Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27](C)(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:31])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)COc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3,4-difluorophenyl)-4-(2-methylpropoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 35 mg, 42%). mp 169-171° C. 1H NMR (300 MHz, DMSO-d6) δ 0.78 (d, 6H), 1.84, (m, 1H), 4.2 (d, 2H), 7.54 (m, 3H), 7.6 (m, 1H), 7.82 (m, 3H), 7.91 (d, 2H), 8.21 (s, 1H). MS (DCI/NH3) m/z 436 (M+H)+, 453 (M+NH4)+. Anal. calc. for C20H19F2N3O4S.0.25H2O: C, 55.17; H, 4.40; N, 9.65. Found: C, 54.19; H, 4.25; N, 9.35
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2.O>C1(C)C=CC=CC=1.[Ti]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([C:13]([F:15])([F:14])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: COc1cc(F)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(F)ccc1C(C)(C)CC(O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
0.25 ml of titanium tetraethylate is added to 150 mg (0.48 mmol) of 4-(4-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal and 85 mg (0.48 mmol) of 5-amino-7-fluoro-2-methylquinazoline in 8 ml of toluene, and the mixture is heated to 100° C. over 2 hours. After cooling, it is poured into water, and vigorous stirring is continued. The suspension is filtered through Celite, and it is rewashed thoroughly with ethyl acetate. The phases of the filtrate are separated, and it is extracted again with ethyl acetate. It is dried on sodium sulfate, and the solvent is removed in a vacuum. 220 mg of 4-(4-fluoro-2-methoxyphenyl)-1-(7-fluoro-2-methylquinazolin-5-ylimino)-4-methyl-2-(trifluoromethyl)-pentan-2-ol that is thus obtained in crude form is taken up in 8 ml of dichloromethane, and it is cooled to −70° C. 3 ml (3 mmol) of a 1 M titanium tetrachloride solution in dichloromethane is added in drops over 10 minutes, and it is allowed to heat for 4 hours to room temperature. The solution is poured into a saturated sodium bicarbonate solution and vigorously stirred for 5 minutes. It is extracted with ethyl acetate, washed with saturated sodium chloride solution and dried on sodium sulfate. After concentration by evaporation and chromatography on silica gel (dichloromethane/methanol 10%), 25 mg of the desired product is obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1C[CH2:37][CH2:36][CH2:35]1>O>[CH2:20]([NH:19][N:16]1[C:17](=[O:18])[C:12]([C:4]2[NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[S:2](=[O:1])(=[O:28])[N:3]=2)=[C:13]([OH:27])[C:14]2[S:26][CH:25]=[CH:24][C:15]1=2)[C:21]1[CH:22]=[CH:37][CH:36]=[CH:35][CH:23]=1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 269A (0.116 g, 0.257 mmol) in tetrahydrofuran (5 mL) and methanol (0.021 mL, 0.514 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.19 mL, 0.386 mmol). The reaction was stirred at 25° C. for 2 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.97 (d, J=5.54 Hz, 2 H) 6.17 (t, J=6.43 Hz, 1 H) 7.08 (d, J=5.52 Hz, 1 H) 7.21 (d, J=8.09 Hz, 1 H) 7.33 (m, 4 H) 7.47 (d, J=6.62 Hz, 2 H) 7.55 (t, J=6.99 Hz, 1 H) 7.66 (d, J=7.35 Hz, 1 H) 7.73 (d, J=5.52 Hz, 1 H) 15.92 (s, 1 H). MS (ESI−) m/z 451 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1O)=O.O.[NH2:13][NH2:14].O.C(O)(=O)C>C(O)CO>[CH3:1][C:2]1[C:4]2[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:14][N:13]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: NN
Solvent: O
Solvent: OCCO
Solvent: CC(=O)O
Product: Cc1n[nH]c2cccc(O)c12
Temperature: 160 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 2,6-dihydroxy acetophenone (0.50 g, 3.31 mmol) in ethylene glycol (7 ml) was slowly added a solution of hydrazine hydrate (3.3 g, 6.59 mmol) in ethylene glycol (2 ml). The reaction mixture was stirred for 20 min at room temperature and for an additional 2 hours at 160° C. After cooling to room temperature and dilution with distilled water (20 ml), the acetic acid (0.25 ml) was added to adjust the pH of the solution to 6. The resulting mixture was extracted four times with ethyl acetate, washed with a 5% sodium sulfite solution, dried over magnesium sulfate, filtered, and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give 0.37 g of 3-Methyl-1H-indazol-4-ol (Yield 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[C@@H:16]([CH:22]([CH3:24])[CH3:23])[CH2:15]1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CS(C)=O.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]>[CH3:23][CH:22]([C@H:16]1[CH2:15][C@H:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:19][CH2:18][S:17]1(=[O:21])=[O:20])[CH3:24]
Reactant: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(Br)cc23)CCS1(=O)=O
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@H]1C[C@H](c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CCS1(=O)=O
Reaction time: 0.08 h
Yield: 26.4 %

Procedure:
(racemic)-5-Bromo-3-[trans-2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol) was placed in a microwave vial and dissolved in 1,4-dioxane (2 mL) and water (1.000 mL). Phenylboronic acid (19.17 mg, 0.157 mmol) and K2CO3 (65.2 mg, 0.472 mmol) were added. Argon was bubbled in the mixture for 10 min, and then PdCl2(dppf) (6.07 mg, 0.013 mmol) was added, and argon was bubbled another 10 min. The vial was sealed and put under microwave 5 mins at 100° C. with high absorption parameter. The crude was run through a thiol-SPE cartridge eluting with methanol (2 mL) and the treated solution was evaporated to remove the biggest part of dioxane and methanol. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and solvent removed in vacuo to give crude material which was dissolved in 1-2 mL of DMSO filtered through a syringe filter (Acrodisc CR 13 mm; 45 um PTFE filter), and run through the ammonium Gilson eluting with 35% to 90% organic in 15 min. The product was isolated to afford 17 mg of the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[CH2:16]([O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: CCOCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CCOCC1CNCCO1
Reaction time: 24 h
Yield: 70.9 %

Procedure:
4-Benzyl-2-ethoxymethylmorpholine (1.6 g) and 10% palladium-carbon (200 mg) are added to ethanol (30 ml), and the mixture is stirred under hydrogen pressure of 5 kg/cm2 for 24 hours. Palladium-carbon is filtered off, and the solvent is distilled off under reduced pressure to give the title compound (0.7 g) as colorless liquid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[CH:27]1([NH:30][C:31]([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH:39]C(=O)O)[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:31]([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH:39][C:24]([C:21]3[C:17]4[N:18]=[CH:19][N:20]=[C:15]([C:7]5[C:8]6[O:12][CH2:11][O:10][C:9]=6[CH:13]=[CH:14][C:6]=5[O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)[C:16]=4[NH:23][CH:22]=3)=[O:26])[CH2:35][CH2:34]2)=[O:32])[CH2:29][CH2:28]1
Reactant: O=C(O)N[C@H]1CC[C@H](C(=O)NC2CC2)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(N[C@H]1CC[C@H](C(=O)NC2CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and trans-(4-cyclopropylcarbamoyl-cyclohexyl)-carbamic acid tart-butyl ester (A195) the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=C)[CH3:15])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.FC1C=CC([C@H](CC=C)CN(C)C(=[O:53])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]([N:14]([CH2:16][C@H:17]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:18][CH:19]=[O:53])[CH3:15])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(F)cc2c1CCCC2)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(F)cc2c1CCCC2

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3-fluoro-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 68%). 1H NMR (500 MHz, CDCl3): 1.6-4.2 (cm, 16H), 6.2-7.8 (cm, 6H), 9.8 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24](O)=[O:25])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:40][C@H:41]1[O:46][C@@H:45]([CH3:47])[CH2:44][NH:43][CH2:42]1.C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([N:43]2[CH2:42][CH:41]([CH3:40])[O:46][CH:45]([CH3:47])[CH2:44]2)=[O:25])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)N3CC(C)OC(C)C3)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (200 mg, 0.451 mmol) in THF (2 ml) were added DMF (0.020 ml) and oxalylchloride (0.0471 ml, 0.540 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of cis-2,6-dimethylmorpholine (104 mg, 0.900 mmol), triethylamine (0.251 ml, 1.80 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane and ethyl acetate.
Reaction SMILES: Br.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH3:15])[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1>O>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH3:15])[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2cc(C)c(=O)[nH]c2c1
Agent: Br
Solvent: O
Product: Cc1cc2ccc(O)cc2[nH]c1=O
Yield: 86.6 %

Procedure:
47% hydrobromic acid (60 ml) suspension of 2.12 g of 7-methoxy-3-methyl-1H-quinolin-2-one was refluxed for six hours. After cooling, water was added to the reaction solution and precipitated crystals were separated by filtration. The crystals were dissolved in a mixed solvent of dichloromethane and methanol and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure and 1.7 g of 7-hydroxy-3-methyl-1H-quinolin-2-one was obtained in the form of a brown powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:24])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH2:23])=[O:22])[CH2:16][CH2:15]2)=[CH:2]1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([NH:23][C:21]([NH:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH2:11][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:24])[CH2:19][CH2:18]1)=[O:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(=O)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1
Product: O=C(NC(=O)c1ccccc1)NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1

Procedure:
The product may be prepared by the alternative method of treating 1-[1-(4-[3-indolyl]-4-oxobutyl)piperid-4-yl]urea with benzoyl chloride following the procedure of Example 1.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:18]([O-:20])=[O:19])[CH:26]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)o1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2cccc([N+](=O)[O-])c2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromofuran-2-carboxamide) and 3-nitrophenylboronic acid, using tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in a mixture of ethylene glycol dimethyl ether and water. The compound was purified by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The product-containing fractions were then evaporated and the residue dissolved in methanol. Excess hydrogen chloride solution (1M in diethyl ether) was added and the solution was evaporated. Recrystallisation from methanol/diethyl ether gave the hydrochloride salt of the title compound as a yellow solid; MS (ES+) 342 (MH+).
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:21](=O)([O-])O.[Na+]>CO>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:5][C:6]([O:8][CH3:21])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: O=C(O)CC(c1cccc(O)c1)C1CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(c1cccc(O)c1)C1CC1

Procedure:
To a solution of 3-cyclopropyl-3-(3-hydroxyphenyl)propanoic acid (1.45 g) in methanol (20 mL) was added conc. sulfuric acid (75 μL), and the mixture was heated under reflux for 14 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (1.43 g) as a pale-brown oil. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[N:12]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:23][CH2:24][C@H:25]([CH2:28][C:29]([N:6]4[CH2:7][CH2:8][CH2:9][C@H:5]4[C:4]([O:3][CH3:2])=[O:10])=[O:30])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)=[N:12]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
L-Proline methyl ester hydrochloride (0.03 g, 0.18 mmol) was added to a stirred solution of the product from Example 37C (0.05 g, 0.17 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.042 g, 0.22 mmol), 1-hydroxybenzotriazole hydrate (0.03 g, 0.22 mmol) and N-methyl morpholine (0.1 mL, 0.87 mmol) in N,N-dimethylformamide (4 mL) at room temperature. The reaction was stirred at room temperature for 12 h and then quenched by addition of water. It was then extracted with ethyl acetate (3×25 mL), the organic extracts washed with water, brine, dried (MgSO4) and concentrated to afford the titled compound as a clear oil. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 2 H), 1.40-1.51 (m, 2 H), 1.75-1.86 (m, 6 H), 1.88-1.94 (m, 2 H), 2.13-2.27 (m, 3 H), 2.40-2.49 (m, 1 H), 3.51-3.58 (m, 2 H), 3.61 (s, 3 H), 4.30 (dd, J=10, 5 Hz, 1 H), 6.64 (d, J=3 Hz, 1 H), 7.27 (d, J=10 Hz, 2 H), 7.66-7.72 (m, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.[CH3:26]O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]([O:18][CH3:26])=[O:17])=[CH:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: CO
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Into a suspension of 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.5 g, 8.7 mmol) from Example 32, Step A in methanol (350 mL) was bubbled HCl gas until the resulting solution was saturated. The mixture was stirred at rt for 72 h. The reaction was concentrated in vacuo, made basic with saturated sodium carbonate solution, and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (3.8 g) which was purified by flash column chromatography on silica gel eluted with 100% methylene chloride, then a gradient of 1 to 3% methanol in methylene chloride to give methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate as an off-white solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CC#N>[Br:1][C:13]1[S:9][C:10]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccs2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)s2)CC1
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
N-Bromosuccinimide (4.9 g, 28.08 mmol) was added in portions to a solution of tert-butyl 4-(thiophen-2-yl)piperidine-1-carboxylate (5.0 g, 18.72 mmol) in MeCN at −10° C. The reaction mixture was stirred for 30 minutes and treated with sat. aq. NaHCO3 solution. The mixture was extracted with CH2Cl2 and the organics washed with water and brine solution, dried (Na2SO4), filtered, and evaporated to obtain crude product. Purification by silica gel chromatography (2% EtOAc/pet ether) yielded tert-Butyl 4-(5-bromothiophen-2-yl)piperidine-1-carboxylate (1.5 g, 21% from tert-butyl 4-hydroxy-4-(thiophen-2-yl)piperidine-1-carboxylate); 1H-NMR (400 MHz, CHCl3): 6.85 (d, 1 H), 6.58 (d, 1 H), 4.22-4.10 (d, 2H), 3.90-3.78 (m, 3H), 1.98-1.90 (d, 2 H), 1.65-1.48 (m, 2 H), 1.45 (s, 9 H); ES-MS: 346.3, 348.3 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:11]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(-c2cccnc2)cc1
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 3-pyridylboronic acid (500 mg, 4.06 mmol), 1-iodo-4-nitrobenzene (1.01 g, 4.06 mmol) and Pd(Ph3P)2Cl2 (140 mg, 0.199 mmol) in dioxane (15 mL), a solution of Na2CO3 (1.00 g, 9.43 mmol) in H2O (10 mL) was added. The mixture was stirred at 100 C for 2 h. Water and EtOAc were added. Organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column on ISCO, eluted with 20-100% EtOAc in hexanes to give 3-(4-nitrophenyl)pyridine as a solid (487 mg). A mixture of 3-(4-nitrophenyl)pyridine (487 mg, 2.43 mmol) and Pd—C (10%, 80 mg) in MeOH (25 mL) and EtOAc (5 mL) was hydrogenated under balloon H2 for 5 h. The mixture was then filtered through celite. The filtrate was concentrated in vacuo to give 4-(pyridin-3-yl)aniline as a solid (403 mg).
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:19]O>>[C:1]([O:18][CH3:19])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CO
Reactant: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC

Procedure:
The ZrO2 materials functionalized with sulfonic acid and phenolsulfonic acid groups were used as the solid acid catalysts in the liquid phase esterifications of palmitic acid (PA) with MeOH. The reactions were carried out at the reflux temperature of MeOH. Methyl palmitate was obtained as the only product in the present reaction condition based on the GC and GC-MS analyses. The esterification of palmitic acid (PA) with MeOH was carried out at 60° C. in order to totally dissolve PA in the reaction mixture.