Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1>C1COCC1>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=2)[CH:12]=1
Reactant: Cc1cccc(C)c1-c1cccc(CO)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc(C#N)cn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In an atmosphere of nitrogen, sodium hydride was added under ice-cooling to a THF solution of (2′,6′-dimethylbiphenyl-3-yl)methanol, followed by stirring at that temperature for 15 minutes. Thereafter, 6-chloronicotinonitrile was added to the reaction mixture under ice-cooling, followed by warming up to room temperature and stirring for 3 hours to obtain 6-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]nicotinonitrile.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:39])=[CH:10][CH:11]1[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][CH:24]=[N:25][C:26]=3[NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(OP(C=CC1C(O)C(O)C(N2C3N=CN=C(NC(=O)C4C=CC=CC=4)C=3N=N2)O1)(=O)OCC)C>>[CH2:6]([O:5][P:4]([C:9]([F:39])=[CH:10][CH:11]1[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[CH:29]=[N:28][C:27]3[C:22]2=[N:23][CH:24]=[N:25][C:26]=3[NH:30][C:31](=[O:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[O:12]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C(F)=CC1OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C2OC(C)(C)OC12
Agent: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C(O)C1O)OCC
Product: CCOP(=O)(OCC)C(F)=CC1OC(n2cnc3c(NC(=O)c4ccccc4)ncnc32)C(O)C1O
Yield: 75.4 %

Procedure:
Compound 7.4 (70 mg, 76% yield) was synthesized from compound 7.3 (100 mg) using the procedure described for the preparation for compound 6.5. 1HNMR (300 MHz, CD3CN) δ 1.21-1.38 (m, 6H), 4.06-4.24 (m, 4H), 4.47 (s, 1H), 4.92 (s, 1H), 5.00 (s, 1H), 6.08 (d, 1H, J=4.8), 6.31-6.47 (m, 1H), 7.57-8.06 (m, 5H), 8.31 (s, 1H), 8.72 (s, 1H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH3:9]O>>[CH3:9][O:7][C:1](=[O:8])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: CO
Product: COC(=O)CCC(C)=O
Reaction time: 24 h

Procedure:
Combine levulinic acid (6.0 g) and Amberlyst 15 in methanol (75 mL). After 24 hours, remove the resin by filtration and evaporate in vacuo to obtain a residue. Partition the residue between ethyl acetate and saturated sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C1(OC)C=CC=CC=1>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of anisole (4 ml) at 90° C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with anisole (2×2 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (215 mg, 64%, 96% e.e.) as an off-white powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Br)cc2n1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
A solution of 7-bromoquinaldine (22 g, 0.1M) and ethyl 4-(3-formylphenoxy)butanoate (20 g) in acetic anhydride (100 ml) was heated at 135° for 34 hours cooled and evaporated. Flash chromatography of the residue using 1:1 ether in hexane as eluant afforded crude adduct. Recrystallization from hexane ethyl acetate afforded the title compound: m.p. 92-93°.
Reaction SMILES: [Br:1]Br.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>[N+](C1C=CC=CC=1)([O-])=O.C1(C)C=CC=CC=1>[Br:1][C:16]1[CH:17]=[N:18][C:19]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([C:8]1[CH:9]=[CH:10][C:5]([F:4])=[CH:6][CH:7]=1)[CH:20]=2
Reactant: BrBr
Reactant: Fc1ccc(-c2ccc3cccnc3c2)cc1
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccc3cc(Br)cnc3c2)cc1
Temperature: 140 °C
Reaction time: 6 h
Yield: 57.8 %

Procedure:
A solution of bromine (0.9 mL, 17.6 mmol) in nitrobenzene (2.5 mL) was added dropwise over 15 minutes to a thick slurry of 7-(4-fluorophenyl)quinoline hydrochloride (3.80 g, 14.6 mmol) in nitrobenzene (7.5 mL) at 140° C. (oil bath temperature). The resulting mixture was stirred at 140° C. for 6 hours, allowed to cool to ca. 80° C., diluted with toluene (30 mL) and then cooled to room temperature. The orange solid was collected under suction and washed with toluene followed by diethyl ether. The solid was suspended in water (100 mL), the mixture basified with aqueous sodium carbonate and extracted with dichloromethane (2×50 mL). The combined extracts were dried (MgSO4) and evaporated to give a yellow solid. This was purified by flash chromatography, eluting with 2:1 dichloromethane/isohexane, dichloromethane then 5% ethyl acetate/dichloromethane, to afford 3-bromo-7-(4-fluorophenyl)quinoline as an off-white solid (2.55 g, 58%). 1H NMR (500 MHz, CDCl3) δ 8.93 (1H, d, J 2.2 Hz), 8.33 (1H, d, J 2.1 Hz), 8.24 (1H, s), 7.82-7.78 (2H, m), 7.71-7.69 (2H, m), 7.20 (2H, t, J 8.6 Hz).
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[C:24]([CH3:26])([OH:25])[C@:23]([F:28])([CH3:27])[CH:22]([O:29][CH3:30])[O:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>>[F:28][C@@:23]1([CH3:27])[CH:22]([O:29][CH3:30])[O:21][C@H:20]([CH2:19][OH:18])[C:24]1([CH3:26])[OH:25]
Reactant: COC1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C)(O)[C@@]1(C)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Product: COC1O[C@H](CO)C(C)(O)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
To a solution of (2R,4R)-2-((tert-butyldiphenylsilyloxy)methyl)-4-fluoro-5-methoxy-3,4-dimethyl-tetrahydrofuran-3-ol (about 1.5 g, 3.4 mmol) in tetrahydrafuran (about 25 ml) at about 0° C. was added 1M tetra butyl ammonium fluoride solution (about 3.47 ml, 3.4 mmol) drop wise for about 10 minutes and stirred at room temperature for about 1.5 hours. Completion of the reaction monitored by thin-layer chromatography and neutralized with saturated sodium bicarbonate. Aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with water, brine and dried over sodium sulphate and concentrated under reduced pressure, purified by silica gel column chromatography using 50% ethyl acetate: hexane as eluent furnished the title compound (0.5 g) as a colorless liquid. Yield: 75%; 1H NMR (300 MHz, CDCl3): δ 4.84 (d, 1H, J=15.3 Hz), 4.00-3.98 (m, 3H), 3.45 (s, 3H), 1.34 (d, 3H, J=24.3 Hz), 1.17 (s, 3H); Mass: [M+Na]+: 217 (100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+]>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:12]([C:11]([O:18][CH3:19])=[O:17])[C:13]([O:15][CH3:16])=[O:14])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 2-chloro-5-nitropyridine (25.0 g, 158 mmol) and dimethyl malonate (21.9 g, 166 mmol) in DMF (150 mL) was cooled to 0° C., and sodium hydride (6.50 g of a 60% dispersion in mineral oil, 162 mmol) was added in small portions. The mixture was stirred at 0° C. for 1 hour following completion of the addition. Then, another equivalent of sodium hydride (6.5 g of a 60% dispersion in mineral oil, 162 mmol) was added in small portions. The reaction was quenched by the addition of acetic acid (10 mL), and the mixture was evaporated to dryness. The residue was triturated with diethyl ether (150 mL) overnight and filtered, providing crude dimethyl 2-(5-nitropyridin-2-yl)malonate as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:24]([C@@H:26]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[NH:27]1)[CH3:25].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:27]3[C@H:26]([CH2:24][CH3:25])[CH2:30][CH2:29][S:28]3(=[O:32])=[O:31])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1
Yield: 31.7 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108, (R)-3-ethylisothiazolidine 1,1-dioxide (150 mg) described in Preparation Example 3, potassium carbonate (276 mg) and copper(I) iodide (95 mg) were added toluene (3 mL) and N,N′-dimethylethylenediamine (110 μL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (140 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8](=[O:15])[NH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27]Br)[CH:22]=1>CN(C)C=O>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:10]2[C:11]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=3)[NH:7][C:8](=[O:15])[C:9]2=[O:14])[CH:22]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(=O)c(=O)[nH]c3cc([N+](=O)[O-])ccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
Under an N2 stream and exclusion of moisture, 1.03 g (5 millimoles) of 6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline is combined with 50 ml of dimethylformamide at room temperature. To this mixture is added 330 mg (11 mmol) of sodium hydride (80% strength) in 3 portions. The mixture is then stirred for one hour at room temperature. To this mixture is added dropwise 1.26 g (5.5 mmol) of 3-bromomethylbenzoic acid methyl ester in 5 ml of dimethylformamide, and the mixture is further stirred for 3 1/2 hours. After concentration, the residue is distributed in acetic water/ethyl acetate. The organic phase is separated, dried, filtered and concentrated. The residue is chromatographed over silica gel with dichloromethan ethanol=95:5, thus obtaining, besides 211 mg of 3-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl-methyl) benzoic acid methyl ester, which is not further purified, also 222 mg of 3-(7-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-ylmethyl)benzoic acid methyl ester, mp: 265-267° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([OH:28])[C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[CH:13][C:12]1[CH2:23][CH2:24][CH2:25][CH2:26][C:11]=1[CH:10]=2)[CH3:2].Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OC(C)(C)C)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([O:28][C:6]([CH3:7])([CH3:15])[CH3:5])[C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)=[CH:13][C:12]1[CH2:23][CH2:24][CH2:25][CH2:26][C:11]=1[CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)nc2cc3c(cc2c1-c1ccc(C)cc1)CCCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2cc3c(cc2c1-c1ccc(C)cc1)CCCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.7 %

Procedure:
To a 50 mL flask containing a stirred suspension of hydroxy-(2-methyl-4-p-tolyl-6,7,8,9-tetrahydro-benzo[g]quinolin-3-yl)-acetic acid ethyl ester (15.3 mg, 39.0 μmol) in tert-butyl acetate (4 mL) under nitrogen was added perchloric acid (72%, 9.80 uL, 117 μmol) and the clear solution was stirred at ambient temperature for 3 hours. Added sodium carbonate solution (10%) until neutralization had occurred and extracted with ethyl acetate (10 mL). Organics were dried using a hydrophobic frit and evaporated onto silica. Chromatographed using ISCO Companion with a Redisep silica gel 4 g cartridge and a gradient of heptane and ethyl acetate (0-20%). Evaporation gave tert-butoxy-(2-methyl-4-p-tolyl-6,7,8,9-tetrahydro-benzo[g]quinolin-3-yl)-acetic acid ethyl ester as a clear oil 11.1 mg (63.8% Yield). LCMS (5 min acidic) 2.66 min 100% pure by ELSD and UV ES+ and AP+ 446. HNMR (CDCl3) >95% pure 7.76 (br-s, 1H), 7.37-7.32 (m, 3H), 7.22-7.20 (m, 1H), 7.03 (br-s, 1H), 5.14 (s, 1H), 4.21-4.15 (m, 2H), 3.00 (br-t, 2H), 2.85-2.73 (m, 5H), 2.50 (s, 3H), 1.88-1.77 (m, 4H), 1.22 (t, 3H), 0.97 (s, 9H).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCn1nccc1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2)s1
Reaction time: 1 h
Yield: 50 %

Procedure:
1,1-Dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (74 mg, 0.16 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 1 h, the solution was concentrated and neutralized through silica using 4% MeOH in DCM (1% NH4OH). The title compound was further purified using reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) affording the bis-TFA salt of the title compound (47 mg, 50%) as a white solid: LCMS (ES) m/z 355 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.71 (d, J=3.8 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.34-7.22 (m, 6H), 6.51 (d. J=1.8 Hz, 1H), 4.55 (m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.22 (dd, J=3.5, 13.1 Hz, 1H), 3.13 (dd, J=10.1, 13.1 Hz, 1H), 3.00 (m, 2H), and 1.42 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound. HR-MS (ES, m/z) calculated for C31H30N4O3F3Cl2 [(M+H)+] 633.1642, observed 633.1638.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[O:18])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([C:17](=[O:18])[CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:27])=[O:5])=[CH:10][CH:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.6 %

Procedure:
3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid tert-butyl ester (210 mg, 0.56 mmol) was dissolved in DCM (5 ml) and trifluoroacetic acid was added (2 ml). The reaction was stirred at room temperature for 12 h. The solvent was evaporated under vacuo giving 200 mg of 3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid.
Reaction SMILES: O.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:29]([NH:2][CH:3]2[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][CH:12]=3)[CH2:5][CH2:4]2)=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NC1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
Condensation of 3-[2-(4-aminopiperidyl)ethyl]indole, hydrate (1.31 g.) and 3,4-dichlorophenyl isocyanate (0.99 g., 5% excess) in the manner of Example 1 gave the crude title compound (2.03 g.) from which a pure hydrochloride (1.70 g., m.p. 258.4°, dec.) was obtained by treatment with ethanolic HCl/ether.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.[CH2:5]([O:12][C:13]1[CH:24]=[CH:23][C:16]([C:17]([NH:19][CH2:20]CO)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:1][Cl:4])=[O:18])=[CH:23][CH:24]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(NCCO)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)Cl
Solvent: C1COCCO1
Product: O=C(NCCCl)c1ccc(OCc2ccccc2)cc1
Yield: 68 %

Procedure:
Phosgene was bubbled through a suspension of 4-benzyloxy-N-(2-hydroxy-ethyl)-benzamide (22.49 g, 82.8 mmol) in dioxane (130 ml) until all the insoluble material had dissolved. Excess phosgene was removed by a stream of carbon dioxide. The solvent was removed at reduced pressure, and the residue was dried for 1 h. at 100° C. The crude product was recrystallized from ethyl acetate to yield 4-benzyloxy-N-(2-chloro-ethyl)-benzamide (16.3 g, 68%).
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([N:11]1[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]1)=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>CS(C)=O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([N:11]2[CH2:14][CH:13]([CH2:15][OH:16])[CH2:12]2)=[N:7]3)[CH2:36]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(CO)C3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(CO)C3)nc2c1C#N
Temperature: 150 °C
Reaction time: 19 h
Yield: 130.3 %

Procedure:
7-Fluoro-2-[3-(hydroxymethyl)azetidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-192) (220 mg, 0.37 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (166 μl, 1.19 mmol) and (3S)-3-(dimethylamino)pyrrolidine (159 μl, 1.25 mmol) were added, followed by stirring in a sealed tube at 150° C. for 19 hours. After cooling, concentration under reduced pressure, dilution with methylene chloride and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (208 mg, 74%) as a white amorphous substance.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:26](OCC)(=O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCC>>[CH3:1][C:2]([CH3:26])([CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)OCC
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)C(=O)OCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCC(C)(C)C(=O)OCC

Procedure:
The ethyl 2-methylarachidonate produced in Example 1 is substituted for the ethyl arachidonate in Example 1 and the procedure of Example 1 is repeated to afford ethyl 2,2-dimethylarachidonate. That compound is represented structurally by the following formula ##SPC3##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:20])[CH:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:37]([F:42])[CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-3-fluoro-benzoic acid ethyl ester (CAS Reg. No. 73792-12-8) in the presence of DMAP to give the title compound as colorless oil. MS: m/e=534.3 [M+H+].