Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]1=[O:8]
Reactant: CC1CCCCC1=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCCC(=Cc2ccccc2)C1=O

Procedure:
It is also known to react 2-methylcyclohexanone with benzaldehyde in the presence of a solution of sodium hydroxide in a mixture of 37.5% by volume alcohol and 62% by volume water. In this way, it is possible over the course of 3 hours to obtain, in a yield of from 65 to 70%, 2-benzal-6-methylcyclohexanone (=2-methyl-6-benzylidenecyclohexanone (see J. Am. Chem. Soc. 65, 1317 (1943)). Disadvantages are the relatively low yield and the fact that the product is obtained as an oil which must be extracted and worked up by distillation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:31]([O-])=O)=[C:13](/[CH:15]=[CH:16]/[C:17](=[O:30])[CH2:18][C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC=CC=2[N+]([O-])=O)=CC=1>>[NH2:31][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][C:13]=1/[CH:15]=[CH:16]/[C:17](=[O:30])[CH2:18][C:19](=[O:29])/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1
Reactant: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=C(/C=C/c1ccc(O)cc1)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Product: Nc1ccc(OCc2ccccc2)cc1/C=C/C(=O)CC(=O)/C=C/c1ccc(O)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 349, but with (1E,6E)-1-(5-benzyloxy-2-nitrophenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (10 mg, 22 μmol, synthesized in Example 342) as the starting material instead of (1E,6E)-1-(4-hydroxyphenyl)-7-(2-nitrophenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel column chromatography eluting with hexane/ethyl acetate=75/25 to 60/40. The product was obtained as a solid (3.3 mg, 35%) having the following characteristics.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([OH:25])[CH:15]=2.N1C=CC=CC=1.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([O:25][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[CH:15]=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(O)ccc12
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-7-hydroxy-4-(2-methoxy-ethyl)-chromen-2-one (1.8 g, 5.2 mmol) and pyridine (30 mL) were dissolved in CH2Cl2 (200 mL) at room temperature and the reaction mixture was cooled to 0° C., then treated with Tf2O (1.3 mL). After 1 hour, ethyl acetate (200 mL) was poured into the reaction mixture and the reaction mixture was transferred into a separation funnel. The reaction mixture was then washed with 5% sodium bicarbonate (2×250 ml), water (250 ml) and then brine. The organic layer was dried over sodium sulfate and concentrated. Flash column chromatography on silica gel eluted with 20-50% ethyl acetate in hexane yielded the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]([Cl:30])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21]([O:23]C(C)(C)C)=O)[CH2:15][O:16][CH:17]([F:19])[F:18])[NH:8]1)=[O:6].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[C:52]([O:56][C:57]([NH:59][C@H:60](C(O)=O)[CH:61]([CH3:63])[CH3:62])=[O:58])([CH3:55])([CH3:54])[CH3:53].F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>ClCCl.C(#N)C>[Cl:30][C:2]([Cl:1])([Cl:29])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:28])[C@@H:14]([NH:20][C:21](=[O:23])[C@@H:60]([NH:59][C:57]([O:56][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:58])[CH:61]([CH3:63])[CH3:62])[CH2:15][O:16][CH:17]([F:18])[F:19])[NH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](COC(F)F)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](COC(F)F)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A cooled (0° C.) solution of (S)-1-((S)-2-tert-butoxycarbonylamino-3-difluoromethoxy-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (143 mg, 0.287 mmol) in dichloromethane (5 mL) was treated with trimethylsilyl trifluoromethanesulfonate (72 μL, 0.431 mmol). After stirring at 0° C. for 30 minutes the reaction mixture was treated with N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) and the volatiles were removed in vacuo to provide a brown solid which was then dissolved in anhydrous acetonitrile (5 mL) and this mixture was subsequently treated with N-(tert-butoxycarbonyl)-L-valine (75 mg, 0.344 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (153 mg, 0.402 mmol) and N,N-diisopropylethylamine. After stirring at room temperature for 16 h, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and water. The organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography eluting with a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to provide the title compound (105 mg, 61%) as a pale yellow gum and as a complex mixture of rotamers. LCMS (m/z) 597.0, 599.0 [M+H], Tr=3.18 min.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:19][CH3:20])[CH2:16][C:17]#[N:18])[CH3:14].[C:21](OCC)(=[O:24])[CH2:22][CH3:23]>C1COCC1.CCCCCC>[C:17]([CH:16]([CH:15]([CH2:19][CH3:20])[CH2:13][CH3:14])[C:21](=[O:24])[CH2:22][CH3:23])#[N:18]
Reactant: CCC(CC)CC#N
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)C(C#N)C(CC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part B. A solution of diisopropylamine (7.50 mL, 57.2 mmol) in THF (100 mL) was cooled to −78° C., and treated with n-butyllithium (34.0 mL of a 1.6 M solution in hexane). The solution was warmed briefly to 0° C., and then recooled to −78° C. The nitrile compound from Part A was then added by syringe, and the solution was allowed to stir for 1 hour. Then, ethyl propionate (6.50 mL, 56.7 mmol) was added by syringe, and the resulting mixture was allowed to stir and warm to ambient temperature for 12 hours. It was poured into 200 mL of satd. aq. NH4Cl solution, and this was extracted with ethyl acetate (2×200 mL). The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The residual oil was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the product, 4-cyano-5-ethyl-3-heptanone, as an oil 4.06 g, 24.3 mmol, 49%). TLC RF 0.47 (20:80 ethyl acetate-hexane). Spectral data: 1H NMR (300 MHz, CDCl3): δ 3.49 (1H, d, J=4.4 Hz), 2.74 (2H, q, J=7.3 Hz), 2.08-1.98 (1H, m), 1.70-1.58 (1H, m), 1.50-1.20 (3H, m), 1.12 (3H, t, J=7.3 Hz), 0.95 (3H, t, J=7.3 Hz), 0.91 (3H, t, J=7.3 Hz). MS (H2O-GC/MS): m/e 167 (100).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][C@H:15]([C:18]([O:20]CC)=[O:19])[O:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1.O[Li].O.Cl.O1CCOCC1>O.C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[O:14][C:12]=3[N:13]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCc2cnc(NC3CCOCC3)nc2O1
Yield: 109.9 %

Procedure:
A solution of 406 (0.310 g, 1.01 mmol), THF (5 mL), LiOH.H2O (0.0508 g, 1.21 mmol) and water (1 mL) was stirred for 3 h. To the solution was added 4N HCl in dioxane (0.303 mL, 1.21 mmol) and concentrated to afford 0.31 g (95%) of (R)-2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxylic acid (408) which was used without further purification: MS m/z (APCI-pos) M+1=280.1.
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:11]=[C:12]([C:18]2[N:19]=[CH:20][N:21]([C:23]([N:25]([CH3:32])[CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:24])[CH:22]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].Cl[CH2:34][CH2:35][C:36]#[N:37]>ClCCl.C(O)(C)C>[C:36]([CH2:35][CH2:34][N:29]1[CH2:30][CH2:31][CH:26]([N:25]([CH3:32])[C:23]([N:21]2[CH:22]=[C:18]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([F:9])[CH:11]=3)[N:19]=[CH:20]2)=[O:24])[CH2:27][CH2:28]1)#[N:37]
Reactant: COc1ccc(-c2cn(C(=O)N(C)C3CCNCC3)cn2)cc1F
Reactant: N#CCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(-c2cn(C(=O)N(C)C3CCN(CCC#N)CC3)cn2)cc1F
Temperature: 25 °C
Yield: 68 %

Procedure:
Triethylamine (0.159 mL, 1.139 mmol) was added to a stirred suspension of 4-(3-fluoro-4-methoxyphenyl)-N-methyl-N-(piperidin-4-yl)-1H-imidazole-1-carboxamide hydrochloride (0.200 g, 0.542 mmol) and 3-chloropropanenitrile (0.058 g, 0.651 mmol) at room temperature. The clear solution was allowed to stir at reflux for 2 h, during which time a white suspension formed. The mixture was allowed to cool to room temperature, diluted with a mixture of dichloromethane/isopropanol (7:3) and then washed with water. The organic layer was dried (MgSO4), filtered and evaporated to give a colourless solid that was triturated with ethanol to give the product (142 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[CH3:32])[NH2:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27](/[N:28]=[C:18](/[C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[NH:10][C:11]=3[CH:17]=2)\[C:19]([F:22])([F:20])[F:21])[CH:29]=[CH:30][C:31]=1[CH3:32]
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2[nH]1
Reactant: Cc1ccc(N)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(/N=C(/c2ccc3nc(-c4c(C)cccc4C)[nH]c3c2)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoro-ethanone (710 mg), 3,4-dimethylaniline (150 mg) and diisopropylethylamine (150 mg) in methylene chloride (15 mL) was added dropwise 1.1 mL of a 1.0M solution of TiCl4 in methylene chloride. The mixture was stirred at ambient temperature for 10 min then was washed with NaHCO3 solution. The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using 10% EtOAc/methylene chloride as eluent to give (3,4-dimethyl-phenyl)-[1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoroeth-(Z)-ylidene]-amine as an oil. This was used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([C:13]1[CH:14]=[C:15]([C:23](=[O:25])[CH3:24])[CH:16]=[CH:17][C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])=[N:7]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([C:13]1[CH:14]=[C:15]([CH:23]([OH:25])[CH3:24])[CH:16]=[CH:17][C:18]=1[S:19]([CH3:22])(=[O:21])=[O:20])=[N:7]2
Reactant: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(-c2cc(C(C)O)ccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Temperature: 0 °C

Procedure:
The 1-(3-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-4-(methylsulfonyl)phenyl)ethanone (40 mg, 0.072 mmol) was dissolved in THF (1.00 mL) and cooled to 0° C. To the solution was added 1M lithium aluminum hydride (0.072 mL, 0.072 mmol) in THF and the reaction mixture was allowed to warm to rt over a period of 1.5 h. The reaction was then worked up via the method found in the Fieser and Fieser (Vol. 1) and the mixture was filtered over a short plug of silica gel and washed with EtOAc. The filtrate was cond to give (+/−)-1-(3-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)-quinolin-2-yl)-4-(methylsulfonyl)-phenyl)ethanol. 1H NMR (CDCl3) δ ppm 8.14 (1H, dd, J=8.2, 4.1 Hz), 7.93 (1H, t, J=2.4 Hz), 7.75 (1H, dd, J=4.1, 2.5 Hz), 7.68 (1H, ddd, J=18.5, 8.3, 1.6 Hz), 7.42-7.58 (3H, m), 7.09 (1H, ddd, J=13.4, 8.6, 2.5 Hz), 6.63-6.73 (1H, m), 5.06 (1H, q, J=6.7 Hz), 3.78 (4H, t, J=4.8 Hz), 3.20 (4H, q, J=3.9 Hz), 3.12 (3H, d, J=1.6 Hz), 1.91 (3H, d, J=5.3 Hz), 1.57 (3H, d, J=6.7 Hz). Mass Spectrum (ESI) m/e=555.2 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:17])=[CH:4][CH:3]=1.N.[CH3:19][N:20]1CCCN(C)C1=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:17])=[CH:4][CH:3]=1)#[N:20]
Reactant: CN1CCCN(C)C1=O
Reactant: Cc1nc2ccccc2n1-c1ccc(I)cc1
Agent: [Cu]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: Cc1nc2ccccc2n1-c1ccc(C#N)cc1
Temperature: 100 °C

Procedure:
Cuprous cyanide (8.323 g, 93 mmol) was added to a mixture of 1-(4-iodophenyl)-2-methylbenzimidazole (5.184 g, 15.5 mmol) and palladium (II) acetate (170 mg) in N,N'-dimethyl-1,4,5,6-tetrahydro-2-pyrimidone (15 ml) and the resulting solution was heated under nitrogen at 100° C. for 15 hours. The mixture was cooled, poured into saturated aqueous ammonia (150 ml) and shaken to dissolve the copper salts. The mixture was extracted with ether (3×150 ml), and the combined extracts were washed consecutively with water (3×150 ml), brine (150 ml), and then dried (MgSO4) and concentrated under reduced pressure to give 1-(4-cyanophenyl)-2-methylbenzimidazole, 941 mg, as a white solid.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]([CH2:21][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@@H:12]([CH2:13][N:14]([CH2:21][CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:10]
Reactant: CCN(C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(C[C@H](N)CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a stirred solution of (S)-4-[(ethyl-phenyl-amino)-methyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (462 mg) at r.t. in dioxane (5.85 ml) under an argon atmosphere was added HCl solution (4 M in dioxane; 4.14 ml). The mixture was stirred at r.t. overnight and concentrated. The residue was taken up in EtOAc and washed with 10% aq. potassium bicarbonate solution. The aqueous layer was back extracted with EtOAc. The combined organics were washed with water and then with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (Isolute® SPE flash NH2 column, aminopropyl-functionalized silica; CH2Cl2/MeOH 9:1) to give (S)-2-amino-3-(ethyl-phenyl-amino)-propan-1-ol (133 mg, 62%) as a light brown viscous oil. MS (ISP): 195.1 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][OH:38])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].O>ClCCl>[CH3:48][S:49]([O:38][CH2:37][C@@H:13]1[CH2:14][C@H:15]([S:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][N:12]1[C:10]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:40][CH:39]=1)=[O:11])(=[O:51])=[O:50]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (5.0 g: 9.01 mmole) in dichloromethane (50 ml) stirring at -15° C., triethylamine (1.63 ml: 1.3 eq.) and methanesulfonyl chloride (0.85 ml: 1.1 eq.) are added. The mixture is stirred at -15° to -10° C. for 30 minutes. The reaction mixture is poured into water and extracted with dichloromethane. The extract is successively washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=9:1) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (4.86 g). Yield: 85.2%. NMR δ(CDCl3) ppm: 1.65 to 1.93(m, 1H), 2.00 to 2.26(m, 1H), 2.68 to 2.92(m, 3H), 2.96(s, 3H), 3.78 to 3.98(m, 1H), 4.16 to 4.30(m, 1H), 4.38 to 4.52(m, 1H), 5.11(br s, 2H), 7.08 to 7.52(m, 17H), 8.24(d, J=9 Hz, 2H). IR ν (CHCl3) cm-1 : 1699, 1606.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5]1=[O:11].[NH2:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]2[O:26][CH3:27])=[O:18])=[C:15]([O:31][CH3:32])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]([C:17]([NH:19][C@H:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][N:6]([CH2:9][CH3:10])[C:5]3=[O:11])[CH2:22][C@H:21]2[O:26][CH3:27])=[O:18])=[C:15]([O:31][CH3:32])[CH:14]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Reactant: CCN1CCN(CCCl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(CCN2CC[C@H](NC(=O)c3cc(Cl)c(N)cc3OC)[C@H](OC)C2)C1=O
Temperature: 70 °C
Yield: 67.8 %

Procedure:
A mixture of 2.21 parts of 1-(2-chloroethyl)-3-ethyl-2-imidazolidinone, 3.13 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.58 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated for 48 hours at 70° C. The reaction mixture was evaporated. Water was added and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.08 parts (67.8%) of cis-4-amino-5-chloro-N-[1-[2-(3-ethyl-2-oxo-1-imidazolidinyl)ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 152.8° C. (compound 1).
Reaction SMILES: B(F)(F)F.CSC.C[O:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1>ClCCl>[OH:9][C:10]1[CH:11]=[C:12]([C:17]2[N:21]([CH2:22][C:23]#[N:24])[N:20]=[CH:19][C:18]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=3)[CH:26]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: COc1cc(C)cc(-c2c(-c3ccnc(-c4cccc(NC(C)=O)c4)c3)cnn2CC#N)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2cc(-c3cnn(CC#N)c3-c3cc(C)cc(O)c3)ccn2)c1
Reaction time: 24 h

Procedure:
Borontrifluoride-dimethylsulfide (0.13 mL, 1.2 mmol) was dropwise added to a solution of the methoxy compound (52.5 mg, 0.12 mmol) prepared in Example 39 in dichloromethane (4 mL) at room temperature under nitrogen atmosphere, and stirred for 24 hours. The reaction mixture was concentrated by vacuum distillation. The residue was treated in ethyl acetate (100 mL) and brine (50 mL) and the organic layer was dried over anhydrous magnesium sulfate and distilled under vacuum. Purification through column chromatography (silica gel, ethyl acetate) afforded pure hydroxy products (28 mg, 55%).
Reaction SMILES: OO.NC(N)=[O:5].C1(=O)OC(=O)C2=CC=CC=C12.[C:18]([Si:22]([CH3:56])([CH3:55])[O:23][CH2:24][CH2:25][N:26]([CH2:53][CH3:54])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH3:52])[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:34][CH2:33]1)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([Si:22]([CH3:55])([CH3:56])[O:23][CH2:24][CH2:25][N:26]([CH2:53][CH3:54])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([N+:38]([O-:5])([CH3:52])[S:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:50])([F:51])[F:49])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:36][CH2:37]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: NC(N)=O
Reactant: CCN(CCCCC[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Agent: O=C1OC(=O)c2ccccc21
Agent: OO
Solvent: ClCCl
Product: CCN(CCCCC[C@H]1CC[C@H]([N+](C)([O-])S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
175 mg (1.86 mmol) H2O2-Urea adduct suspended in 2 ml CH2Cl2 were treated with 137 mg (0.9 mmol) phthalic anhydride. After stirring at RT for 15 min to this mixture was added 500 mg (8.4 mmol) crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 3 ml CH2Cl2 and the solution was stirred at RT. The mixture was washed with an aqueous solution of NaHCO3, the organic phase was washed with brine and dried over Na2SO4.348 mg crude trans-N-[4-(5-{[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-ethyl-amino}-pentyl)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide N-oxide were isolated as colorless oil.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O>[CH2:8]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCNCCCCCC
Solvent: CS(C)=O
Product: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 81.6 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and a nitrogen inlet was added di-n-hexylamine (14.1 grams, 0.3 moles), 1-fluoro-4-nitrobenzene (14.1 grams, 0.1 moles) and anhydrous methyl sulfoxide (40 ml). The contents of the flask were heated at 100° C. for 20 hours; cooled to room temperature; partitioned between diethyl ether (300 ml) and water (100 ml); filtered. The ether layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield a yellow oil containing excess dihexylamine. The yellow oil was purified by passing through a short column of silica gel and elating with hexane (300 ml) to yield 25.0 grams of product as a yellow oil. 1H NMR (CDCl3) δ 8.1(d, 2H), 6.5(d, 2H), 3.3 5(t, 4H), 1.6(pent, 4H), 1.2-1.4(m, 12H), 0.9(t, 6H).