Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])[C:9]([CH2:24]Cl)=[CH:8]2.CN(C=O)C.[N-:31]=[N+:32]=[N-:33].[Na+]>>[N:31]([CH2:24][C:9]1[C:10]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:2])=[N+:32]=[N-:33]
Reactant: Fc1ccc(C(F)(F)F)c(-c2nc3c(Cl)cccc3cc2CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(chloromethyl)-2-(5-fluoro-2-(trifluoro-methyl)phenyl)quinoline hydrochloride (0.3482 g, 0.8480 mmol) in DMF (4.240 mL, 0.8480 mmol) was added sodium azide (0.1103 g, 1.696 mmol) at room temperature and the mixture was stirred at room temperature. After 1.5 h, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinoline as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (1H, s), 8.12 (1H; dd, J=8.3, 1.3 Hz), 7.99-8.06 (2H, m), 7.69 (1H, dd, J=8.1, 7.5 Hz), 7.58-7.66 (2H, m), 4.44-4.59 (2H, m); LC-MS (ESI) m/z 381.1 [M+H]+. To a solution of 3-(azidomethyl)-8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)-quinoline (0.2573 g, 0.676 mmol) in methanol (6.76 mL, 0.676 mmol) was added palladium, 10 wt. % on activated carbon (0.0360 g, 0.0338 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2. After 30 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give green syrup. The green syrup was purified by column chromatography on a 40 g of Redi-Sep™ column using 0% to 20% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min, and then 20% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) for 20 min as eluent to give (8-chloro-2-(5-fluoro-2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (1H, s), 8.04 (1H, dd, J=8.4, 1.2 Hz), 8.01 (1H, dd, J=8.5, 5.4 Hz), 7.93 (1H, dd, J=7.4, 1.4 Hz), 7.54-7.67 (3H, m), 3.48-3.74 (2H, m), 1.96 (2H, br. s.); LC-MS (ESI) m/z 355.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Methyl 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10a) (3.7 g, 8.3 mmol) was dissolved in MeOH/THF (1:1.5, 30 mL) and treated with aqueous NaOH (3 N, 15 mL). The mixture was stirred at ambient temperature overnight, then MeOH and THF were removed in vacuo. The resulting aqueous solution was acidified with 6 N aq HCl to a pH of ˜3 and extracted with EtOAc (3×40 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by recrystallization from EtOH to afford pure 4-(N-(4-fluorobenzyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (2.1 g, 58.6%). MS (M−H, 428.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.66 (s, 3H), 4.23 (s, 2H), 4.26 (s, 2H), 6.72 (d, 2H, J=8 Hz), 6.95 (m, 6H), 7.92 (d, 2H J=8 Hz), 8.07 (d, 2H, J=8 Hz). The compound had an IC50 on hT2R14 bitter receptor of 1.97 μM.
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>>[CH3:1][C:2]([O:10][Si:11]([CH3:12])([CH3:13])[CH3:14])(/[CH:3]=[CH:4]\[Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(C)(CCCCC)O[Si](C)(C)C
Product: CCCCCC(C)(/C=C\[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Yield: 66 %

Procedure:
The compound 7 was prepared according to the procedure for the synthesis of 3. The 3-methyl-3-trimethylsilyloxy 1-octyne (48 retool) was treated with tributyl tinhydride to yield 7 (66 %).
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([O:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:10]([OH:26])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(C)(C)C.Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>C1COCC1>[CH2:1]([C:8]1[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[C:11]([O:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[C:10]([O:26][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: COC(=O)c1nc(Cc2ccccc2)nc(O)c1OC(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1nc(Cc2ccccc2)nc(OCCN2CCOCC2)c1OC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 2-benzyl-5-[(tert-butoxycarbonyl)oxy]-6-hydroxypyrimidine-4-carboxylate (N-1) (prepared from B-5 in Example 3, Step 1 by protection of the 5-hydroxyl group with pivaloyl chloride using a procedure similar to those set forth in Example 6, Step 2) in THF, CsCO3 (2 eq.) and 4-(2-chloroethyl)morpholine (1.5 eq.) hydrochloride were added and mixture reacted at 60° C. for 1 h. Further addition of 4-(2-chloroethyl)morpholine (1 eq.) allowed the complete consumption of starting material after 2 h. The mixture was then allowed to cool to room temperature, poured into EtOAc, extracted with brine, dried (Na2SO4), filtered and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[Cl:18].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])[C:25](O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][C:9]=2[Cl:18])=[CH:6][C:5]2[NH:19][C:25]([C:24]([F:28])([F:29])[C:23]([F:30])([F:31])[C:22]([F:33])([F:32])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Yield: 54 %

Procedure:
A solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]benzene-1,2-diamine (120 mg, 0.37 mmol), heptafluorobutanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath. The solution was diluted with water (100 ml), adjusted to pH 7 with saturated aqueous sodium carbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenyl]-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (100.3 mg, 54%).
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[OH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2]>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[OH:19])=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: OB(O)c1ccccc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2-c2ccccc2O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (540 mg, 2.0 mmol, see Preparation 2), 2-hydroxy-phenylboronic acid (71) (303.6 mg, 2.2 mmol), K3PO4 (818 mg, 4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl2 (73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C. under nitrogen atmosphere overnight. The reaction mixture was filtered through CELITE® and washed with EtOAc (50 mL). The filtrate was concentrated and the crude product was purified by silica gel column to give (72) (601.7 mg, 1.84 mmol, yield 91.85%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Na].[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>CO>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH:15]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]ccc2n1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Cl)nc23)CC1
Temperature: 0 °C
Yield: 28.2 %

Procedure:
To a solution of 0.66 gm (4.3 mMol) 5-chloropyrrolo-[3,2-b]pyridine in 50 mL methanol were added 1.09 gm (47.6 mMol) sodium. The reaction mixture was stirred until all of the sodium had dissolved and then 1.6 mL (13 mMol) 1-methyl-4-piperidone were added. The reaction mixture was stirred at reflux for 7.5 hours and was then cooled to 0° C. To this mixture were then added hydrochloric acid until the pH of the solution was about 8. The reaction mixture was then concentrated under reduced pressure to an oil. This oil was dissolved in 3:1 chloroform:isopropanol and the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0-10% methanol. Fractions containing product were concentrated under reduced pressure to provide 0.30 gm (28%) of the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[N:9]=[C:10]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:11][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1csc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1csc(CN2CCNCC2)n1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Tert-butyl 4-((4-(tert-butylcarbamoyl)thiazol-2-yl)methyl)piperazine-1-carboxylate (2.1 g, 5.49 mmol) was dissolved in dichloromethane (20 mL). 2,2,2-Trifluoracetic acid (20 mL) was added and the reaction mixture was stirred for 2 hours. The reaction was concentrated under reduced pressure and purified by SCX column chromatography to give the title compound (1.28 g). MS (ESI) m/z 283.4 [M+H]+
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cc(C(=O)c2cc(-c3ccccc3)on2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of 40i (0.110 g, 0.73 mmoL) in 8 mL anhydrous CH2Cl2 was added Dess-Martin reagent (0.274 g, 0.645 mmol). The mixture was allowed to stir for 30 min and quenched with sat. Na2S2O3 solution, extracted with ethyl acetate and dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to give pure compound 1i (70.1%). 1H NMR (CDCl3) δ 7.87-7.85 (m, 2H), 7.72 (s, 2H), 7.53-7.49 (m, 3H), 7.05 (s, 1H), 7.82 (d, 1H, J=1.5 Hz), 3.97 (s, 3H), 3.96 (s, 6H); MS (ESI) m/z 362.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][CH:22]=1>>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([NH:20][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:19])[F:18])[N:8]=4)[CH2:14][CH2:13]3)=[O:17])[CH:30]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C1CCN(c2cccc(C(F)(F)F)n2)CC1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)C1CCN(c2cccc(C(F)(F)F)n2)CC1

Procedure:
Using the procedure outlined in Example 107, the title compound was prepared from 1-(6-trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D102) (100 mg, 0.36 mmol) and 7-aminoquinoline (D55) (27 mg, 0.19 mmol) as an off white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=O)[CH2:20]Br>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[O:3][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1ccc(-c2nc(-c3cccc(C(F)(F)F)c3)co2)cc1
Yield: 21 %

Procedure:
In the same manner as in Example 1, methyl 4-carbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 4-[4-(3-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 134 to 135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([S:13][C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][N:19]=2)[C:10]([N+:21]([O-])=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[Na].N>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]2[NH:21][C:15]3[N:16]=[CH:17][CH:18]=[N:19][C:14]=3[S:13][C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Sc2nccnc2Cl)cc1OC
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(cc1OC)Sc1nccnc1N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 2.7 g of methyl 2-methoxy-4-(2-chloropyrazin-3-yl)thio-5-nitrobenzoate in tetrahydrofuran (100 ml) were added 50 ml of a saturated aqueous solution of sodium hydrosufide and 30 ml of 27% aqueous ammonia and the resulting mixture was vigorously stirred at room temperature for 1 hour. Then the reaction mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, a solution of the residue in tetrahydrofuran was stirred at 70° C. for 1 hour. After distilling off the solvent under reduced pressure, dichloroemthane was added to the residue. The crystals thus precipitated were filtered to thereby give 1.9 g of the title compound as red crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2([OH:15])C(=O)N[C:9](=[O:13])[NH:8][C:7]2=[O:14])=[CH:2]1.[OH-].[Na+]>>[O:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:15][C:9](=[O:13])[NH:8][C:7]2=[O:14])=[CH:2]1
Reactant: O=C1NC(=O)C(O)(c2ccoc2)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Product: O=C1NC(=O)C(c2ccoc2)O1
Reaction time: 0.25 h
Yield: 36.5 %

Procedure:
5-(3-Furyl)-5-hydroxy-2,4,6(1H,3H,5H)pyrimidinetrione (1.62 g.) was dissolved in 15 ml. of 1 N sodium hydroxide, and allowed to stand for 15 minutes at room temperature, and then extracted with 5 ml. of ethyl acetate. The aqueous layer was acidified with glacial acetic acid (about 1.5 ml.) and product extracted into 25 ml. of ethyl acetate. The extract was back washed with 5 ml. of water, filtered through a bed of anhydrous sodium sulfate, and evaporated to yield crude product as an oil (470 mg., m/e 167). Crystallization from chloroform gave purified 5-(3-furyl)oxazolidine-2,4-dione (129 mg., m.p. 88°-90° C., m/e 167). A second, lower melting crop was obtained from mother liquor.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1(C)[C:18](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]([CH3:18])=[CH2:13])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)c1ccc(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 52.9 %

Procedure:
To 1-chloro-4-methoxy-2-nitrobenzene (5.03 g, 26.8 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.41 g, 32.2 mmol), bis(triphenylphosphine)palladium(II) chloride (1.50 g, 2.15 mmol), and sodium carbonate (3.41 g, 32.2 mmol) was added dioxane/water (4:1, 100 mL:25 mL). The reaction was heated at 80° C. for 5 hours. The reaction was cooled to room temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate (3×), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography using 0-5% ethyl acetate/hexanes as eluent followed by drying in vacuum oven provided the title compound as an orange oil (2.74 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=2.7 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 7.08 (dd, J=8.5, 2.6 Hz, 1H), 5.24-4.75 (m, 2H), 3.86 (s, 3H), 2.19-1.88 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 158.79, 148.61, 142.53, 131.41, 131.32, 119.24, 115.20, 108.64, 55.84, 23.38; EIMS m/z 193 ([M]+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][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:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:25](B(O)O)=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>>[CH3:22][O:23][C:24]1[C:25]([C:2]2[N:7]=[N:6][C:5]([CH2:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[CH:4][CH:3]=2)=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)nn2)CC1
Reactant: COc1cc2ccccc2cc1B(O)O
Product: COc1cc2ccccc2cc1-c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)nn1
Yield: 45 %

Procedure:
tert-butyl 4-((6-(3-methoxynaphthalen-2-yl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (63 mg, 0.145 mmol, 45% yield) was prepared from tert-butyl 4-((6-chloropyridazin-3-yl)methyl)piperidine-1-carboxylate and (3-methoxynaphthalen-2-yl)boronic acid using GENERAL METHODS 1-4.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([O:19]C)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[C:13]1[C:12]1[C:7](=[C:8]([CH3:21])[C:9]([OH:19])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)c(C)c1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C=C1c1ccc(O)c(C)c1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.1 %

Procedure:
A solution of 9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (28.4 mg, 0.1 mmol) in anhydrous CH2Cl2 (1.7 mL) was stirred under a nitrogen atmosphere and cooled in a dry ice-acetone bath while 1M BBr3 in CH2Cl2 (0.30 mL, 0.3 mmol) was added dropwise by syringe. The cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with EtOAc (8 mL), water (3 mL) and 1N HCL (1 mL) and shaken vigorously. The EtOAc layer was separated, washed with water (3 mL), 1M pH 3 phosphate (3 mL) and brine (3 mL), dried over MgSO4, filtered and evaporated under vacuum to give an ochre solid (26.8 mg). The crude product was suspended in CDCl3 (1 mL) and filtered. The solid portion was dried under vacuum to afford 9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-3H-tetrahydro-fluoren-3-one as an olive colored powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:24]2[CH2:25][CH2:26][NH:27][CH2:28][C:23]=2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1>[Pd].C1(C)C(C)=CC=CC=1>[CH3:29][C:2]1([CH3:1])[C:24]2=[CH:25][CH:26]=[N:27][CH:28]=[C:23]2[C:5]2[C:6]([OH:22])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 4.75 g. of 5,5-dimethyl-8-[5-(4-fluorophenyl)-2-pentyl]-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 1.0 g. of 10% palladium on carbon, and 120 ml. of xylene was stirred and refluxed for 22 hours. After removal of the catalyst, the filtrate was evaporated in vacuo and the residue was purified by chromatography on a Florisil column (150 g.). The column was first eluted with chloroform, followed by 5% methanol in chloroform to give the pure product; m.p. 72°-74°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8].CI.[CH3:34]C([O-])(C)C.[Na+].C1COCC1>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([N:25]([CH3:34])[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-2-methylpropanamide (15.0 mg, 0.0357 mmol), MeI (5.07 mg, 0.0357 mmol), NaOtBu (6.86 mg, 0.0714 mmol) and THF (1.00 mL) was stirred for 5 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 4.0% of NH3 (2.0 M in methanol) in CH2Cl2 to afford the desired product N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-N,2-dimethylpropanamide (13.8 mg, 89.1%): 1H NMR (400 MHz, CDCl3) 7.76 (s, 1H), 7.72 (dd, 1H, J=1.8, 7.7 Hz), 7.33 (t, 1H, J=8.8 Hz), 7.22 (d, 1H, J=7.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.01 (m, 2H), 3.24 (s, 3H), 3.10 (d, 1H, J=10.6 Hz), 3.00 (t, 1H, J=7.6 Hz), 2.49–2.44 (m, 4H), 2.33 (s, 6H), 2.112.10 (m, 2H), 1.99 (m, 1H), 1.79–1.77 (m, 4H), 1.26 (t, 2H, J=7.6 Hz), 1.02 (d, 6H, J=7.6 Hz); ESMS m/e: 435.2 (M+H)+.