Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:22])=[CH:5][N:6]=1
Reactant: Nc1ncc(Sc2ccncc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Nc1ncc(S(=O)c2ccncc2)s1
Yield: 58.1 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (4.0 g) in a mixture of chloroform (300 ml) and N,N-dimethylformamide (10 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.5 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 26 hours under ice cooling. The reaction mixture was washed with aqueous sodium bicarbonate and water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subject to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-pyridylsulfinyl)thiazole (2.5 g, yield: 58.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:41][C:42]([N:44]([CH:53]([CH3:55])[CH3:54])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[O:43]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]([CH2:41][C:42]([N:44]([CH:53]([CH3:55])[CH3:54])[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:43])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: O=C(NC1N=C(c2cccnc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)OCc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A solution of 1.000 g of 3-(benzyloxycarbonyl-amino)-5-pyridin-3-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (2.591 mmol, Pat. App. WO 93/16999) in 7 mL dimethylformamide at 0° C. under nitrogen was treated with 5.44 mL (2.72 mmol) of potassium bis(trimethylsilyl)amide (0.5M in toluene). After stirring for 10 min., a solution of 0.779 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (2.72 mmol), prepared as in Intermediate 5, in 2 mL of dimethylformamide was added to the mixture. The reaction was stirred to ambient temperature over 2 hrs. and then quenched into a mixture of ethyl acetate, water and saturated aqueous brine. The phases were separated and the aqueous phase was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was purified on flash grade silica gel using 9:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a foam and triturated with hexane. After evaporation of the hexane in vacuo, the residual solid was dried under high vacuum to provide 1.295 g of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) -- =8.70 (m, 2H), 8.56 (d, 1H, J=8.6), 7.92 (m, 1H), 7.71 (m, 1H), 7.52 (m, 2H), 7.32 (m, 9H), 7.07 (d, 2H, J=8.8), 5.19 (d, 1H, J=8.8), 5.08 (s, 2H), 4.71 (m, 1H), 4.27 (d, 1H, J=16.5), 4.12 (d, 1H, J=16.5), 3.81 (s, 3H), 0.95 (m, 6H); MS (ESI): [M+H]+ =592.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.ClC1C(C=O)=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:28][CH2:29]C)=[CH:21][CH:22]=2)[N:17]=1>>[CH3:29][O:28][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:5]([C:4]([OH:3])=[O:14])[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:17]2)=[CH:22][CH:21]=1
Reactant: CCOc1ccc2cc(C=O)c(Cl)nc2c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: COc1ccc2cc(C(=O)O)c(-c3ccccc3)nc2c1

Procedure:
Following the procedure of Example 36 (a)-(b) substituting ethylbenzoylacetate in step 36 (a) gave the above named compound. LCMS m/e [M+H]+=280.2
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH2:36][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C=O)c2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(CN3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-formyl-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (143 mg of 50% pure material, approx. 0.142 mmol) was dissolved in DCE (1.5 mL) and AcOH (0.15 mL). Morpholine (18.5 uL, 0.213 mmol) and sodium triacetoxyborohydride (75 mg, 0.355 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between dichloromethane and 10% aqueous NaHCO3. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were evaporated to dryness and the product (90 mg) was used without further purification.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:27]C[O-].[Na+].CCO.O>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 mL and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.35; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.69; s, 7.97.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[C:6]([C:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:7][C:6]=1[C:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[C:11](=[O:17])[N:10]([CH3:18])[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)n2cncc2c1=O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of the title compound from Example 129, Step 2 (140 mg, 0.38 mmol) in THF (20 ml) was added pyridine (152 mg, 1.90 mmol). Then methanesulfonyl chloride (48 mg, 0.46 mmol) was added to the solution at 0° C. The solution was allowed to warm up to room temperature and heated to reflux for overnight. The reaction mixture was concentrated under reduced pressure to yield the crude product that was purified by prep-HPLC to give the title compound (75.26 mg, 44%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J=2.8 Hz, 1H), 7.30 (dd, J=8.8, 2.4 Hz, 1H), 7.18 (td, J=8.8, 5.3 Hz, 1H), 7.00-6.88 (m, 2H), 6.83 (s, 1H), 6.78 (d, J=8.8 Hz, 1), 3.60 (s, 3H), 3.03 (s, 3H). LCMS: 447.0 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH2:43]C)([CH2:41]C)[CH2:33][O:34]C1CCCCO1)([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH2:26]C)([CH2:24]C)[CH2:16][O:17]C1CCCCO1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)C>Cl.O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([CH3:41])([CH3:43])[CH2:33][OH:34])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:24])([CH3:26])[CH2:16][OH:17])[C:4]([O:3][CH2:1][CH3:2])=[O:45])[CH3:10]
Reactant: CCOC(=O)C(CCCCC(CC)(CC)COC1CCCCO1)(CCCCC(CC)(CC)COC1CCCCO1)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(CCCCC(C)(C)CO)(CCCCC(C)(C)CO)C(=O)OCC
Yield: 0.1 %

Procedure:
A solution of 2,2-bis-[5,5-diethyl-6-(tetrahydropyran-2-yloxy)-hexyl]-malonic acid diethyl ester (2.92 g, 5 mol) in concentrated HCl (2.4 mL) and water (1.6 mL) was refluxed for 1 h. Ethanol (8.2 mL) was added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was diluted with water (20 mL) and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over Na2SO4. The solution was concentrated to furnish 2,2-bis(6-hydroxy-5,5-dimethyl-hexyl)-malonic acid diethyl ester (1.74 g, 84%). 1H NMR (300 MHz, CDCl3/TMS): (ppm) 4.13 (q, J=7.2 Hz, 4H), 3.25 (s, 4H), 2.42 (s, 2H), 1.90-1.75 (m, 4H), 1.30-1.12 (m, 18H), 0.84 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm) 172.0, 71.7, 60.9, 57.4, 38.2, 34.9, 32.1, 24.8, 24.0, 23.7, 14.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:25]C)[C:22]=1[O:23]C)[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2.B(Br)(Br)Br.O>ClCCl>[OH:25][C:21]1[CH:20]=[C:5]([CH:4]=[C:3]([OH:2])[C:22]=1[OH:23])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:19])[C:15]=1[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: COc1cc(-c2oc3ccccc3c(=O)c2C(=O)O)cc(OC)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1c(-c2cc(O)c(O)c(O)c2)oc2ccccc2c1=O
Temperature: 25 °C
Yield: 85 %

Procedure:
4.0 g of 3',4',5'-trimethoxyflavone-3-carboxylic acid were added to 200 ml of absolute dichloromethane and reacted with 82 ml of a 1 molar boron tribromide solution in absolute dichloromethane under a nitrogen atmosphere at 0° C. The reaction mixture was stirred for twelve hours during which it was allowed to warm to room temperature. Then, for working up, water was carefully added under ice cooling, then made up to twice the volume with water and intensively stirred. The resulting 3',4',5'-trihydroxyflavone-3-carboxylic acid precipitated and was filtered out. The filter cake was washed with water several times and recrystallized from methanol. 3 g of pure 3',4',5'-trihydroxyflavone-3-carboxylic acid were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Li])[CH:15]=2)[N:10]=1.COC1C=CC2C(=CC=C(C3C=CN=NC=3)C=2)N=1>>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:6]3[N:1]=[N:2][CH:3]=[CH:4][CH:5]=3)[CH:15]=2)[N:10]=1
Reactant: c1ccnnc1
Reactant: [Li]c1ccc2nc(OC)ccc2c1
Agent: COc1ccc2cc(-c3ccnnc3)ccc2n1
Product: COc1ccc2cc(-c3cccnn3)ccc2n1

Procedure:
The following compounds were prepared similarly to the previous Preparation using pyridazine and 2-methoxy-6-lithioquinoline as starting materials. In this case a mixture of 2-methoxy-6-(4-pyridazinyl)quinoline and 2-methoxy-6-(3-pyridazinyl)quinoline was formed which was separated by chromatography on silica (Merck "MK. 60.9385") eluting with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:25]/[CH2:24][C:23]([C:20]1[CH2:21][CH2:22][N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH:19]=1)([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)C1=CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCN(Cc2ccccc2)CC1
Yield: 101.2 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.84 g, 6.4 mmol) was reacted with 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-butyraldehyde (1.65 g, 6.4 mmol) in CH2Cl2 at room temperature for 5 h to give [3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (2.4 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)[C:6]=1[CH3:7]>CO.O1CCCC1.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])[C:6]=1[CH3:7]
Reactant: Cc1ncn(-c2cccc([N+](=O)[O-])c2)c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncn(-c2cccc(N)c2)c1C
Yield: 98.2 %

Procedure:
A suspension of 4,5-dimethyl-1-(3-nitrophenyl)imidazole (130 mg) in methanol (2 ml) and tetrahydrofuran (2 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 50 mg) under hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4,5-dimethyl-imidazol-1-yl)aniline (110 mg, 98.2%).
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([O:14][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
190 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 5[a]), 0.2 ml. of freshly distilled dihydropyran, and 1.4 mg. of p-toluenesulfonic acid in 5 ml. of absolute methylene chloride were stirred for 30 minutes at ice bath temperature under argon. After dilution with methylene chloride, the mixture was shaken successively with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated under vacuum. The residue was recrystallized from diisopropyl ether/methylene chloride, thus obtaining 204 mg. of the title compound as colorless crystals, m.p. 113°. IR: 1770, 1630, 1600, 975 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C=O)C.O>[CH2:20]([O:12][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([OH:13])[C:2]=1[Br:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)c(Br)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol) and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was added benzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight, diluted with 200 mL water and acidified to pH 1 by slow addition of concentrated hydrochloric acid. The solution was extracted with 1:1 ethyl acetate/ether (6×) and the combined extracts were washed with water (8×), saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to an orange solid. The solids were suspended in DCM (200 mL) and stirred overnight. The solids (primarily unreacted 4-bromo-3,5-dihydroxybenzoate) were removed by filtration and the filtrate was concentrated to an orange oil which was purified by column chromatography (80 g silica gel, 2:1 DCM in heptane elution, followed by DCM elution) to provide methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz, 1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as the di-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([NH:36][CH3:37])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:16]([N:23]1[CH2:27][C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C@H:25]([N:36]([CH3:37])[C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:5]=2)[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(=O)N(C)[C@@H]2CN(Cc3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of 4-methoxy-3-trifluoromethyl-benzoyl chloride (commercially available) (0.88 g, 2.76 mmol) in CH2Cl2 (10 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.80 g, 2.38 mmol) and ethyl-diisopropyl-amine (0.61 ml, 3.58 mmol) in CH2Cl2 (10 ml). The reaction mixture was stirred 4 h, concentrated under vacuo and purification by flash chromatography (SiO2, CH2Cl2/MeOH, 99:1) yielded 1.09 g (86%) of the title product as colorless oil. ES-MS m/e: 537.5 (M+H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Yield: 95.3 %

Procedure:
In a similar manner as described in Preparation Example 9, by using 3-(trifluoromethyl)benzaldehydeoxime (30.0 g, 158.60 mmol), dimethylformimide (300 mL) and N-chlorosuccinimide (23.31 g, 174.46 mmol), a pale yellow solid required compound (33.81 g, 151.22 mmol, 95%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:10]1[CH2:11][CH2:12][CH:7]([NH:6][C:4](=[O:5])[C:3]2[CH:13]=[CH:14][C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:23])([F:21])[F:22])=[CH:16][C:2]=2[Br:1])[CH2:8][CH2:9]1)(=[O:35])[CH3:34]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% diethyl ether/n-pentane to afford the title compound as a white solid (0.054 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]C3C=CC=C4C(NC(=O)C=34)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28]N>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH2:28])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Reactant: NN
Solvent: CO
Product: NCCCN1CCC(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(4-fluorophenyl)piperidin-1-yl] propylphthalimide (4.5 g, 12.3 mmol) in methanol (200 mL) was added 4 ml of hydrazine and the mixture was refluxed for 8 h. It was cooled, and the white solid was filtered and washed with methanol (20 mL). Solvent was evaporated, and the residue was dried under vacuum for 4 h. Chloroform (50 mL) was added to this material, it was stirred for 1 h and filtered. The white solid was washed with more chloroform (20 mL), and the solvent was evaporated from the combined filtrates to leave the crude product as an oil. It was purified by column chromatography on silica gel using dichloromethane/methanol/2M ammonia in methanol (10/3/1) as the eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>CCO>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1)[NH2:12]
Reactant: NN
Reactant: COc1nccc(Cl)n1
Solvent: O
Solvent: CCO
Product: COc1nccc(NN)n1
Temperature: 85 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a stirred solution of 4-chloro-2-methoxypyrimidine (5.7 g, 39.4 mmol) in EtOH (100 mL) under Ar was added hydrazine hydrate (3.83 mL, 79 mmol) and the reaction mixture was heated up and stirred at 85° C. for 1 hr. Volatiles were removed under reduced pressure and the resulting crude material was purified by silica gel column chromatography (CH2Cl2/MeOH/1-5%/NH3 1%) to afford the title product (4.40 g, 31.4 mmol, 80% yield) as white solid. ESI-MS: 141 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[O:7])=[CH:4][CH:3]=1.[CH3:18][N:19]([CH:21](N(C)C)OC(C)(C)C)[CH3:20]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[NH:12][C:13]=2[CH:14]=[CH:18][N:19]([CH3:21])[CH3:20])=[O:7])=[CH:16][CH:17]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1
Solvent: C1COCCO1
Product: CN(C)C=Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1

Procedure:
m.p. 265°-268° C. with decomposition, 53.8 g, was prepared following the procedure described in Example B-2 using 44 g of 5-(4-bromobenzoyl)-6-methyl-2(1H)-pyridinone, 300 ml of p-dioxane and 35 ml of bis-(dimethylamino)-t-butoxymethane.