Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](OCC)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:24])(=O)C.[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1)=[O:28].O>CN(C)C=O>[CH3:25][N:26]([CH3:38])[C:27]([CH2:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37]/[C:14](=[C:6]2\[C:5](=[O:24])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=3)/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:33][CH:32]=1)=[O:28]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(Cl)ccc21)c1ccccc1
Reactant: CN(C)C(=O)CNc1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CNc1ccc(N/C(=C2\C(=O)Nc3cc(Cl)ccc32)c2ccccc2)cc1
Temperature: 120 °C
Reaction time: 4.5 h

Procedure:
6.0 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-2-indolinone (educt IX) and 3.9 g of N-(dimethylcarbamoylmethyl)-p-phenylenediamine (educt XV.208) are dissolved in 50 ml of dimethylformamide and stirred for 4.5 hours at 120° C. After cooling water is added, the precipitate formed is suction filtered and washed with methanol. The product is purified through a silica gel column with methylene chloride/methanol (100:1) as eluant and finally recrystallised from ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][O:7][C:8]([C:10]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:14][C:15]=1[CH3:16])=[O:9].C(O)C>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16]
Reactant: COc1ccc(COC(=O)C2=C(C)NC(C)=C(C(=O)OC(C)C)C2c2cccc([N+](=O)[O-])c2)cc1OC
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccc(COC(=O)/C=C(/C)N)cc1OC
Yield: 77 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3,4-dimethoxybenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dimethoxybenzyl ester of melting point 154° C (from ethanol).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:11][CH2:12][C@H:13]([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([C:27]#[N:28])=[C:22]([F:29])[CH:21]=3)=[N:16]2)[CH3:14])=[O:10])[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[C:27]([C:23]1[C:24]([F:26])=[CH:25][C:20]([C:17]2[CH:18]=[CH:19][N:15]([C@H:13]([CH3:14])[CH2:12][NH:11][C:9]([C:6]3[CH:5]=[C:4]([CH:1]([OH:3])[CH3:2])[O:8][N:7]=3)=[O:10])[N:16]=2)=[CH:21][C:22]=1[F:29])#[N:28]
Reactant: CC(=O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)NC[C@@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)no1
Yield: 82.4 %

Procedure:
(R)-5-acetyl-N-(2-(3-(4-cyano-3,5-difluorophenyl)-1H-pyrazol-1-yl)propyl)isoxazole-3-carboxamide (0.047 g, 0.136 mmol) of Example 226 was reacted with sodium borohydride (0.010 g, 0.272 mmol) using the method described in Example 84. Yield of the title compound 0.045 g. 1H NMR (400 MHz; MeOD): δ 1.50 (dd, 3H), 1.59 (d, 3H), 3.75 (m, 2H), 4.93 (m, 1H), 6.53 (m, 1H), 6.79 (d, 1H), 7.67 (m, 2H), 7.73 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.S([O:19][CH3:20])(OC)(=O)=O>C(#N)C.C(=O)(O)[O-].[Na+].O>[CH2:11]([O:10][C:8]([C:7]1[C:2]([Cl:1])=[CH:3][C:20](=[O:19])[N:5]([CH3:4])[CH:6]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(C)c(=O)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
Ethyl 4,6-dichloronicotinate [prepared according to the literature procedure of J. Chem. Soc. 5163 (1963)] (3.19 g, 14.5 mmol) and dimethyl sulfate (6.0 mL, 63 mmol) were combined in a thick-walled glass tube with a Teflon cap. The tube was sealed and heated in a 120° C. sand bath. After 5 h, the reaction was cooled to ambient temperature and diluted with acetonitrile (100 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The reaction mixture was stirred vigorously overnight (ca. 18 h). This mixture was further diluted with water and extracted with dichloromethane (3×). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 4-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (2.65 g, 85% yield) as an oil that solidified upon standing.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:12])=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[Cl:2][C:3]1[C:4]([F:12])=[C:5]([C@@H:9]([NH:11][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(Cl)c1F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Cl)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 555 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)(=[O:16])=[O:15])[CH:6]=[CH:5][C:4]1=2.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.O>[F:23][C:19]1[CH:18]=[C:17]([S:14]([NH:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH:3]([CH2:2][NH:1][C:24](=[O:26])[CH3:25])[CH2:12][CH2:11][CH2:10]3)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of 0.18 grams (0.538 mmoles) N-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-fluoro-benzenesulfonamide in 25 mL pyridine was added 0.052 grams (0.511 mmole) acetic anhydride. The reaction mixture was stirred at 23° C. for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with 0.5M hydrochloric acid, water, and saturated aqueous sodium chloride. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. N-[6-(3-Fluoro-benzenesulfonylamino)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-acetamide was obtained as a crystalline solid from ethyl acetate/ethyl ether, 0.18 grams (89%), m.p. 136-137° C., M+H=377.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][CH:8]([CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1)[C:9](OCC)=[O:10].Cl.C(OCC)(=O)C>C1COCC1>[F:7][CH:8]([CH2:14][CH:15]1[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:20]1)[CH2:9][OH:10]
Reactant: CCCC1CCC(CC(F)C(=O)OCC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC1CCC(CC(F)CO)CC1
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 0.3 g of lithium aluminum hydride and 10 ml of THF were added, and the resultant mixture was cooled to −10° C. Thereto, 1.1 g of ethyl 2-fluoro-3-(4-propylcyclohexyl)propanoate (e-11) dissolved in 10 ml of THF was added dropwise in a temperature range of −10° C. to 0° C. Then, the resultant mixture was heated to 25° C., and stirred for 1 hour. Subsequently, 100 ml of 1 N HCl aqueous solution and 100 ml of ethyl acetate were added to separate the mixture into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was isolated, and washed with water, and then the resultant solution was dried over anhydrous magnesium sulfate. The resultant solution was concentrated under reduced pressure, the resultant residue was purified by a preparative isolation operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=5:1 in a volume ratio) as an eluent and silica gel as a filler, the resultant product was dried, and thus 0.68 g of 2-fluoro-3-(4-propylcyclohexyl)propan-1-ol (e-12) was obtained. A yield based on compound (e-11) was 75.7%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:14]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of crude methyl-8-hydroxy-octanoate (7, 1.24 g, 7.13 mmol, 1.0 equiv.) in CH2Cl2 (15 mL, 0.48 M) at 0° C. was treated successively with CBr4 (3.07 g, 9.27 mmol, 1.3 equiv.) and PPh3 (2.61 g, 9.98 mmol, 1.4 equiv.) and the reaction mixture was stirred at 4° C. for 10 h. The reaction mixture was then concentrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2,5 cm×15 cm, hexanes) afforded 8 as a clear, colorless oil (1.25 g, 1.69 g theoretical, 74.0%): 1H NMR (CDCl3,250 MHz) δ 3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J=6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, CH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 6H, alkyl protons).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[O:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
Ethyl 5-[3,5-bis(trifluoromethyl)phenyl]furan-2-carboxylate (61 mg, 0.17 mmol) and LiOH (9.4 mg, 0.22 mmol) were diluted with THF/H2O=1:1 (1.5 mL), and then stirred for 2 hrs at room temperature. The mixture was acidified with 1N HCl, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to yield the crude title compound as a white solid (30 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH:18]=[CH2:19].Cl>O1CCCC1>[OH:7][CH:6]([C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C=CCCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CCCCC(O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Trimethoxybenzaldehyde (25.48 g) was dissolved in tetrahydrofuran (50 ml), and 4-pentenylmagnesium bromide (a 1M solution in tetrahydrofuran, 200 ml) was added thereto, followed by stirring at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1-hydroxy-1-(3,4,5-trimethoxyphenyl)-5-hexene (Compound VIII-1, 34.58 g)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][NH:17]4)[N:9]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[CH3:26][CH:27]([NH2:29])[CH3:28]>C1COCC1>[NH:17]1[C:18]2[C:14](=[C:13]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:29][CH:27]([CH3:28])[CH3:26])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=4)[O:12][N:11]=3)[CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: CC(C)N
Reactant: Fc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1C(F)(F)F
Temperature: 52.5 °C
Reaction time: 40 h

Procedure:
To a solution of 4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indole (300 mg) in THF (1.5 ml) was added, propane-2-amine (0.75 ml), and after sealing the tube, the solution was stirred at 50 to 55° C. for 40 hours. It was concentrated under reduced pressure, and then purified by silica gel chromatography (n-hexane:EtOAc). The obtained solid was dissolved in acetone under heating, and added with n-hexane, and the precipitate was filtered to obtain 4-[3-(1H-indol-4-yl)-1,2,4-oxadiazol-5-yl]-N-isopropyl-2-(trifluoromethyl)aniline (295 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9](=[O:16])[NH:8][C:7]1=[O:17].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOCC>C1COCC1>[F:14][C:12]([F:13])([F:15])[C:10]1[C:9](=[O:16])[NH:8][C:7](=[O:17])[N:6]([CH2:5][CH2:4][CH2:3][CH:2]=[O:1])[CH:11]=1
Reactant: O=c1[nH]c(=O)n(CCCCO)cc1C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=CCCCn1cc(C(F)(F)F)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.7 %

Procedure:
1-(4-Hydroxy-butyl)-5-trifluoromethyl-1H-pyrimidine-2,4-dione (Prep 23, 44 mg, 0.17 mmol) was dissolved in dry THF (5 mL), the solution was cooled to 0° C. and Dess-Martin periodinane (127 mg, 0.28 mmol) was added. The mixture was stirred at 0° C. for 1.5 hours. Et2O was added and the solution washed with aqueous saturated NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to give 22 mg of the title compound (50% yield).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:12]C1C=CC(C(O)=O)=NC=1.FC1N=C(C(O)=O)C=CC=1>>[F:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([NH:10][NH2:11])=[O:9])=[N:7][CH:2]=1
Reactant: NNC(=O)c1cccc(F)n1
Reactant: O=C(O)c1ccc(F)cn1
Agent: O=C(O)c1cccc(F)n1
Product: NNC(=O)c1ccc(F)cn1

Procedure:
5-Fluoro-2-pyridinecarbohydrazide was prepared in a manner analogous to that described above for 6-fluoro-2-pyridinecarbohydrazide (I23) but using 5-fluoro-2-pyridinecarboxylic acid (CAS [107504-08-5], commercially available e.g. from Apollo Scientific or Beta Pharma) in the place of 6-fluoro-2-pyridinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(S(F)(F)[F:26])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:8]2([F:26])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH:10]([CH3:18])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)(c2ncccc2Cl)CCC12OCCO2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1CC(F)(c2ncccc2Cl)CCC12OCCO2
Temperature: -78 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of Example 32E (1.30 g, 4.58 mmol) in dichloromethane (100 mL) was cooled to −78° C., treated with diethylaminosulfur trifluoride (0.730 ml, 5.96 mmol) (Aldrich), and the reaction mixture was stirred at −78° C. for 2 hours. After 2 hours the reaction was partially complete and the mixture was allowed to stir for 2 additional hours. The reaction mixture was poured into dichloromethane (200 mL) and washed with saturated Na2CO3, dried over Na2SO4, and concentrated in vacuo. The material was purified on SiO2 and eluted with hexane/ethyl acetate (20%) to give a white solid (0.625 g) in 48% yield. 1H NMR (300 MHz, CDCl3) δ ppm 8.46 (dd, J=1.6, 4.7, 1H), 7.67 (dt, J=1.2C, 8.0, 1H), 7.17-7.09 (m, 1H), 4.17-3.92 (m, 4H), 2.72 (ddd, J=5.4, 10.7, 19.5, 3H), 2.57-2.50 (m, 1H), 2.25-2.15 (m, 1H), 2.06-1.94 (m, 1H), 1.83 (dd, J=6.0, 14.1, 1H), 1.08 (dd, J=6.9, 20.9, 3H). MS (DCI+) M/Z 286 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:9][CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[C:6]([C:7]1[CH:22]=[CH:21][C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CCCCCCCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OCCCCCCC)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
Heptyl 4-[(trimethylsilyl)ethynyl]benzoate (3a) (10.4 g, 32.8 mmol) was dissolved in tetrahydrofuran/methanol (3/1, v/v) (400 mL), potassium carbonate (1.00 g, 7.24 mmol) was added, and the mixture was stirred at −10° C. for 1 hr. The reaction solvent was concentrated, and the residue was diluted with ethyl acetate, washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:25) to give heptyl 4-ethynylbenzoate (4a) (6.58 g, yield 82%) as an oily liquid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]O.O>CC(O)=O>[CH3:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[N:10][C:9]([S:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:31])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(SCc3ccccc3)nn2)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-c2ccc(S(=O)Cc3ccccc3)nn2)cc1

Procedure:
3-Benzylsulfanyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-pyridazine (0.08 g, 0.19 mmol) was dissolved in CH3CO2H (3 mL) and a 50% solution of H2O2 in H2O (0.026 mL, 0.16 mmol) was introduced. The reaction mixture was stirred and monitored by LC-MS, and after 5 h was evaporated to a residue, which was treated with H2O (20 mL) and CH2Cl2 (30 mL). The organic layer was washed with saturated NaHCO3 solution (20 mL), saturated brine (10 mL) and dried (MgSO4) before being evaporated to a white solid (0.051 g, 64%), m.p. 145° C.
Reaction SMILES: [CH2:1]([C:5]1([N:24]([CH3:26])[CH3:25])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Si]([Cl:31])(C)(C)C>C(OCC)(=O)C>[ClH:31].[CH2:1]([C:5]1([N:24]([CH3:26])[CH3:25])[CH2:6][CH2:7][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCCO)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
3-(2-(4-Butyl-4-(dimethylamino)cyclohexyl)-1H-indol-3-yl)propan-1-ol (less polar diastereomer) (110 mg, 0.25 mmol) was dissolved in ethyl acetate (10 ml). Me3SiCl (63 μl, 0.5 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 182 (104 mg, m.p. 218-222° C., 85%) was obtained as a white solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[C:18]([CH3:19])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[N:20]1[N:21]=[C:22]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[NH:23][CH:24]=1>>[CH3:19][C:18]1[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:27]([C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[C:22]4[NH:23][CH:24]=[N:20][N:21]=4)=[O:28])[CH2:8]3)[CH2:1]2)=[N:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=1
Reactant: Cc1nc2ccccc2nc1N1CC2CNCC2C1
Reactant: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1nc2ccccc2nc1N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 29 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for C24H23N7O, 425.49; m/z found, 426.3 [M+H]+. 1H NMR (CDCl3): 8.13 (d, J=7.3 Hz, 1H), 8.01 (s, 1H), 7.83 (dd, J=8.2, 1.1 Hz, 1H), 7.72 (dd, J=8.3, 1.0 Hz, 1H), 7.59-7.35 (m, 5H), 4.00-3.65 (m, 5H), 3.47 (s, 2H), 3.22-2.89 (m, 3H), 2.70 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=1.[C:15]([S:18][CH2:19][CH2:20][C:21](Cl)=[O:22])(=[O:17])[CH3:16]>O.C(=O)(O)[O-].[Na+].CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>[C:15]([S:18][CH2:19][CH2:20][C:21]([N:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH2:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8]1)=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)SCCC(=O)Cl
Reactant: O=C(O)C1CC(c2ccccn2)=NN1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)SCCC(=O)N1N=C(c2ccccn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-3-(2-Pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid (3.82 g) is dissolved in 100 ml of water containing 2.12 g of sodium bicarbonate at 10° C. 3-(Acetylthio)propionyl chloride (3.9 g) in 15 ml of ether and 20% sodium carbonate solution are added simultaneously; the pH is maintained between 7.5 and 8.5. The reaction mixture is then stirred at room temperature for 2 hours and extracted with ether (discarded). The aqueous layer is acidified with acetic acid and extracted with ethyl acetate three times. The solvent is dried over anhydrous magnesium sulfate and concentrated in vacuo, yielding the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[CH2:14]O)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].[CH3:21][O:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]2[NH:29][CH:30]=[N:31][C:27]=2[CH:26]=1)=[O:24]>>[CH3:21][O:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]2[N:29]([CH2:14][C:12]3[CH:11]=[C:10]([O:16][C:17]([F:20])([F:19])[F:18])[CH:9]=[C:8]4[C:13]=3[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7]4)[CH:30]=[N:31][C:27]=2[CH:26]=1)=[O:24]
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: CC(C)Cn1ncc2cc(OC(F)(F)F)cc(CO)c21
Product: COC(=O)c1ccc2c(c1)ncn2Cc1cc(OC(F)(F)F)cc2cnn(CC(C)C)c12
Yield: 65 %

Procedure:
Compound 40 was prepared following general method 3A, using compound 21 as a starting material and 1H-benzoimidazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 65%.
Reaction SMILES: [C:1]1([C@@H:7]([OH:25])[C@@H:8]([N:10](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)=O.[H][H]>CO.[Pd]>[CH3:9][C@@H:8]([NH2:10])[C@@H:7]([OH:25])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: C[C@@H]([C@H](O)c1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: C[C@@H](N)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To remove the benzyl group, 3.9 mmol of (1R,2S)-1-phenyl-2-(N,N-dibenzylamino)-1-propanol are dissolved in 5 ml of methanol. This solution is added to a mixture of 40 ml of methanol, 10.6 g of formic acid and 50 mg of palladium black. The air is displaced from the reaction vessel using hydrogen. After hydrogenation for 1 hour, the palladium catalyst is filtered off, and the solution is concentrated in vacuo. The residue is taken up in 10 ml of methanol and stirred with 1 g of silica gel and 5 drops of concentrated hydrochloric acid at room temperature for 1 hour. The residue obtained after removal of the silica gel by filtration and concentration of the filtrate is purified by chromatography. 243 mg (=60% of theory) of analytically pure norephedrine are obtained.