:5]([O:25][CH2:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCCCCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#CCCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
tert-Butyldiphenylchlorosilane (3.2 mL, 12.4 mmol) was added dropwise to a stirring, 0° C. solution of 5-hexyn-1-ol (4, 1.07 g, 10.9 mmol) and anhydrous imidazole (1.84 g, 27.1 mmol) in anhydrous CH2Cl2 (20 mL) under an argon atmosphere. After complete addition, the reaction mixture was stirred at room temperature for 12 hours, then quenched with saturated aq. NH4Cl solution (50 mL) and extracted with Et2O (3×50 mL). The combined ethereal extracts were washed with saturated aq. NaCl solution (25 mL), dried over NaSO4, and the solvent was removed in vacuo. The residue was purified by flash chromatography (5% ethyl acetate/hexane) to yield 1-tert-butyldiphenylsilyloxy-hex-5-yne (5) (3.54 g, 10.5 mmol, 96%) as a colorless oil. TLC: 5% EtOAc/hexanes, Rf˜0.65; 1H NMR (400 MHz, CDCl3) δ 7.77-7.65 (m, 4H), 7.40-7.30 (m, 6H), 3.70 (t, 2H, J=5.6 Hz), 2.40-2.25 (m, 2H), 2.05 (t, 1H, J=2.8 Hz), 1.90-1.70 (m, 4H), 1.18 (s, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>CN(C)C1C=CN=CC=1.O>[CH3:39][C:38]([O:8][C:9]1[S:17][C:16]2[CH2:15][CH2:14][N:13]([CH:18]([C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:12][C:11]=2[CH:10]=1)=[O:40]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Oc1cc2c(s1)CCN(C(C(=O)C1CC1)c1ccccc1F)C2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-(Tert-butyldimethylsilyloxy)-5-(α-cyclopropylformyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.0 g) was dissolved in the solvent described in Table 1 to form a solution and the solution was cooled to 0° C. Triethylamine (1.02 g) was then added followed by 4-dimethylaminopyridine (DMAP) (0.02 g). After the reaction mixture was stirred for 10 minutes at the same temperature, acetic anhydride (0.83 g) was added to the solution. The reaction was monitored by Thin Layer Chromatography (TLC) (petroleum ether/ethyl acetate=10/1 or 5/1) until the reaction was completed. After the reaction was completed, cold water was added to the reaction mixture and the mixture was stirred for 15 minutes. It was then cooled to −5° C. and further stirred for 3 hours before collecting the crystal as prasugrel free base. Solid precipitate was collected. The yield of prasugrel was calculated and the results were shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([NH2:7])=O.Cl.C(OCC)(=O)C>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[CH2:5][NH2:7]
Reactant: COc1ccc(C)cc1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(C)cc1CN

Procedure:
2-Methoxy-5-methylbenzamide was treated in the same manner as the reduction shown in Reference Example 2 and further treated with 4 M hydrogen chloride/ethyl acetate solution to obtain 2-methoxy-5-methylbenzylamine. F: 152.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH2:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[Na+]>>[NH2:16][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:15]([OH:18])=[O:19]
Reactant: O=C1Cc2cccc(C(=O)c3ccccc3)c2N1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1c(CC(=O)O)cccc1C(=O)c1ccccc1

Procedure:
A mixture of 1.0 g. (0.004 mole) of 7-benzoylindolin-2-one was added to 30 ml. of 3N sodium hydroxide and the basic solution was refluxed for 45 minutes under nitrogen. The mixture was filtered and the filtrate was neutralized with glacial acetic acid. The precipitate was filtered off, washed with water and dried. The material melted at 122° C. (dec.). The yield was 0.8 g. (72%).
Reaction SMILES: [CH3:1][S:2]Cl.[CH2:4]([N:7]([CH2:25][CH2:26][CH3:27])[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])=[CH:10][C:9]=1[N+:22]([O-:24])=[O:23])[CH2:5][CH3:6].N1C=CC=CC=1>ClCCl>[CH2:25]([N:7]([CH2:4][CH2:5][CH3:6])[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([S:17]([N:20]([S:2][CH3:1])[CH3:21])(=[O:19])=[O:18])=[CH:10][C:9]=1[N+:22]([O-:24])=[O:23])[CH2:26][CH3:27]
Reactant: CSCl
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)NC)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(S(=O)(=O)N(C)SC)cc1[N+](=O)[O-]

Procedure:
A 1.1 g (0.012 mol) sample of methylsulfenyl chloride was added dropwise to a cooled (-5° to -10° C.) solution of 3.6 g (0.01 mol) 4-dipropylamino-N-methyl-3,5-dinitrobenzenesulfonamide and 1.1 g (0.014 mol) pyridine in 25 ml dichloromethane. The reaction mixture was then stirred at about 0° C. until the sulfonamide reactant could not be detected by thin layer chromatography on silica gel (benzene/acetone eluant). The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give a yellow semi-solid residue. The residue was recrystallized from ethanol to give 2.3 g of the product, as a yellow solid, m.p. 119°-121° C. Elemental analysis for C14H22N4O6S2 showed: % S, calc. 15.8, found 15.9.
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:10])[CH2:7][C:8]=1[CH3:9])[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([Cl:24])[Cl:23])[C@H:19]1[C:25](Cl)=[O:26]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:28])[C@H:20]([CH:21]=[C:22]([Cl:23])[Cl:24])[C@H:19]1[C:25]([O:10][CH:6]1[CH2:7][C:8]([CH3:9])=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:26]
Reactant: C=CCC1=C(C)CC(O)C1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=C(C)CC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 84.5 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-ol (190 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (140 mg) and toluene (10 ml), (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (310 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 379 mg of (RS)-3-(2-propenyl)-4-methyl-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 18). Yield 77% nD24 1.5112
Reaction SMILES: NCCC1C=CC(O)=C(O)C=1.[C:12]([N:17]1[C:21](=O)[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=O)(OCC)=O.[Cl-].[Cl-].[Ca+2]>CO.[CH2-]C(C)=O>[CH:18]1[C:19]2[C:20](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:12][N:17]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: NCCc1ccc(O)c(O)c1
Agent: [CH2-]C(C)=O
Agent: [Ca+2]
Solvent: CO
Product: c1ccc2cnccc2c1

Procedure:
In this example the inventors use the novel method of the present invention to synthesize acetonide-protected dopamine-containing compounds. In general, the N-phthaloyl (Phth) protective group was introduced to dopamine by N-carbethoxyphthalimide in methanol. The resulting Phth-dopamine (8) was then refluxed and volatile byproducts were removed from the reaction system by distillation. The condensed liquid was recycled using a Soxhlet extractor, the thimble of which was filled with anhydrous CaCl2 to absorb water and methanol. In addition, anhydrous solvent and argon protection were used to prevent introduction of water from external sources, shortening the reaction time to ca. 1-2 h from the 24 h sometimes required for traditional methods.43 The raw product was subjected to GC-MS analysis, which gave a major peak in the chromatogram and a molecular ion at 323 (calcd. 323.12) in the mass spectrum, indicating that full protection of the amine group results in acetonide cyclization rather than isoquinoline formation.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:25]1([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.[NH2:38][CH2:39][C:40]1[CH:56]=[CH:55][C:43]([C:44]([N:46]([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=2)[CH3:47])=[O:45])=[CH:42][C:41]=1[CH3:57]>ClCCl.CN(C=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([N:46]([CH3:47])[C:44]([C:43]2[CH:55]=[CH:56][C:40]([CH2:39][NH:38][C:35]([CH:32]3[CH2:31][CH2:30][N:29]([CH2:28][CH:25]4[CH2:26][CH2:27]4)[CH2:34][CH2:33]3)=[O:37])=[C:41]([CH3:57])[CH:42]=2)=[O:45])=[CH:49][CH:50]=1
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)C1CCN(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
PyBroP (212 mg, 0.45 mmol) and 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (76 mg, 0.42 mmol) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloromethane (5 ml) and DMF (1 ml). The mixture was stirred at room temperature for 18 h then solvents were removed in vacuo and azeotroped with toluene. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white powder identified as the title compound (34 mg, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36].Cl>C1COCC1>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl
Reaction time: 144 h
Yield: 49 %

Procedure:
To a 0.4M solution of 3,5-dichloro-4-(napthalen-2-ylsulfanyl)-phenylamine (90) (153 mg, 0.48 mmol) in THF was added pyridine, obtained from aldrich, (0.19 mL, 2.4 mmol) followed by 2,4-dichlorobenzenesulfonyl chloride, obtained from Maybridge, (129 mg, 0.53 mmol). The resulting mixture was stirred for 6 days. A 1M aqueous solution of HCl (20 mL) was added and the crude reaction mixture was extracted 3× with EtOAc (20 mL). The organic layers were combined and washed once with a brine solution (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (5-15% EtOAc in hexane) to yield 125 mg (49%) of 93 as an off white solid.