Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC[C@H](c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated to give a brownish foam. The foam was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2 over 20 minutes gave the title compound as the second eluting enantiomer. 1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: C(C1(CC)C2CCCC=2C2C([O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=CC(CCCCC)=CC=2O1)C.[CH2:35](C1C=C(OC(=O)CCCN2CCSCC2)C2C3C=C(C)CCC3C(C)(C)OC=2C=1)CCCC.C(C1C=C(OC(=O)CCN2CCCC2)C2C3CC(C)=CCC3C(C)(C)OC=2C=1)CCCC.O1CCN(CCCC(OC2C3C4CCCCC4COC=3C=C(CCCCC)C=2)=O)CC1>>[CH3:35][CH:23]([CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[C:22]([OH:21])=[O:32]
Reactant: CCCCCc1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(CC)(CC)C1=C2CCC1
Reactant: CCCCCc1cc(OC(=O)CCCN2CCSCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Agent: CCCCCc1cc(OC(=O)CCN2CCCC2)c2c(c1)OC(C)(C)C1CC=C(C)CC21
Agent: CCCCCc1cc2c(c(OC(=O)CCCN3CCOCC3)c1)C1CCCCC1CO2
Product: CC(CCN1CCCCC1)C(=O)O

Procedure:
Some of the compounds produced according to the invention are: 4,4-diethyl-7-n-pentyl-9-[4-(piperidino)-butyryloxy]-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran, 4,4-di-(1-hexyl)-7-(3-methyl-2-octyl)-9-[4-(morpholino)-butyryloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 4,4-dimethyl-7-(3-methyl-2-octyl)-9-[4-(piperidino)-butyryloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 4,4-diethyl-7-octadecyl-9-[3-pyrrolidino)-propionyloxy]-1,2,3,4,12,13-hexahydrocyclopenta[c][1]benzopyran, 3-pentyl-1-[4-(thiomorpholino)-butyryloxy]6a,7,8,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, 3-pentyl-1-[3-(pyrrolidino)-propionyloxy]-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, 1-[4-(homopiperidino)-butyryloxy]-7,8,9,10-tetrahydro-6H-dibenzo-[b,d]pyran and 1-[4-(morpholino)-butyryloxy]-3-pentyl-6a, 7,8,9,10,10a hexahydro-6H-dibenzo[b,d]pyran.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][C:12]#N)[CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])C=1Cl.[H-].[Na+]>>[Cl:14][C:15]1[CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=[C:19]([Cl:22])[C:12]=1[CH2:11][C:3]1[CH:2]=[N:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: N#CCc1cnc2ccccc2c1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(Cl)c(Cc2cnc3ccccc3c2)c(Cl)c1

Procedure:
3-(2,6-Dichloro-4-nitro-benzyl)-quinoline was synthesized (71%) from quinolin-3-yl-acetonitrile (228, 1.41 g, 8.4 mmol), 3,4,5-trichloronitrobenzene (Acros, 1.90 g, 8.4 mmol) and NaH (Aldrich, 740 mg, 60%, 18.5 mmol) in a similar manner in two steps as described in Example 222. 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.42 (d, J=0.9 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.92-7.86 (m, 2H), 7.72 (td, J=7.0, 1.3 Hz, 1H), 7.58 (td, J=8.0, 1.0 Hz, 1H), 4.59 (s, 2H). MS (EI): m/z 333 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].Cl>N1C=CC=CC=1>[C:13]([O:16][NH:12][C:6]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: NC1(c2cccs2)CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)ONC1(c2cccs2)CCCCC1
Reaction time: 4 h

Procedure:
The amine of Stage 17c (3 g, 16.6 mmoles) in pyridine (100 ml) is introduced into a 250 ml three-necked flask, and acetic anhydride (51 g, 50 mmoles) is added dropwise. After 4 hours under agitation at ambient temperature, 100 ml of an HCl solution (10%) is added and the product formed is extracted with ether (3×50 ml). The organic phase is washed with an HCl solution (10%) (2×80 ml), then with water (2×80 ml), dried over MgSO4 and concentrated to dryness. In this way, a white solid is obtained (3.1 g, 84%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:32]([O:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)C>[CH2:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:2][C@H:3]([CH2:21][OH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)=[CH:49][CH:50]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Reactant: N[C@H](CO)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(Nc1ccccc1)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of N-[4-[(2S)-2-amino-3-hydroxypropyl]phenyl]-N′-phenylurea hydrochloride (222 mg) in ethanol (5.0 ml) were added successively N,N-diisopropylethylamine (264 μl) and (2S)-2-[[4-(benzyloxy)phenoxy)methyl]oxirane (212 mg) and the solution was refluxed for 13.5 hours. After cooling to room temperature, the precipitates were collected by filtration, washed with ethanol, and dried under reduced pressure to give N-[4-[(2S)-2-[[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]phenyl]-N′-phenylurea (166 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=1>C(Cl)Cl>[CH:8]([NH:11][C:12]1[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:42][C:43]4[CH:47]=[C:46]([CH3:48])[NH:45][N:44]=4)=[O:32])=[CH:28][N:27]=3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:9])[CH3:10]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: Cc1cc(N)n[nH]1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2ccc(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)nc2)n[nH]1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Triethylamine (0.8 ml) was added to 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2 g) in methylene chloride (30 ml) for dissolution and cooled. With the slow addition of pivaloyl chloride (0.7 ml) at 0° C.˜5° C., the mixture was stirred at 5° C. for 1 hour. With the addition of triethylamine (0.9 ml) and 3-amino-5-methylpyrazole (0.56 g), the mixture was stirred at 5° C.˜10° C. for 3 hours. The solution was slowly heated and stirred at 15° C.˜20° C. for 30 minutes. The solution was washed with an aqueous sodium bicarbonate and water twice. The separated organic layer was concentrated under reduced pressure. The concentrated residue was chromatographed on column (chloroform/isopropanol=10/1, v/v). The purified solution was recovered and concentrated under reduced pressure. The residue was treated with ether for crystallization and with the addition of isopropyl ether (20 ml), and stirred for 2 hours, filtered and washed to give a desired compound of 1.77 g (yield: 73%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCC.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15][Br:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol (0.88 g, 3.2 mmol) and CBr4 (1.3 g, 4.0 mmol) were dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over 0.5 h. The mixture was stirred at 0° C. for 10 min., then diluted with pentane (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was separated and washed with ethyl ether, and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (99:1 ethyl ether-hexane) to yield 0.8 g, (74%) of the 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:28]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][C:23]=3[NH:22][N:21]=2)=[O:19])[CH2:14][CH2:13]1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[C:28]3[CH2:27][CH2:26][NH:25][CH2:24][C:23]=3[NH:22][N:21]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4c(F)cccc4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2c(F)cccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 3-(4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (55, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2N in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the mixture concentrated under reduced pressure to yield (4-(2-fluoro-6-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (56) as a white solid (80 mg, 97%): 1H NMR (300 MHz, DMSO-d6) δ 9.39-9.26 (m, 2H), 7.63-7.47 (m, 3H), 4.76-4.40 (m, 1H), 4.35-4.25 (m, 2H), 3.78-3.39 (m, 4H), 3.25-3.08 (m, 2H), 2.91-2.78 (m, 3H), 2.11-1.88 (m, 2H), 1.81-1.66 (m, 2H); ESI MS m/z 397 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[CH:6][C:7]=1[CH:8]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1
Reactant: O=c1cnn(-c2ccc(C(Cl)c3ccc(Cl)cc3)c(Cl)c2)c(=O)[nH]1
Reactant: OC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cnn(-c2ccc(C(c3ccc(Cl)cc3)N3CCC(O)CC3)c(Cl)c2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 1 %

Procedure:
A mixture of 2-[3-chloro-4-[chloro(4-chlorophenyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (0.015 mol), 4-hydroxypiperidine (0.02 mol) and sodiumbicarbonate (0.02 mol) in DMF (100 ml) was stirred for 16 hours at 80° C. The mixture was cooled. The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 0.070 g (±)-2-[3-chloro-4-[(4-chlorophenyl)(4-hydroxy-1-piperidinyl)methyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 119).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1O.C([NH2:21])CCCCCCC>O1CCCC1>[C:4]1([CH2:9][C:10]([NH2:21])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CCCCCCCCN
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Solvent: C1CCOC1
Product: NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.61 g 1,1'-carboxyldiimidazole (CDI) in 60 ml of anhydrous tetrahydrofuran (THF) is added, dropwise, a solution of 3-chloro-4-hydroxyphenylacetic acid (3.00 g) in 20 ml THF under N2. The reaction solution is stirred for 30 minutes at room temperature following the addition and then refluxed for 30 minutes under N2 When the reaction solution is cooled to room temperature, a solution of 2.7 ml octylamine in 5 ml THF is added dropwise, and the resulting reaction solution is allowed to stir overnight at room temperature under N2. After evaporation the reaction mixture is partitioned between 1N HCl and CH2Cl2. The CH2Cl2 layer (100 ml) is washed with 50 ml portions of 1N HCl, H2O, saturated NaHCO3, H2O, and brine. The resulting product is flash chromatographed over 230-400 silica gel eluting with hexanes/ethylacetate (3:2) to yield benzeneacetamide, 3-chloro-4 -hydroxy-N-octyl-, in a yield of 2.18 g (45.5%) mp 81°-82° C.
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:12]1[CH:11]=[C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
5-Amino-1-(3-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (125.1 mg) was dissolved in dimethyl sulfoxide (5 ml), and to the solution was added CuCN (102.6 mg). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.134 ml) was added dropwise during 30 minutes. After the addition was completed, the mixture was stirred at 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3:methanol=10:1) and then preparative TLC (2 mm, 20×20 cm, hexane:ethyl acetate=2:1) to give the title compound (31.4 mg, 24%).
Reaction SMILES: [CH:1](=[O:7])[CH:2]=[CH:3][CH2:4][CH2:5][CH3:6].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1.C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C@H:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH:1]=[O:7])=[CH:10]1
Reactant: CCCC=CC=O
Reactant: Cn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: CCC[C@H](CC=O)c1cn(C)c2ccccc12
Yield: 80.2 %

Procedure:
Prepared according to the general procedure from 2-hexenal (174 μL, 1.50 mmol), 1-methyl-1H-indole (64 μL, 0.50 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.85 mL) and isopropanol (0.15 mL) at −60° C. for 6 h to provide, after silica gel chromatography (5:95 EtOAc/hexanes), the title compound as a colorless oil (92 mg, 80% yield, 93% ee). IR (film) 2959, 2923, 2870, 1720, 1483, 1470, 1425, 1376, 1327, 1244, 1159, 1132, 1016, 734 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.71 (dd, J=2.1, 2.1 Hz, 1H, CHO), 7.67 (d, J=8.4 Hz, 1H, ArH), 7.35-7.24 (m, 2H, ArH), 7.12 (ddd, J=1.5, 7.2, 8.1 Hz, 1H, ArH), 6.87 (s, 1H, NCH), 3.76 (s, 3H, NCH3), 3.55 (m, 1H, ArCH), 2.83 (m, 2H, CH2CO), 1.79 (m, 2H, CHCH2CH2), 1.34 (dt, J=7.2, 22.8 Hz, 2H, CHCH2CH3), 0.92 (dd, J=7.2, 7.2 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 203.0, 137.2, 127.0, 126.0, 121.6, 119.2, 118.7, 117.0, 109.4, 49.7, 38.5, 32.8, 31.4, 20.8, 14.2; HRMS (CI) exact mass calcd for (C15H19NO) requires m/z 229.1467, found m/z 229.1464. [α]D=−1.7 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AS and AS guard column (2:98 ethanol/hexanes, 1 mL/min); S isomer tr=16.1 min and R isomer tr=18.1 min.
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14].[N:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=1.Cl>CO.CN(C)C=O>[NH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]1[CH2:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: CCc1cccc(CC)c1-n1cccc1C(C)=O
Reactant: C1=NCCCC1
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-n1cccc1C(=O)CC1CCCCN1
Temperature: 120 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 186 g (0.5 mole) of magnesium methyl carbonate reagent (2.69 millimoles/g) and 300 ml of dry dimethylformamide are heated to 120°C. under an atmosphere of carbon dioxide. The compound 1-(2,6-diethylphenyl)pyrrol-2-yl methyl ketone, 36.1 g (0.15 mole), is added and the mixture stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 15.1 g (0.18 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirring continued at room temperature for a period of 40 hours under an atmosphere of carbon dioxide. The reaction mixture is poured into a solution of 2 N hydrochloride acid and extracted with ethyl ether. The combined extracts are washed with water, dried over sodium sulfate and the solvent removed. The remaining aqueous phase is made alkaline using a solution of 2 N sodium carbonate and extracted with ethyl ether. The ether extract is washed, dried over sodium sulfate and the solvent removed. The residue is converted to the hydrochloride salt, triturated with ether to solidify and the crude 1-(2,6-diethylphenyl)pyrrol-2-yl 2-piperidylmethyl ketone recrystallized from a methylene dichloride-ethyl ether mixture to yield 16.4 g (30% yield) of a product having a M.P. of 162-4°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]([CH3:33])[CH3:32])[C:6]2[O:10][C:9]([C:11]3[CH:29]=[CH:28][C:14]([C:15]([NH:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([CH2:25][CH:26]=[O:27])[CH2:23][CH2:24]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:30]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CCO)CC4)cc3)oc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@H]4CC[C@H](CC=O)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-{[trans-4-(2-hydroxyethyl)cyclohexyl]methyl}benzamide (50 mg, 0.112 mmol) in dichloromethane (2 ml) was added Dess-Martin periodinane (60 mg, 0.141 mmol). The mixture was stirred for 2 h at 25° C., at which point LC/MS analysis showed no starting material. The mixture was purified by flash chromatography on a Biotage Horizon, 25M column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (48 mg, 0.108 mmol, 96% yield). Mass spectrum (ESI) 444.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Cl:27][C:28]1[CH:43]=[CH:42][C:31]2[N:32]([CH3:41])[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:34][C:30]=2[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:38]2[CH2:39][CH2:40][N:35]([C:33]3[N:32]([CH3:41])[C:31]4[CH:42]=[CH:43][C:28]([Cl:27])=[CH:29][C:30]=4[N:34]=3)[CH2:36][CH2:37]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Cn1c(N2CCNCC2)nc2cc(Cl)ccc21
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2cc(Cl)ccc21

Procedure:
Prepared analogously to Example 18 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 5-chloro-1-methyl-2-piperazin-1-yl-1H-benzimidazole
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[C:36](Cl)=[N:37][CH:38]=[C:39]([CH:45]=1)[C:40]([O:42][CH2:43][CH3:44])=[O:41].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:36]2[C:35]([Cl:34])=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][N:37]=2)[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cnc(N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of 100 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 59.4 mg of ethyl 5,6-dichloronicotinate, and 37.3 mg of potassium carbonate was added 2.0 mL of DMSO at room temperature, and the mixed solution was stirred at 100° C. overnight. After cooling to room temperature, water was added thereto. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 128 mg of ethyl 6-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-5-chloronicotinate as a colorless foamy substance. FAB+: 628