Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH2:22][OH:23])=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1.S(OC)(O[CH3:28])(=O)=O>CN(C=O)C>[Br:3][C:4]1[C:5]([CH2:22][O:23][CH3:28])=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)c(CO)n2)CC1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (57.7 mg, 60% in oil) was added to tert-butyl 4-[4-bromo-3-(hydroxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (200 mg) dissolved in degassed DMF (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 10 minutes. Dimethyl sulfate (0.068 ml) was added and the resulting solution was stirred at 25° C. for 1 hour. The reaction mixture was quenched with water and diluted with ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated in presence of silica gel to afford the crude, which was purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(methoxymethyl)pyrazol-1-yl]piperidine-1-carboxylate (180 mg). NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.71 (dd, 1H), 1.76 (dd, 1H), 1.96 (bs, 1H), 1.98 (bs, 1H), 2.87 (bs, 2H), 3.22 (3H), 4.02 (bs, 2H), 4.28 (s, 2H), 4.29-4.36 (m, 1H), 8.04 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:23])([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2c(CC(C)(C)CC(=O)O)nc3ccccc32)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(CC(=O)O)Cc1nc2ccccc2n1Cc1ccc(O)cc1
Yield: 20.8 %

Procedure:
2 g of 4-[1-(4-methoxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid, prepared in Example 68, are dissolved in 40 ml of acetic acid and 40 ml of 48% hydrobromic acid. The mixture is refluxed for 3 hours and the solvents are evaporated off under vacuum. The residue is taken up with a 1N solution of sodium hydroxide so as to adjust the pH to 9-10, and the resulting aqueous phase is washed with ether and then acidified with sulfur dioxide to pH 5.5. The crystals obtained re filtered off, washed with water and then with ether and then chromatographed on silica gel in a 9:1 chloroform/methanol eluent to give 0.4 g of 4-[1-(4-hydroxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid in the form of crystals melting at 215°-216° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]([CH:13]=[O:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:17][C:18]([CH:20]=[CH2:21])=[O:19]>C(N(CC)CC)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8]([CH:13]=[O:14])([CH2:21][CH2:20][C:18](=[O:19])[CH3:17])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: C=CC(C)=O
Reactant: CC1(C)CC(C=O)C(=O)c2cc(Br)ccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)CCC1(C=O)CC(C)(C)c2ccc(Br)cc2C1=O
Temperature: 0 °C
Yield: 87.2 %

Procedure:
7-Bromo-4,4-dimethyl-2-formyl-1-oxo- 1,2,3 ,4-tetrahydronaphthalene (1.0 g, 3.56 mmol) was dissoved in methylvinylketone (dist., 0.468 g, 6.7 mmol) and this mixture was cooled down to 0° C. Triethylamine (3 drops) was then added and the mixture was stirred at 0° C. for an hour and then at room temperature overnight. The reaction mixture was dissolved in ethyl ether and concentrated to give the title material (1.09 g, 87%) as a yellow oil.
Reaction SMILES: C=O.O.[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1.[CH3:32]CN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:4][C:5]1[C:6]([CH3:31])=[C:7]([CH:25]2[CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]2)[C:8]([O:23][CH3:24])=[C:9]([CH:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CCN(C)CC1
Reaction time: 0.17 h

Procedure:
12.0 M Formaldehyde in water (0.4 mL, 5 mmol) was added to a mixture of N-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-purin-6-amine (200 mg, 0.5 mmol) and DIPEA (0.35 mL, 2.0 mmol) in methylene chloride (5 mL) at 0° C. The reaction was stirred for 10 minutes, and after this time sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. The reaction was stirred at 0° C. for 1 hour. The mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H28ClN6O (M+H)+: m/z=415.2. found: 415.3. 1H NMR (DMSO-d6, 500 MHz) δ 9.67 (1H, br s), 8.72 (1H, br s), 8.35 (2H, s), 7.51 (1H, s), 5.75 (1H, m), 3.88 (3H, s), 3.49 (2H, m), 3.34 (1H, m), 3.12 (2H, m), 2.81 (1.5H, s), 2.80 (1.5H, s), 2.44-2.31 (2H, m), 2.36 (3H, s), 1.79 (2H, m), 1.49 (3H, d, J=6.5 Hz) ppm.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH3:7][O:8][C:9]1[CH:20]=[C:19]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH2:18])=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:20]=[C:19]2[C:12](=[CH:11][CH:10]=1)[NH:13][CH:14]=[C:15]2[CH2:16][CH2:17][NH:18][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CCCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCNC(=O)NCCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
0.851 g of propyl isocyanate is added to a suspension of 1.902 g of 5-methoxytryptamine in 4 cm3 of pyridine at +5° C. The mixture is stirred at room temperature for 2 hours and then the reaction medium is poured onto ice-water. The mixture is acidified slightly with a lN hydrochloric acid solution. The resulting precipitate is isolated by filtration, washed with water, dried and then recrystallised in toluene, yielding 2.34 g (85%) of N-[2-(5-methoxyindol-3-yl)ethyl]-N'-propylurea.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH:14]C(=O)C)=[C:7]2[CH2:6][CH2:5]1)(=O)C.[ClH:18]>CCO>[ClH:18].[NH:4]1[C:8]2=[N:9][CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(=O)NCc1ccnc2c1CCN2C(C)=O
Agent: Cl
Solvent: CCO
Product: NCc1ccnc2c1CCN2
Temperature: 70 °C

Procedure:
A mixture of N-(1-acetyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl)-acetamide (0.50 g, step A), HCl (conc., 3 mL) and EtOH (12 mL) was heated to 70° C. for overnight. Additional 3 mL of conc. HCl was added to the reaction and the heating was continued for 3 more days. Solvent was evaporated to give a white residue as crude C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine HCl salt, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([C:6]([Cl:9])=[CH:7][CH:8]=1)[NH2:5].[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O.C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][CH3:17])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)ccc(Br)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1c(Cl)ccc(Br)c1F
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 65.3 %

Procedure:
3-Bromo-6-chloro-2-fluoroaniline (1.2 g, 5.2 mmol) was dissolved in THF (12 mL) in a 100 mL round bottomed flask and treated with tetra-N-butyl ammonium bromide (0.015 g, 0.05 mmol) and powdered sodium hydroxide (0.83 g, 20.9 mmol) with stirring. After 5 minutes, the dark mixture was treated with dimethyl sulfate (1.3 g, 10.4 mmol) and the mixture heated at 60° C. for 2 hours. Analysis by TLC (hexanes: ethyl acetate/20:1) indicated some starting material remained. Added additional dimethyl sulfate (0.66 g, 5.2 mmol) and continued heating for 1.5 hour then stirred at room temperature overnight. The reaction was partitioned between diethyl ether and water and the layers separated and the aqueous phase extracted with ether. The combined ether layers were washed with water and dried (MgSO4). Filtration, concentration and purification by flash silica gel chromatography (hexanes) gave N-(3-bromo-6-chloro-2-fluorophenyl)-N-methylamine (0.81 g) as a colorless oil: 1H NMR (300 MHz, CDCl3): δ 6.93 (dd, 1H, J=8.4), 6.83 (dd, 1H), 4.00 (bs, 1H), 3.09 (d, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]=[CH:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[C:3]=1[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: [H][H]
Reactant: CCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CCc3c(C)cc(OCC)c(F)c3F)CC2)CC1
Yield: 80.7 %

Procedure:
0.31 g of Pd/C was added to 6.20 g of the compound 1-3-3-9 having been dissolved in 50 mL of toluene and 50 mL of Solmix, and under a hydrogen atmosphere, the mixture was stirred at room temperature until hydrogen was not absorbed. Pd/C was removed, and the solvent was distilled off. The residue was purified by silica gel column chromatography and recrystallization to obtain 5.03 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-propylcyclohexyl)cyclohexyl)ethane (Compound 1-3-3-1) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[C:13]([CH2:19][CH2:20][CH3:21])=[N:12][C:7]=3[C:8]([NH2:34])=[N:9][C:10]=2[CH:11]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline (51.1 g, 0.148 mol) in dichloromethane (1 L) was slowly added 3-chloroperoxybenzoic acid (1.0 equivalent of 50% pure material) in small portions. The reaction was maintained at room temperature for one hour. Concentrated ammonium hydroxide (600 mL) was added with stirring. After 15 minutes, p-toluenesulfonyl chloride (1.1 equivalents.) was added in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by adding water (1 L) and stirred for an additional hour. A solid was present and was isolated by filtration to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17](/[CH:18]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(/C=C/c1ccc(F)cc1)c1ccccc1
Reaction time: 3 h

Procedure:
52.0 g. (433 mmoles) of acetophenone is added to a solution of 21.8 g. (545 mmoles) of sodium hydroxide in a mixture of 196 ml. of water and 122.5 ml. of 95% ethanol stirred at 20°-25° C., the resulting suspension is cooled to 0°-5° C., and 53.74 g. (433 mmoles) of 4-fluorobenzaldehyde is added portionwise, the temperature of the reaction mixture rising to 20° C. during the addition. The solidified reaction mixture is kept at 20°-25° C. for 3 hours and refrigerated for 16 hours. The solid is collected by filtration, rinsed with about 2 l. of water until the rinses are neutral, rinsed with 200 ml. of cold 95% ethanol and recrystallized from 95% ethanol to obtain the product as yellow flakes (66.25 g. (68%)), m.p. 83°-86° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][CH:8](O)[C:7]=2[CH:14]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)C(O)CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)C=CCCO2
Yield: 95.2 %

Procedure:
18.9 g (0.1 mole) of 7-cyano-5-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin are heated with 0.3 g of p-toluenesulfonic acid monohydrate in toluene with a water trap for 1.5 hours. After the solution has cooled it is washed with 1N potassium bicarbonate solution, water and saturated sodium chloride solution and, after drying over sodium sulfate, the solvent is evaporated off in vacuo. 16.3 g of solid of melting point 69°-71° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[CH2:12][S:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH3:19]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[CH2:10][S:11][CH2:12][C:13](=[O:15])[N:14]2[CH2:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(=O)OCc1ccccc1
Reactant: O=C1CSC[C@@H](c2cc(F)cc(F)c2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (5R)-5-(3,5-difluorophenyl)thiomorpholin-3-one (247 mg, 1.08 mmol, prepared by analogy to Intermediate 2) in THF (8.0 mL) was added sodium hydride (38 mg, 1.5 mmol, 95% by weight). After 5 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. Once hydrogen gas evolution had ceased, as judged by an oil bubbler, the reaction mixture was cooled to 0° C., prior to the introduction of benzyl acetate (272 mg, 1.19 mmol). After 5 minutes, the ice bath was removed and the reaction was stirred for 15 hours. The bulk of the THF was removed under reduced pressure. The residue was then diluted with water and ether. The aqueous layer was extracted once with ether and the combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM—0.5:99.5 to 5:95, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: C(N(CC)CC)C.[N:8]1([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:26]([N:11]1[CH2:12][CH2:13][N:8]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[C:16]([NH2:25])=[N:17][C:18]([NH2:24])=[N:19]3)[CH2:9][CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4)CC3)cccc2n1
Temperature: 60 °C
Yield: 64.4 %

Procedure:
In a 20 mL vial with stir bar, triethylamine (40 mg; 0.4 mmol) was added to a mixture of 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and benzyl bromide (45 mg; 0.27 mmol) in N,N-dimethylformamide and heated to 60° C. for 16 hours. Mixture was quenched with 1 mL of 1N NaOH and after 1.5 hours solids were collected by filtration and triturated with ethanol to obtain 43.1 mg of title compound. (64% yield).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1.ClC(Cl)C>[CH2:1]([N:5]([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:10]2[CH:26]=[CH:27][CH:28]=[CH:29][C:9]=2[N:8]=1)[C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:39]([F:40])[C:31]=1[F:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CCCCNCc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCN(Cc1nc2ccccc2n1Cc1ccccc1CN1CCCCC1)C(=O)c1cccc(F)c1F

Procedure:
A solution of 0.9 g (1.7 mmole) of compound D was treated with 10 mL of butyl amine in 50 mL of acetonitrile at room temperature for 2 hr. The resulting solution was concentrated and partitioned between ethyl acetate and 1N NaOH. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 0.55 g of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine. 1H NMR (300 MHz, CDCl3) 7.8 (d, 1H), 7.2 (m, 5H), 7.05 (d, 1H), 6.4 (d, 1H), 5.8 (s, 2H), 4.0 (s, 2H), 3.6 (s, 2H), 2.6 (t, 2H), 1.2-1.6 (m, 14H), 0.8 (t, 3H). A quantity of 0.1 mL of a 0.2 M solution of Butyl-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-amine in toluene is treated with 0.15 mL of a 0.2 M solution of 2,3-Difluoro-benzoyl chloride in dichloroethane at room temperature for 1 hr. The resulting mixture was chromatographed on SiO2 with ethyl acetate to yield 9 mg of N-Butyl-2,3-difluoro-N-[1-(2-piperidin-1-ylmethyl-benzyl)-1H-benzoimidazol-2-ylmethyl]-benzamide. LCMS MF=C32H36F2N4O MW=530.6 found 531. B. N-Butyl-2,3-difluoro-N-[1-(4-piperidin-1-yl-but-2-Enyl)-1H-benzoimidazol-2-ylmethyl]-benzamide
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]CCl>CN(C)C=O>[CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]([Cl:23])=[O:22])[CH:15]=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)NCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a suspension of 3-(3-(benzylsulfamoyl-phenyl)-acrylic acid (5g) (0.16 g, 0.52 mmol) in dichloromethane (2.0 ml) oxalyl chloride (0.16 ml, 1.79 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.17 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH:16]=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][C:7]1=[O:18].[CH3:19][Mg]Br>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][CH2:8][C:7](=[O:18])[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]=2[CH:12]=1)[CH3:19]
Reactant: COCCCN1C(=O)COc2ccc(C=O)cc21
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COCCCN1C(=O)COc2ccc(C(C)O)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The solution of 1.0 g of 4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde and 30 ml of tetrahydrofuran is cooled to 0° C. and admixed dropwise with 1.4 ml of methylmagnesium bromide (35% in THF). The reaction mixture is stirred at 0° C. for a further 15 minutes, subsequently quenched with saturated ammonium chloride solution (50 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed successively with ice-water (50 ml) and brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (3:1 EtOAc-heptane); Rt=2.96.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21]C)=[O:20]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:9]/[CH:10]=[CH:23]/[C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=CC=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(C(=C/C=C/C(=O)O)c2ccc(C)cc2)cc1
Yield: 67.4 %

Procedure:
In the manner described in Example 99, 3,3-bis(4-methylphenyl) -2-propenal (9.45 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (15.3 g) in carbon tetrachloride (95 ml) for 3 days at room temperature. The solvent was removed under reduced pressure and the residue was stirred at reflux in mixture of methanol (40 mL) and 2N NaOH for 45 minutes. The cooled solution was diluted with water (300 ml), extracted with dichloromethane (3×100 mL) to remove non-acidic material, and then acidified with 6N HCI (50 ML) and extracted with dichloromethane. The dried (MgSO4) extracts were evaporated and the crude product was crystallized from 2-propanol to afford 7.5 g of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid, mp 224 5°-226.5° C.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([OH:25])[CH:24]=2)[O:21][C:20]([CH3:27])([CH3:26])[CH2:19][C:18]3([CH3:29])[CH3:28])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[K+]>CO.O1CCCC1>[OH:25][C:23]1[CH:24]=[C:15]([C:14]#[C:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:30])=[O:2])=[CH:8][CH:9]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:27])([CH3:26])[CH2:19][C:18]2([CH3:29])[CH3:28]
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc(O)c2O1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 2-[4-(8-hydroxy-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-2-methyl-propionic acid methyl ester (Intermediate 23, 0.035 g, 0.087 mmol) in methanol (2 mL) and tetrahydrofuran (1 mL) was treated with a 1M solution of potassium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was stirred at 80° C. for 2 h. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a yellow solid (0.034 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][CH:14]([CH2:18][CH2:19]Cl)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[C:7]([C:6]1[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][O:3][C:2]=1[N:1]1[CH2:19][CH2:18][CH:14]([CH3:13])[C:15]1=[O:16])#[N:8]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1coc(N)c1C#N
Solvent: Cc1ccccc1
Product: CC1CCN(c2occ(C(C)(C)C)c2C#N)C1=O
Yield: 21.7 %

Procedure:
To 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)furan and 4.3 g of 2-methyl-4-chlorobutyryl chloride was added 150 ml of toluene. The reaction mixture was allowed to reflux for about 72 hours. The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 1.3 g of N-[3-cyano-4-(1,1-dimethylethyl)-2-furyl]-3-methyl-2-pyrrolidinone. mp=88°-90° C. Yield 21%.