Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1)(=O)C.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[OH:29][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[N:6]([CH3:20])[CH:5]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(=O)c(C(C)=O)cn2C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)c(=O)c(O)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of ethyl 3-acetyl-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.79 g, 6.55 mmol) in dichloromethane (40 ml) was added meta-chloroperbenzoic acid (2.2057 g, 9.84 mmol). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to roughly one half of the reaction volume. The resulting precipitate (O-acetate) was collected, added to methanol (20.0 ml), and heated at 65° C. overnight. After cooling, the reaction was filtered, and the precipitate was washed with dichloromethane to give ethyl 3-hydroxy-1-methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (0.9956 g, 4.03 mmol, 61.5% yield) as white solid. LCMS: (M+H)+: 248.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[CH:9]=[N:8][CH:7]=[CH:6]2.C[S-].[Na+]>CN(C)C=O>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[OH:2]
Reactant: COc1cc2ccncc2cc1-c1ccccn1
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cc2ccncc2cc1-c1ccccn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
6-Methoxy-7-pyridin-2-yl-isoquinoline (118 mg) and sodium thiomethoxide (350 mg) were suspended in N,N-dimethylformamide (3 ml), and the mixture was stirred at 150° C. for 4 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. The residue was purified by thin layer chromatography using chloroform-methanol to give 7-pyridin-2-yl-isoquinolin-6-ol (30 mg, yield 27%).
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:37][C:34]1[CH:35]=[CH:36][C:31]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][CH:17]=4)[CH:10]=3)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]2)=[N:32][CH:33]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)nc3)cc2[C@H](Nc2ccc(F)cn2)C[C@@H]1C
Temperature: 120 °C
Yield: 51 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (145 mg, 0.368 mmol), 2-bromo-5-fluoropyridine (129 mg, 0.735 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (29 mg, 0.074 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) and sodium tert-butoxide (71 mg, 0.739 mmol) were combined in 1,4-dioxane (4 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 30 mins. A further portion of 2-bromo-5-fluoropyridine (129 mg, 0.735 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (29 mg, 0.074 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) were added, The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 30 mins. The mixture was partitioned between water (20 mL) and DCM (3×15 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by chromatography (25 g column, (MeOH/DCM gradient) to give 1-((2S,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (91 mg, 0.186 mmol, 51% yield). LCMS: (Formate, 2 min), Rt=0.73 mins, MH+490.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[CH2:11](Br)[CH3:12]>O.CO>[CH2:11]([S:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCBr
Reactant: Fc1ccc(S)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSc1ccc(F)cc1
Yield: 79.1 %

Procedure:
To a stirring solution of NaOH (11.26 g, 281.6 mmol) in water (500 mL) was added dropwise a solution of 4-fluorothiophenol (25 mL, 234.6 mmol) in methanol (50 mL). After 15 minutes ethyl bromide (14.4 mL, 281.6 mmol) was added. After 6 hours more NaOH (1 g) was added and the reaction mixture was extracted with ether (3×300 mL). The combined organic extracts were treated with brine followed by MgSO4 then concentrated down to give 1-(ethylthio)-4-fluorobenzene (29 g, 80%) as a slightly yellow colored liquid.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].O=[C:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.[NH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]([O:39][C:40]([CH3:43])(C)C)=[O:38])[CH2:31][CH2:30]1.[OH-].[Na+]>C1COCC1>[N:29]1([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:30][CH2:31][CH:32]([O:35][CH2:36][C:37]([O:39][CH2:40][CH3:43])=[O:38])[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)COC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.90 g (13.3 mmol) NaBH(OAc)3 were added batchwise to a solution of 2.58 g (11.1 mmol)) tert. butyl 4-oxo-piperidine-1-carboxylate and 2.80 g (12.4 mmol) tert. butyl (piperidin-4-yloxy)-acetate in 30 mL THF and the reaction mixture was stirred overnight at RT. 50 mL of 1 M NaOH was added, the mixture was stirred for 1 h at RT, extracted exhaustively with EtOAc and the combined organic phases were dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (Alox, activity stage II-III, DCM/MeOH 100:1).
Reaction SMILES: O[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cc(-c3nc(C)cs3)c(=O)n(C)c2Cl)cc1
Reaction time: 1.5 h

Procedure:
6-Hydroxy-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one (0.13 g) was dissolved in freshly distilled POCl3 (5 cm3) under N2 and heated to refiux for 1.5 h. The excess reagent was then removed by evaporation and the residue partitioned between ethyl acetate (100 cm3) and saturated sodium bicarbonate solution (50 cm3). The aqueous layer was washed with ethyl acetate (2×100 cm3) and the combined organic phase dried (MgSO4) and evaporated. Purification on silica gel eluting with ethyl acetate-hexane mixtures afforded 6-chloro-5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one as a yellow powder. δH (250 MHz; CDCl3); 2.49 (3H, s), 3.86 (3H, s), 3.93 (3H, s), 6.96 (2H, d, J8.7 Hz), 7.01 (1H, s) 7.33 (2H, d, J8.7 Hz) and 8.60 (1H, s).
Reaction SMILES: COC(Cl)=O.C(O[C:11]1N=[C:18]([CH3:20])[C:17](Cl)=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])CCC.NCCC1C=CC(C(O)=O)=CC=1.[Na].C([O-])(=O)C.[Na+]>CC(C)=O.C(N(CC)CC)C>[C:13]([OH:15])(=[O:14])[C:12]1[CH:11]=[CH:20][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCOc1nc(C)c(Cl)cc1C(=O)O
Agent: CC(=O)[O-]
Agent: COC(=O)Cl
Agent: NCCc1ccc(C(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1
Reaction time: 2 h

Procedure:
2.8 g of triethylamine and 2.6 g of chloroformic acid methyl ester are added, while stirring and cooling with ice, to 6.1 g of 2-butoxy-5-chloro-6-methyl-nicotinic acid (melting point 95°-97° C., prepared by chlorinating 2-butoxy-6-methyl-nicotinic acid in dilute glacial acetic acid) in 75 ml of acetone. The mixture is stirred for a further 15 minutes and then added, while stirring, to 25 ml of a 1-molar solution of 4-(2-amino-ethyl)-benzoic acid-sodium, additionally containing 0.025 mol of sodium acetate and to which 25 ml of acetone has been added. Stirring of the mixture is continued for 2 hours at room temperature, the acetone is removed under reduced pressure, the remaining aqueous solution is acidified, the precipitated reaction product is filtered off with suction, reprecipitated from ammonia and recrystallized from dilute methanol or ethyl acetate. The 4-(2-<2-butoxy-5-chloro-6-methyl-nicotinamido>-ethyl)-benzoic acid obtained melts at 148°-150° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1)=O.O.NN.[OH-].[Na+]>C(O)COCCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: O=C(Cc1ccccn1)c1ccnc2ccccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(CCc2ccnc3ccccc23)nc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 g of 2-(2-pyridyl)-1-(4-quinolyl)-ethanone and 25 ml of 85% hydrazine hydrate in 250 ml of diethylene-glycol is heated at 160° C. for 30 minutes. After cooling to 60° C., 22 g of sodium hydroxide pellets are added and the mixture is heated at 160° C. for 2 hours. The reaction mixture is diluted with water, then extracted 3 times, each by 300 ml of methylene chloride. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. 12.5 g are thus obtained of 4-[-2-(2-pyridyl)-ethyl]-quinoline in the form of a lacquer. N.M.R. spectrum of the product obtained:
Reaction SMILES: COC[O:4][C:5]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C@H:20]2[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:26]COC)[CH:6]=1.Cl>C1COCC1.[Cl-].[Na+].O>[CH2:24]([O:23][C:22]1[C:5]([OH:4])=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[CH2:18][CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[OH:26])[CH3:25]
Reactant: CCOC1=C[C@H]2C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OCOC)CC[C@@H]32)C=C1OCOC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
To a solution of 2 (6.0 g, 14.8 mmol) in THF (100 ml) was added 6 N HCl (100 ml) at room temperature and the resulting solution was stirred at room temperature for 6 hr. The reaction mixture was poured into brine (200 ml) and the products were extracted with ethyl acetate (3×100 ml). The ethyl acetate layers were washed with saturated sodium bicarbonate (100 ml) and brine (100 ml), combined and dried over sodium sulfate, and evaporated to dryness. Chromatography of the residue (silica gel 230-400 mesh, methylene chloride:ethyl acetate 9:1 by volume) gave compound 3 (4.04 g, 85%), which was crystallized from ethyl acetate/hexane to afford white crystals: mp 151-150° C. (lit.4 mp 154-155° C.); 1H NMR (CDCl3) δ6.95 (s, 1 H), 6.65 (s, 1 H), 4.08 (qd, J=6.8 Hz, J=1.5 Hz, 2 H), 3.73 (t, J=8.4 Hz, 1 H), 2.73 (m, 2 H), 2.30-1.20 (m, 18 H), 0.81 (s,3 H).
Reaction SMILES: FC(F)(F)C[O:4]C1C=CC(OCC(F)(F)F)=CC=1.C[C:20]([C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:23]=1[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:21].C(C1C=CC=CC=1)(=O)C>>[F:37][C:36]([F:39])([F:38])[CH2:35][O:34][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:27][C:22]=1[C:20]([OH:21])=[O:4]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is then treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Subsequently, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpyridine, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide. Finally, the 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide is treated with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(S(Cl)(=O)=O)=CC=1.[NH2:23][C@@H:24]([C:29](O)=[O:30])[C@@H:25]([CH2:27][CH3:28])[CH3:26].CC([C@](N)(C(O)=O)C)C.CC(C1C=CC=CC=1)C(C(O)=O)N.N[C@H](C(O)=O)[C@@H](CC)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:23][C@@H:24]([CH2:29][OH:30])[C@H:25]([CH3:26])[CH2:27][CH3:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CC(C)[C@](C)(N)C(=O)O
Agent: CC(c1ccccc1)C(N)C(=O)O
Agent: CC[C@@H](C)[C@H](N)C(=O)O
Product: CC[C@@H](C)[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The following compounds (Examples 33–39, Table 5) were prepared using 4-bromobenzenesulfonyl chloride, and 4-chlorobenzenesulfonyl chloride, with D-isoleucine, L-α-methyl-valine, β-methyl-DL-phenylalanine, and L-allo-isoleucine and following the procedure outlined in Example 33. This procedure is outlined in the following Scheme.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([O:12][CH3:13])[N:3]=1.[Cl-].[NH4+].[OH-].[NH4+].[CH3:18][N:19](C=O)C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:13][O:12][C:4]1[N:3]=[C:2]([C:18]#[N:19])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(F)(F)F)c(Cl)n1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: COc1ccc(C(F)(F)F)c(C#N)n1
Reaction time: 1.5 h

Procedure:
Heat a solution of 2-chloro-6-methoxy-3-trifluoromethyl-pyridine (211 mg, 1.0 mmol), zinc cyanide (64 mg, 0.55 mmol), pd2(dba)3 (45 mg), DPPF (55 mg) in DMF (3 mL) and water (0.03 mL), under a nitrogen atmosphere, at 120° C. for 1.5 hours. Cool the reaction to 0° C. and add a solution of saturated ammonium chloride solution (2 mL), water (2 mL) and concentrated ammonium hydroxide (0.5 mL) and stir for 1 hour. Extract the mixture with ethyl acetate (3×20 mL) and wash the combined organics with brine (50 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with a 25:1 mixture of hexane:ether to give the title compound.
Reaction SMILES: CC(C)(C)C([O:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1
Reactant: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(CO)n1

Procedure:
A solution of 2-{[(2,2-dimethylpropanoyl)oxy]methyl}-1,3-thiazole-4-carboxylic acid (3 g, 12.33 mmol, commercially available) and potassium carbonate (2.326 g, 16.83 mmol) in methanol (100 ml) and water (30 ml) was heated to reflux for 4 hr. The mixture was cooled and concentrated in vacuo to ˜30 ml. It was then acidified with 2 M HCl (50 ml) and concentrated in vacuo. The resulting solid was treated with hot MeOH/EtOAc (2:1), washing well before filtering off the remaining solid. The filtrate was concentrated in vacuo to give a brown solid which was dissolved in MeOH and added to the top of 2×70 g aminopropyl cartridge that had been preconditioned with MeOH. The cartridges were both eluted with MeOH and then with 10% HCl in MeOH. The acidic fractions were combined and the solvent removed in vacuo to give the title compound as a brown oil (550 mg). LCMS (Method B) Rt=0.36 min, MH+=160.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][C:44]([N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)=[O:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:40]3[CH2:39][CH2:38][N:37]([CH2:43][C:44]([N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)=[O:45])[CH2:42][CH2:41]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. LC-MS: 704.3 [(M+H)+]
Reaction SMILES: [CH:1]1([N:6]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([OH:34])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>N1C(C)=CC(C)=CC=1C>[CH:16]1([N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7](=[O:15])[C:8]2[CH:13]=[CH:12][C:11]([O:34][C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)=[CH:10][CH:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(c1ccc(Br)cc1)N(C1CCCCC1)C1CCCC1
Reactant: COc1cc(O)cc(OC)c1OC
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cc(Oc2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc(OC)c1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-cyclopentyl-N-cyclohexyl amide (2.285 g, 6.52 mmol), 3,4,5-trimethoxy phenol (1.199 g, 6.51 mmol) and cuprous oxide (486 mg, 3.40 mmol) in 2,4,6-collidine (15 ml). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as a crystalline solid that could be recrystallized from ethyl acetate and hexane, m. pt. 166.16° C. (DSC).
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1>C1(C)C=CC=CC=1>[NH:15]1[C:14]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:17][CH:16]1[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: c1ccc2c(c1)CNC2
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CC(Cc1c[nH]c3ccccc13)N2
Yield: 52.7 %

Procedure:
To gramine (731 mgs, 4.2 mmol) in dry PhMe (20 ml) was added 1,2-dihydroisoindole (prepared as in Org. Syn., Coll. Vol. V, p. 406) (500 mgs, 4.2 mmol) and the reaction refluxed for 6 h. The solvent was evaporated, the residue triturated with PhMe and the resultant solid recrystallised from PhMe to yield the title compound (550 mgs, 52%). M.p. 168°-170° C.; (Found: C, 80.44; H, 6.46; N, 10.98. C17H16N2.0.25H2O) requires C, 80.76; H, 6.38; N, 11.08%). δH (CDCl3) 4.00 (4H, s, 2×isoindolinyl CH2), 4.11 (2H, s, NCH2Ar), 7.08-7.23 (7H, m, ArH), 7.36 (1H, d, J 7.9 Hz, ArH), 7.77 (1H, d, J 7.9 Hz, ArH), 8.18 (1H, brs, NH); m/z (CI+, NH3) 249 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH2:4][C:3]5[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=5[F:1])[CH2:28][CH2:27]4)[CH2:22][CH:21]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Reactant: Fc1ccc(F)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(F)c(CN2CCN(C3CC=C(c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from 2,5-difluorobenzyl bromide (0.21 g, 1 mmole), and 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.29 g, 1 mmole), and excess powdered K2CO3 as described in example 45 to give the product (62%, mp: 108-109° C.). Calc'd for C24H26F2N2O2 : C, 69.88%; H, 6.35%; N, 6.79%. Found: C, 69.82; H, 6.35%; N, 6.69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].C([O-])([O-])=O.[K+].[K+].O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C>[F:23][C:20]1[CH:19]=[C:18]([F:24])[CH:17]=[CH:22][C:21]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH:9]([CH3:11])[CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=Cc2ccc(F)cc2F)cc(OC)c1C(C)C
Temperature: 140 °C

Procedure:
A mixture of (3,5-dimethoxy-4-i-propylphenyl)ethene (0.649 g, 3.15 mmol), 1-bromo-2,4-diflurobenzene (1.23 g, 6.37 mmol), dihydrogen di-μ-chlorotetrkis(di-tert-butylphosphinito-κP)dipalladate (0.1409 g, 0.151 mmol), Bu4NI (0.582 g, 1.58 mmol) and K2CO3 (1.45 g, 10.5 mmol) in DMF (10 mL) was heated at 140° C. under argon. After the reaction was complete (6 h), the reaction mixture was poured into water (10 ml). The aqueous was acidified with 2NHCl and extracted with ether (2×50 mL). The extract was washed with saturated sodium chloride and then dried over anhydrous Na2SO4. Evaporation of ether followed by flash chromatography using 2% ethyl acetate in hexane afforded 1-(2,4-difluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene (31) quantitatively as a yellowish crystal. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.63 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.76 (s, 2H), 7.08 (d, J=17 Hz, 1H), 7.27 (d, J=17 Hz, 1H), 7.63 (d, J=8 Hz, 2H), 8.13 (d, J=8 Hz, 2H).