Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39](=[O:48])[N:40]([CH3:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:34][CH:33]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39](=[O:48])[N:40]([CH3:47])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:36][CH:37]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reactant: CN1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(=O)NCCc2ccc(OC(=O)N(C)c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
A solution of 1-methylpiperidine-4-carboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 5% yield as an oil.
Reaction SMILES: COCC([O:6][CH:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:20])[CH3:19])=O.FC1C=C2C(=CC=1)C(C(C)C)C(=O)CC2.[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH2:45][CH2:46][CH2:47][N:48]([CH3:52])[C:49](=[O:51])[CH3:50]>>[NH:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[CH2:45][CH2:46][CH2:47][N:48]([CH3:52])[C:49](=[O:51])[CH2:50][C:7]1([OH:6])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[CH:8]1[CH:18]([CH3:19])[CH3:20]
Reactant: COCC(=O)OC1CCc2cc(F)ccc2C1C(C)C
Reactant: CC(=O)N(C)CCCc1nc2ccccc2[nH]1
Agent: CC(C)C1C(=O)CCc2cc(F)ccc21
Product: CC(C)C1c2ccc(F)cc2CCC1(O)CC(=O)N(C)CCCc1nc2ccccc2[nH]1

Procedure:
A method of preparing 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino)}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting 6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with the dianion of N-[3-(1H-benzimidazol-2-yl)propyl]-N-methylacetamide to form N-[3-(1H-benzimidazol-2-yl)propyl]-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, reducing this to 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (lS,2S)-2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-[3-(1H-Benzimidazol-2-yl)propyl]-N-methylacetamide, and the acetic acid solvate of 2-[2- {[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol dioxalate, are new.
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[C:32]1([CH3:35])[CH:31]=[CH:30][C:29]([C:11]2[NH:10][CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=2)=[CH:34][CH:33]=1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc(C)cc3)n2)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c[nH]c(-c3ccc(C)cc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (11da, 492 mg, 1.0 mmol) in THF (15.0 mL) was added 1.0 M tetrabutyl ammonium fluoride (2.0 mL, 2.0 mmol) and stirred overnight. The reaction mixture was diluted by 30 mL of saturated NaHCO3 solution (aqueous) and extracted by ethyl acetate (80 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was recrystallized from water and methanol to give a white solid of 12da (2-(p-tolyl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone). Yield: 88.5%. mp 201-203° C. 1H NMR (500 MHz, CDCl3) δ 10.40 (br, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.82 (s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.24 (s, 2H), 3.96 (s, 3H), 3.94 (s, 6H), 2.43 (s, 3H). MS (ESI): calculated for C20H20N2O4, 352.10. found 375.2 [M+Na]+. HPLC2: tR 15.45 min, purity 97.4%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([Br:16])[CH3:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: CCc1ccc(C(=O)c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 23.5 parts of p-ethylphenyl 2-thienyl ketone, 19.5 parts of N-bromosuccinimide, 220 parts of carbon tetrachloride, 1.1 parts of benzoyl peroxide and one drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and evaporated. The oily residue solidifies on cooling. The solid product is dissolved in 2-propanol and the product is allowed to crystallize. It is filtered off and dried in vacuo, yielding α-bromo-α-methyl-p-tolyl 2-thienyl ketone; mp. 71.1° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:11][CH2:12][O:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:30]=O)=[CH:20]2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.C(OP([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(OCC)=O)C.Cl>CN(C)C=O>[CH3:3][N:4]([CH2:11][CH2:12][O:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21](/[CH:30]=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:20]2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CN(CCOc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1)c1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 200.0 mg) was added to a solution of 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenylpyrrole-3-carbaldehyde (1.35 g) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, then neutralized using 2N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl (E)-3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propenoate (1.35 g, yield: 85%) was obtained as an oily substance from the fraction eluted with acetone-hexane (1:2, volume ratio).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19].[O:20]=[C:21]1[NH:30][C:29]2[N:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22]1>>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]2[CH2:18][CH2:17][N:16]([CH2:35][CH2:34][CH2:33][CH2:32][O:31][C:27]3[N:28]=[C:29]4[C:24]([CH2:23][CH2:22][C:21](=[O:20])[NH:30]4)=[CH:25][CH:26]=3)[CH2:15][CH2:14]2)[CH2:6][CH2:5][C:4]1=[O:19]
Reactant: CN1C(=O)CCc2cccc(N3CCNCC3)c21
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: CN1C(=O)CCc2cccc(N3CCN(CCCCOc4ccc5c(n4)NC(=O)CC5)CC3)c21

Procedure:
In a manner similar to that of other examples above, 1-methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 464.6 (Exact Mass: 463.26).
Reaction SMILES: [C:1]([O:9][C:10]1([CH2:13][O:14]C2CCCCO2)[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[C:1]([O:9][C:10]1([CH2:13][OH:14])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1(COC2CCCCO2)CC1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: O=C(OC1(CO)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropyl benzoate (2 g, 7.2 mmol) in 30 mL of MeOH was added PPTS (2.7 g, 10.8 mmol, Aldrich) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (4:1 (v/v) petroleum ether/EtOAc) to afford the title compound as colorless oil (1.2 g, 87%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7]([OH:9])=O.[C:24]1([C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([C:30]2[S:34][C:33]([NH:35][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:9])=[N:32][N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Reactant: Nc1nnc(-c2ccccc2)s1
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1nnc(-c2ccccc2)s1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and 5-phenyl-[1,3,4]thiadiazol-2-ylamine in a similar manner as that described for example 102. 1H NMR (CD3CN/CD3OD) δ8.45 (1H, d, J=5.6 Hz), 8.00-7.95 (4H, m), 7.52-7.50 (4H, m), 7.48 (1H, d, J=2.3 Hz), 7.25 (1H, dd, J=8.6, 2.3 Hz), 6.66 (1H, d, J=5.3 Hz), 2.76 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([C:36]2([CH:42]=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH2:37]2)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]([C:36]5([CH:42]=[O:43])[CH:37]=[CH:38][CH:39]=[CH:40][CH2:41]5)[CH:31]=[CH:32][C:33]=4[O:34][CH3:35])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2(C=O)C=CC=CC2)cc1OCCCC1(c2noc3cc(F)ccc23)CCNCC1

Procedure:
A stirred mixture of 6-fluoro-(4-piperidinyl)-1,2 benzisoxazole (201 g; 9.13 mmol), K2CO3 (2.0 g), and 1-[3-(3-chloropropoxy)-4-methoxyphenyl]phenylmethanone (3.93 g; 11.3 mmol) and acetonitrile (50 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was evaporated and the residue was partitioned between water (150 ml) and dichloromethane (400 ml). The dichloromethane solution was washed with water and brine (100 ml), dried over MgSO4, then concentrated to an oil. The purification was done by flash chromatography over a silica gel column (SiO2, 40 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 850 ml). The material thus obtained as a colorless oil solidified on standing. Recrystallization from ethanol (150 ml) gave 1-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-4-piperidinyl]propoxy]4-methoxyphenyl]phenylmethanone as white crystals, 3.07 g (63%), m.p.=140-141° C.
Reaction SMILES: C([Mg]Br)C.[Cl-].[CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](C(C)C)[C:10]=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[O:61][CH3:62].C1(C)C=CC=CC=1[Mg]Br.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C1COCC1>[CH3:62][O:61][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:6]
Reactant: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Reactant: COc1ccccc1Cl
Agent: CC[Mg]Br
Agent: Cc1ccccc1[Mg]Br
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
A THF solution of ethylmagnesium bromide (0.324 mL, 1.08 M, 0.35 mmol) was added to FeF3.3H2O (8.34 mg, 0.05 mmol) and 1,3-bis(2,6-diisopropylphenyl)imidazolinium chloride (63.8 mg, 0.15 mmol) and triphenylphosphine (13.1 mg, 0.05 mmol) at 0° C. under argon atmosphere. The following process was also performed under argon atmosphere. After stirring for six hours at room temperature, 1-chloro-2-methoxybenzene (142.6 mg, 1.0 mmol) and a THF solution of o-tolylmagnesium bromide (1.88 mL, 0.80 M, 1.5 mmol) was added to the mixture. The mixture was reacted at 60° C. for 24 hours, and then at 80° C. for 12 hours. After cooled to the ambient temperature, 2.0 mL of saturated sodium potassium tartrate aqueous solution was added to the reaction mixture. The water layer was extracted five times using Et2O. The total organic extract was filtrated by Florisil pad (100-200 mesh, Nacalai Tesque, Inc.). After removing the solvent under reduced pressure, the crude product was dissolved in CH2Cl2 (1.0 mL). Then, m-chloroperbenzoic acid (MCPBA) (0.06 mmol) was added at room temperature, and the reaction mixture was stirred for 30 minutes. After removing the solvent under reduced pressure, the crude product was purified by silica gel chromatography (toluene=15, 30, 50% in hexane), thereby obtaining the above compound, which was a white solid (0.188 g, yield=95%, purity=>99% (GC analysis)).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:14][CH2:15][CH2:16][CH3:17])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])#[N:2].[OH2:18].[OH-].[NH4+]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:4]([O:14][CH2:15][CH2:16][CH3:17])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:13])[CH:10]([CH3:11])[CH3:12])(=[O:18])[NH2:2]
Reactant: O
Reactant: CCCOc1nsc(NC(=O)C(C)C)c1C#N
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCOc1nsc(NC(=O)C(C)C)c1C(N)=O

Procedure:
A mixture of 8.6 g of N-(4-cyano-3-propoxy-5-isothiazolyl)-2-methylpropanamide, from Example VII, in 20 ml of concentrated sulfuric acid was heated at 50° for 1 hour. Thin-layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was poured into 200 ml of cold water. The solution was neutralized with ammonium hydroxide. The resulting precipitate was collected by filtration. The dried solid was recrystallized from toluene to give 7.7 g of N-(4-carbamoyl-3-propoxy-5-isothiazolyl)-2-methylpropanamide m.p. 153°-154°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]1([CH3:19])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[C:15](=[N:26]/[S:24]([C:21]([CH3:23])([CH3:22])[CH3:20])=[O:25])/[CH2:16][CH3:17])=[N:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CCC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(Cl)Cl
Product: CC/C(=N\S(=O)C(C)(C)C)c1ccn(S(=O)(=O)c2ccc(C)cc2)n1
Reaction time: 0.33 h

Procedure:
To a solution of 1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-propan-1-one (2.10 g, 7.55 mmol) in dichloroethane was added (R)-(+)-2-methyl-2-propanesulfinamide (1.45 g, 12.00 mmol) and titanium (IV) isopropoxide (4.26 g, 15.00 mmol) and the mixture was warmed at reflux overnight. After cooling, the solvent was concentrated in vacuo. The residue was diluted with EtOAc and saturated aqueous NaCl was added dropwise. After 20 minutes, the solution was passed through diatomaceous earth. The combined organics were washed with brine and dried over sodium sulfate. The solvent was concentrated in vacuo to afford 2-methyl-propane-2-sulfinic acid [1-[1-(toluene-4-sulfonyl)-1H-pyrazol-3-yl]-prop-(E)-ylidene]-amide.
Reaction SMILES: C1C=CC(C(O[C@H](C(O)=O)[C@H](OC(C2C=CC=CC=2)=O)C(O)=O)=O)=CC=1.O.[CH3:28][CH:29]([CH2:31][C@H:32]([N:44]([CH3:46])[CH3:45])[C:33]1([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH2:36][CH2:35][CH2:34]1)[CH3:30].C(=O)(O)[O-].[Na+]>>[CH3:30][CH:29]([CH2:31][C@@H:32]([N:44]([CH3:45])[CH3:46])[C:33]1([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH2:34][CH2:35][CH2:36]1)[CH3:28]
Reactant: CC(C)C[C@H](N(C)C)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
The filtrate obtained by filtration after reacting with L-DBTA was neutralized to pH 8.5 with sodium hydroxide, and then extracted with chloroform to obtain (+)-sibutramine, which was nearly pure (+)-isomer. D-DBTA was added thereto to obtain crystals and the crystals were recrystallized from 450 ml of isopropyl alcohol to obtain D-DBTA salt of (+)-sibutramine (ee: ≧99.3%). The D-DBTA salt of (−)-sibutramine was neutralized to pH 8.5 with saturated sodium bicarbonate, and then extracted with chloroform to obtain (+)-sibutramine free base.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:32]([CH:34]5[CH2:39][CH2:38][C:37]6(OCC[O:40]6)[CH2:36][CH2:35]5)[CH3:33])=[CH:27][CH:26]=4)=[O:23])=[CH:15][C:14]=3[CH:44]=2)=[CH:6][CH:5]=1)[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:31][N:32]([CH3:33])[CH:34]5[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]5)=[CH:29][CH:30]=4)=[O:23])=[CH:15][C:14]=3[CH:44]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCS3(=O)=O)cc1
Reaction time: 40 h
Yield: 77.8 %

Procedure:
To a solution of 7-(4-ethoxyphenyl)-N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (140 mg) in THF (20 ml) was added at room temperature 3N hydrochloric acid (1 ml), and the mixture was stirred for 40 hours. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give colorless solid, which was recrystallized from ethyl acetate/hexane to give colorless crystals of 7-(4-ethoxyphenyl)-N-[4-[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 19) (101.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1.Cl[CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH:13]3[CH2:14][CH2:15][N:16]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([OH:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)[CH2:17][CH2:18]3)=[N:10][C:9]=2[CH2:19][OH:20])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cc(CCCl)ccc1O
Reactant: OCc1nc(C2CCNCC2)oc1-c1ccc(F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(CCN2CCC(c3nc(CO)c(-c4ccc(F)cc4)o3)CC2)ccc1O
Reaction time: 16 h
Yield: 16.1 %

Procedure:
A solution of [5-(4-fluoro-phenyl)-2-piperidin-4-yl-oxazol-4-yl]methanol (0.20 g; 0.72 mmol) in dry dioxane (6 ml) is treated with 5-(2-chloroethyl)-2-hydroxy-benzenesulfonamide (0.36 g; 1.45 mmol), sodium iodide (0.22 g; 1.45 mmol) and diisopropylethylamine (0.50 ml; 2.88 mmol) and heated to 100 C. for 16 hours. The reaction is cooled and partitioned between ethyl acetate (30 ml) and water (10 ml). The aqueous phase is washed with ethyl acetate (2×15 ml), dried over sodium sulfate and concentrated to dryness. Purification by radial chromatography using a methanol/ethyl acetate gradient (5%-40%) is followed by a second chromatography using a methanol/dichloromethane gradient (5%-30%). Crystallization from methanol/ethyl acetate afforded the product as a white solid (0.055 g; 16%). HNMR (CD3OD): 7.75 (m, 2H), 7.64 (d, 1H, J=2.1 Hz), 7.31 (dd, 1H, J=8.4; 2.1 Hz), 7.23 (t, 2H, J=8.8 Hz), 6.92 (d, 1H, J=8.4 Hz), 4.63 (s, 2H), 3.12 (m, 2H), 2.96 (m, 1H), 2.82 (m, 2H), 2.66 (m, 2H), 2.34 (m, 2H), 2.17 (m, 2H), 1.99 (m, 2H). Mass spectrum: m/e calculated (MH+)=476.6; observed (MH+)=476.2.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:22]=[CH:23][CH:24]=1>>[N:20]1[N:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[N:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cccc(-n2nccn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.52 min.; [M+H]+: 393.71 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27](O)=[O:28])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)=[CH:5][CH:4]=1.Cl.[CH3:36][NH:37][O:38][CH3:39].CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[CH3:39][O:38][N:37]([CH3:36])[C:27]([C:24]1([C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:16][CH2:17][C:12]4[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[C:13]=4[C:14]3=[O:30])=[CH:23][CH:22]=2)[CH2:26][CH2:25]1)=[O:28]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(=O)O)CC4)cc2)CC3)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C(=O)N(C)OC)CC4)cc2)CC3)cc1
Reaction time: 12 h

Procedure:
1-{4-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-phenyl}cyclopropane carboxylic acid (1.12 g, 2.37 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.255 g, 2.61 mmol) were dissolved in DMF (20.0 mL) and DIEA (2.0 mL, 11.5 mmol) was added dropwise. 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.54 g, 2.8 mmol) was added and the reaction was allowed to proceed under nitrogen at rt for 12 h. The reaction was diluted with EtOAc, washed 1N HCl, brine, dried over Na2SO4, filtered and concentrated. The reaction was purified via flash chromatography (silica, 100% EtOAc, then 10% MeOH/CH2Cl2) to give the title compound. LC/MS (ESI+) 515.6 (M+H).