Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[CH3:17])[C:5]([OH:7])=[O:6])(=[O:26])[CH3:25]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C(=O)O)ccc1N1CCCCC1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of 3-amino-4-(2-methylpiperidin-1-yl)benzoic acid obtained in step 2 (100 mg; 0.43 mmol) in pyridine (69.04 μL, 0.85 mmol) and DCM (4 mL), was added acetyl chloride (36.42 μL; 0.51 mmol). The reaction mixture was then stirred at 40° C. for 5 h after which solvents were evaporated under vacuum, solid residue was triturated with ethylacetate and re-evaporated. Finally, water was added to the reaction mixture which was sonicated, filtered, dried under vacuum to give the title compound as a white solid (95 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 12.76 (bs, 1H), 8.97 (s, 1H), 8.66 (s, 1H), 7.64 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.07-3.01 (m, 1H), 2.86-2.82 (m, 1H), 2.57-2.51 (m, 1H), 2.15 (s, 3H), 1.82-1.77 (m, 4H), 1.47-1.42 (m, 2H), 0.78 (d, J=6 Hz, 3H). LC/MS (Method B): 277.2 (M+H)+. HPLC (Method A) Rt 1.77 min (purity: 91.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1F
Temperature: 50 °C
Yield: 93.6 %

Procedure:
A mixture of 5-bromo-2-fluorobenzoic acid (25 g, 0.11 mol), methyl iodide (8.5 mL, 0.14 mol), and potassium carbonate (31 g, 0.23 mol) in DMF (200 mL) was heated to 50° C. for 18 hr. The cooled reaction mixture was diluted with EtOAc (200 mL) and the organic phase was washed with a saturated aqueous NaCl solution (4×). The organic phase was then dried over sodium sulfate and evaporated to dryness to give 24 g of methyl 5-bromo-2-fluorobenzoate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=O)[CH2:8][CH2:7][C:6]2([CH3:16])[CH3:15].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>>[CH:17]([C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([CH3:13])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=1)([CH3:19])[CH3:18]
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc2c(cc1C)C(=O)CCC2(C)C
Product: COc1cc2c(cc1C)C(C(C)C)=CCC2(C)C
Yield: 52.2 %

Procedure:
Following General Procedure F, 6-methoxy-4,4,7-trimethyl-3,4-dihydro-2H-naphtalen-1-one (compound 30) (1.5 g, 6.9 mmol) was reacted with a solution of 2M isopropylmagnesiumchloride (17 mL, 34.5 mmol), and the crude product was purified by flash column (hexane:ethyl acetate=4:1) to give 0.88 g (53%) of the title product as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:4]=[C:3]1[S:12][CH:13]([CH3:17])[C:14]([OH:16])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=1)[C:45]([NH:47]O)=[NH:46]>C(OCC)(=O)C.CN(C=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([C:45]2[N:47]=[C:14]([CH:13]([S:12][C:3]3[N:2]([CH3:1])[C:6]([C:7]4[S:8][CH:9]=[CH:10][CH:11]=4)=[N:5][N:4]=3)[CH3:17])[O:16][N:46]=2)[CH:49]=[CH:50][CH:51]=1
Reactant: CC(Sc1nnc(-c2cccs2)n1C)C(=O)O
Reactant: N=C(NO)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Sc1nnc(-c2cccs2)n1C)c1nc(-c2cccc(Cl)c2)no1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
DMF was added to a mixture of 2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic acid (50 mg, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (35.7 mg, 0.186 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (28.5 mg, 0.186 mmol) and 3-chloro-N-hydroxy-benzamidine (29.3 mg, 0.172 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (75 ml), washed with water 3 times, once with 1.0 M HCl (30 ml), saturated NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. DMF (1 ml) was added to the residue and the resulting solution was heated at 135° C. for 3 h to effect cyclization to oxadiazole. After cooling the reaction mixture was diluted with ethyl acetate (75 ml), washed with water 3 times, once with 1.0 M HCl (30 ml), saturated NaHCO3 (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The title compound (46.5 mg, 66.9%) was purified by SPE chromatography on silica gel using 50 ml 40%, 150 ml 50% ethyl acetate in hexanes. 1H NMR (CDCl3), δ (ppm): 8.03 (s, 1H), 7.92 (m, 1H), 7.47 (m, 4H), 7.18 (dd, 1H), 4.99 (q, 1H), 3.64 (s, 3H), 1.97 (d, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].CCN=C=NCCCN(C)C.[C:38]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][C:49](O)=[O:50])=[CH:43][CH:42]=1)([OH:40])=[O:39]>CN(C1C=CN=CC=1)C>[C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([O:20][C:49](=[O:50])[CH2:48][CH2:47][C:44]3[CH:45]=[CH:46][C:41]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=3)[CH:18]=[CH:19][C:14]=2[C:13]2[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:1]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: O=C(O)CCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCc3ccc(C(=O)O)cc3)cc1[C@@H](NC(C)=O)CC2
Yield: 70 %

Procedure:
A solution of N-acetyl-colchicinol (0.357 g; 1 mmol), EDCI (0.23 g; 1.2 mmol), DMAP (0.025 g; 0.2 mmol) and 3-(4-carboxyphenyl)propionic acid (0.233 g; 1.2 mmol) was stirred at ambient temperature overnight. After removal of the solvent by evaporation, the residue was purified by preparative HPLC on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g/l pH7) (50/50) to give 4-(3-[(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl]oxy-3-oxopropyl)benzoic acid.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Br)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15]>[N+](C)([O-])=O.C1(C)C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:19][C:18]([CH3:21])([CH2:17][CH:14]([CH3:16])[CH3:15])[CH2:20][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][C:8]([CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:10]=3
Reactant: CC(C)(C)CC(C)(C)Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: CC(C)CC(C)(C)Cc1ccc2[nH]c3ccc(CC(C)(C)CC(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
ZnCl2 (36.8 g, 276 mmol) and carbazole (21.0 g, 126 mmol) are suspended in 600 mL nitromethane in a 1 qt jar in a glove-box. The t-octyl bromide (53.4 g, 276 mmol) is added dropwise to the gray-green suspension via addition funnel. The mixture turns into a black solution during the addition. The solution is allowed to stir at room temperature for two hours and then poured into 500 mL ice water. The product is extracted out of the mixture with 500 mL and 250 mL CH2Cl2. The combined organic portions are dried with MgSO4, filtered and rotovapped to yield a dark residue. This residue is taken up in 200 mL toluene, passed through a plug of silica, and washed through with 150 mL toluene. The yellow solution is reduced to a solid on the rotovap. This material is recrystallized from 100 mL hexane at −13° C. 27 g (55%) of white crystals are collected. The crystallization only moderately improved the purity of the product. 1H NMR (CDCl3): δ 8.02 (d, JH-H=1.6 Hz, 2H), 7.80 (br s, 1H, NH), 7.42 (dd, JH-H=8.6, 1.8 Hz, 2H), 7.29 (d, JH-H=8.5 Hz, 2H), 1.83 (s, 4H, CH2), 1.49 (s, 12H, CMe2), 0.72 (s, 18H, CMe3).
Reaction SMILES: Br[CH:2]([C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[S:22])=[CH:19][CH:18]=1>CN(C)C=O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:23]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([OH:16])=[CH:18][CH:19]=3)[S:22][C:2]=2[CH2:3][C:4]([OH:6])=[O:5])=[CH:9][CH:10]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
3-Bromo-3-(4-chlorobenzoyl)propionic acid (27 g), and 4-hydroxy-thiobenzamide (14.6 g) were heated to 80° in dimethylformamide (50 ml). The reactants were kept at this temperature for 1 hour, cooled and poured onto ice. The resulting gum solidified, and was filtered, and washed with water, to give 31.6 g of powder, m.p. 184°-194° C. (decomp.). This was recrystallised from aqueous isopropanol affording 25.4 g of the title compound, hemihydrate, m.p. 192°-194° (d).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[C:9]=2[CH3:25])[CH:7]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].[H-].[Na+].CN(C=[O:43])C>>[Si:30]([O:29][CH2:28][CH2:27][O:43][C:3]1[CH:2]=[CH:7][C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([C:21]([F:23])([F:22])[F:24])[C:9]=2[CH3:25])=[CH:5][CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc(-n2nc(C(F)(F)F)c(C)c2-c2cccc(O)c2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-n2nc(C(F)(F)F)c(C)c2-c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 5-(hydroxyl)phenyl-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole (5.0 g) and 2-bromoethoxy-tert-butyldimethylsilane (6.87 g) in DMF (100 ml) was added portionwise NaH (919 mg, 50% in oil) at room temperature. The reacion mixture was stirred overnight. The reaction mixture was quenched with water. Aqueouslayer was extracted twice with EtOAc. Combined organic layer was washed twice with water, and brine. Dried, filtered and evaporated under reduced pressure to give 5.29 g (73%) of 5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazole.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[CH:19]=[CH:18][NH:17][C:11]=4[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C)C=O>[CH3:29][NH:30][C:31]([N:17]1[C:11]2[NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[C:10]=2[CH:19]=[CH:18]1)=[O:32]
Reactant: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c21
Reaction time: 8 h

Procedure:
A solution of pyrrolo-pyridine 16 in dimethylformamide under an atmosphere of nitrogen and 3 equivalents of di-iso-propylethylamine (3 eq.) was added 3 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the title compound 17a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83-3.11 (m, 3H) 6.64-6.92 (m, 1H) 7.21-7.43 (m, 1H) 7.44-7.63 (m, 2H) 7.77-8.05 (m, 3H) 8.57-8.81 (m, 1H) 9.48-9.76 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
4-hydroxybenzaldehyde (8.2 mmols), 1-bromooctane (12.3 mmols) and cesium carbonate (16.4 mmols) were dissolved in DMF (13.7 mmols). The mixture was then heated to 80° C. and stirred for 3 hours. After this time, the reaction mixture was filtered through a fine fritted funnel; the eluent was collected and diluted with 200 mLs of EtOAc. The organic layer was extracted with seven 10 mL portions of H2O and two 15 mL portions of brine. The organic layer was dried with MgSO4 and evaporated to dryness. After purification by flash chromatography 7.8 mmols of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 9.86 (d, J=2.9, 1H), 7.94-7.74 (m, 2H), 7.05-6.92 (m, 2H), 4.02 (td, J=3.1, 6.5, 2H), 1.88-1.73 (m, 2H), 1.44 (dd, J=6.8, 14.2, 2H), 1.39-1.21 (m, 8H), 0.99-0.81 (m, 3H). 13C NMR (126 MHz, CDCl3) δ 190.76, 164.24, 131.95, 129.70, 114.71, 68.40, 31.77, 29.28, 29.03, 25.95, 22.63, 14.08.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=2[OH:15])[CH:5]=[C:4](Cl)[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[ClH:34].O1CCOCC1>C(#N)C.C(OCC)(=O)C>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[C:8]([C:6]2([Cl:34])[NH:7][C:2]([NH2:1])=[N:3][CH:4]=[CH:5]2)[CH:13]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Reactant: Cl
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1=NC=CC(Cl)(c2cc(Br)ccc2OCc2ccc([N+](=O)[O-])cc2)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol (0.151 g, 0.50 mmol), 1-bromomethyl-4-nitro-benzene (0.218 g, 1.0 mmol), and cesium carbonate (0.325 g, 1.0 mmol) in acetonitrile (10 ml) was stirred at 80° C. for 2 hours. Filtration and concentration of the filtrate provided a crude product which was dissolved in ethyl acetate (10 ml) and stirred while a 4 M solution of hydrogen chloride in dioxane (0.50 ml, 2.0 mmol) was added. Filtration provided 6-[5-bromo-2-(4-nitro-benzyloxy)-phenyl]-6-chloro-pyrimidin-2-ylamine as hydrochloride salt (0.23 g, 96% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH:14]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[C:16](#[N:20])[CH2:17][C:18]#[N:19].NC(C(O)=O)C.C(O)(=O)C>O.C1C=CC=CC=1>[C:18]([CH:17]([C:16]#[N:20])[CH2:14][CH2:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:6][CH:7]=1)#[N:19]
Reactant: N#CCC#N
Reactant: COC(=O)c1ccc(CCCC=O)cc1
Agent: CC(N)C(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(CCCCC(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3.36 g (1.0 eq) of 4-(4-carbomethoxyphenyl)butanal, 1.29 g (1.2 eq) of malononitrile, 0.05 g of D,L-alanine, 1 mL of glacial acetic acid, and 60 mL of benzene is refluxed with azeotropic removal of water. After 3 hours, about 85% of the theoretical amount of water should be formed and removed. The mixture then is cooled to room temperature and poured into water. The aqueous layer is extracted twice with benzene and the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure. Chromatography with 1:1 ethyl acetate:hexanes and concentration of the eluant yield methyl 4-(5,5-dicyanopentyl)benzoate as an oil. IR (film) max ν max 2240, 1718, 1615, 1280, and 1110 cm-1 ; 1H NMR (CDCl3) delta 7.99 (d, J=8.1 Hz, 2H, Ar), 7.24-7.29 (m, 3H, Ar, vinyl), 3.90 (s, 3H, --CH3), 2.79 (t, J=7.4 Hz, 2H, benzyl), 2.60-2.64 (m, 2H, --CH2C=C), 1.94-1.97 (m, 2H, --CH2 --).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][NH2:15].C(N(CC)CC)C>C(Cl)Cl>[F:12][C:13]([F:17])([F:16])[CH2:14][NH:15][C:9]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)=[O:10]
Reactant: NCC(F)(F)F
Reactant: O=C(Cl)c1cnc(Cl)nc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1cnc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
2,4-Dichloropyrimidine-5-carbonyl chloride (1 g, 5 mmol) was dissolved in CH2Cl2 (20 mL), 2,2,2-trifluoroethylamine (515 mg, 5 mmol) and triethylamine (1.31 mL, 9 mmol) were added. The reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was purified by flash chromatography to yield a white solid (780 mg, 60%). MS: m/z=271.9 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]2[O:14]C2(C)C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.I([O-])(=O)(=O)=O.[K+]>O>[CH:1]1([CH2:7][CH2:8][C@@H:9]([CH3:17])[CH2:10][CH2:11][CH:12]=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](CCC1CCCCC1)CCC1OC1(C)C
Agent: [K+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CCC=O)CCC1CCCCC1
Reaction time: 46 h
Yield: 81.1 %

Procedure:
A flask was charged with 10.65 g (44.7 mmol) of 3-((R)-5-cyclohexyl-3-methyl-pentyl)-2,2-dimethyl-oxirane, 70 mL of acetone, 12.3 g (53.6 mmol) of potassium periodate, 70 mL of water, and 0.765 g (4 mmol) of tosic acid-monohydrate. The mixture was stirred for 46 hours. The acetone was removed under reduced pressure, and the mixture was diluted with water. The aqueous layer was extracted with hexanes and dried with sodium sulfate. The drying agent was filtered off and solvent was removed under reduced pressure to get 7.12 g (81% yield) of a clear oil: 1H NMR (400 MHz, CDCl3) ppm 0.87 (m, 5 H) 1.13 (m, 3 H) 1.25 (m, 5 H) 1.66 (m, 8 H) 2.40 (m, 2 H) 9.75 (s, 1 H). MS (APCl) m+1/z is inconclusive.
Reaction SMILES: [Cl:1]C1C=CC(Cl)=CC=1C=O.COC1C=C(C=CC=1)C=O.[ClH:21].[CH2:22]([CH:29]([CH2:40][N:41]([CH3:43])[CH3:42])[C:30]([C:32]1[CH:37]=[CH:36][C:35](Cl)=[CH:34][C:33]=1[Cl:39])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:1].[CH2:22]([CH:29]([CH2:40][N:41]([CH3:43])[CH3:42])[C:30]([C:32]1[CH:37]=[C:36]([Cl:21])[CH:35]=[CH:34][C:33]=1[Cl:39])=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)CC(Cc1ccccc1)C(=O)c1ccc(Cl)cc1Cl
Reactant: O=Cc1cc(Cl)ccc1Cl
Agent: COc1cccc(C=O)c1
Agent: Cl
Product: CN(C)CC(Cc1ccccc1)C(=O)c1cc(Cl)ccc1Cl

Procedure:
The synthesis was carried out according to the procedure of Example 1, except that 5.0 g (0.028 mole) of 2,5-dichlorobenzaldehyde were used instead of 3-methoxybenzaldehyde. The reaction steps involving Grignard reaction, oxidation and Mannich reaction led to a total yield of 1.4 g (14%) of (2RS)-2-benzyl-1-(2,4-dichlorophenyl)-3-dimethylaminopropan-1-one hydrochloride with a melting point of 140° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:30](=[O:32])=[O:31]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:30]([OH:32])=[O:31])=[N:11][C:10]([C:13]([F:16])([F:14])[F:15])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ncn(-c2ncccc2Cl)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: O=C(O)c1nc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 0.25 g of 3-chloro-2-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)pyridine and 5 ml of tetrahydrofuran was added dropwise 0.50 ml of a 2.0M lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C. and the mixture was stirred at −78° C. for 15 minutes. Carbon dioxide was introduced into the mixture at such a rate that an inner temperature was maintained at −60° C. or lower and, after the mixture turned yellow, the mixture was further stirred at −78° C. for 10 minutes. The temperature of the reaction mixture was raised to room temperature, followed by concentration. A 2N aqueous sodium hydroxide solution was added to adjust the pH of the aqueous layer to 10 to 12, the layers were separated, and the organic layer was extracted with a 0.5N aqueous sodium hydroxide solution. The aqueous layers were combined, and washed with chloroform, and 2N hydrochloric acid was added so that the pH of the aqueous layer became about 3, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 0.13 g of crude 1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-1,2,4-triazole 5-carboxylic acid of the formula:
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].C1(C)C=CC=CC=1.[O:19]1[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20]1>O.S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:19][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][O:11][C:8]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCCCCC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 388.6 %

Procedure:
The sodium salt of 4-nitrophenol (28.19 g, 0.175 mol) was dissolved in water (50 mL) and toluene (300 mL) and tetrabutylammonium sulfate (6.0 g) was added. 1,2-Epoxydecane (27.3 g, 0.175 mol) was added to this mixture and the reaction was heated at 100° C. for 5 days. The toluene layer was separated and washed with water (4×75 mL), 1N hydrochloric acid (2×75 mL) and water (75 mL). The organic layer was dried over sodium sulfate, filtered and the solvent removed. The crude product was purified by silica gel chromatography (2-3% methanol/methylene chloride) to afford 4-(2-hydroxy-1-decyloxy)nitrobenzene as a pale oil (20 g, 0.68 mol, 39% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Cl:11]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.CCCCCCC>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1cc(Cl)cc(Br)c1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: COc1cc(Cl)c(Cl)c(Br)c1
Yield: 197.3 %

Procedure:
1-Bromo-3-chloro-5-methoxybenzene (Preparation 22, 6.0 g, 27 mmol) and trichloroisocyanuric acid (2.3 g, 9.9 mmol) were stirred in dimethylformamide (100 ml) at 50° C. for 3 hours. N-Heptane was added and the mixture filtered to remove insoluble impurities. The mixture was then concentrated in vacuo and the residue purified by silica gel column chromatography, eluting with 90:10 heptane:ethyl acetate to afford the title compound as a white solid (5.0 g).
Reaction SMILES: CN(C=O)C.[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[NH:12][C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:25]=1[CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[C:15]2[N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[N:12]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:25]=3[CH3:34])[C:11]=2[CH:10]=[C:9]([N+:19]([O-:21])=[O:20])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cn2c(C3CC3)nc3c(Br)cc([N+](=O)[O-])cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
To a 250 mL round bottomed flask containing DMF (50 mL) was added 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol), 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (3.6 mL, 21.34 mmol) and potassium carbonate (6.32 g, 45.7 mmol). The resultant suspension was heated to 50° C. and after stirring for 30 minutes the mixture was allowed to cool to rt and diluted with 100 mL H2O. The mixture was stirred overnight and the next day a brown filterable solid was isolated by filtration providing crude 4-bromo-2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-nitro-1H-benzo[d]imidazole (5.97 g, 13.14 mmol, 86% yield). MS (ES+) m/e: 453.0, 454.0 [M+H]+