Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([F:25])([F:24])[F:23])=[C:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1>CCO.[Pd]>[F:1][C:2]1[C:3]([C:22]([F:24])([F:25])[F:23])=[C:4]([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:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)cc(F)c2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
A mixture of tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (26, 0.750 g, 2.11 mmol) and 10% Pd/C (1.0 g) in EtOH (50 mL) stirred at ambient temperature under an atmosphere of H2 for 24 h. The mixture was filtered through Celite and the filtrate concentrated under reduced pressure to afford tert-butyl 4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (27) as a white solid (535 mg, 82%). 1H NMR (300 MHz, CDCl3) δ 6.97-6.85 (m, 1H), 6.85-6.69 (m, 1H), 4.37-4.16 (m, 2H), 3.23-3.05 (m, 2H), 2.89-2.71 (m, 2H), 1.86-1.51 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([O:42][Si](C(C)(C)C)(C)C)[C:38]([CH3:41])([CH3:40])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:27][CH3:28])([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH:37]([OH:42])[C:38]([CH3:40])([CH3:41])[CH3:39])=[C:31]([CH3:50])[CH:30]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Trifluoroacetic acid (0.22 mL) was added to a solution of [4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 65-(1); 31.5 mg, 0.050 mmol) in dichloromethane (1.2 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The solvent in the reaction solution was distilled off under reduced pressure, and the residue was diluted with diethyl ether. The mixture was adjusted to pH 8 with aqueous sodium bicarbonate solution, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=5/1) to give the title compound (21.5 mg, 84%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([O-:14])=[O:13])=[CH:2]1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].C[C@H]1NCCNC1.[NH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31]>>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C@@:11]([OH:15])([C:12]([OH:14])=[O:13])[CH2:31][C@H:30]([NH2:29])[C:32]([OH:34])=[O:33])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1.[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18]
Reactant: O=C([O-])C(=O)Cc1c[nH]c2ccccc12
Reactant: C[C@@H](N)C(=O)O
Agent: CC(=O)C(=O)[O-]
Agent: C[C@@H]1CNCCN1
Product: N[C@@H](C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)C(=O)O

Procedure:
In a specific embodiment, L-tryptophan is converted to D-tryptophan using a tryptophan racemase. D-tryptophan then reacts with pyruvate via a broad specificity D-aminotransferase to produce indole-3-pyruvate and D-alanine. Indole-3-pyruvate then reacts with an R-specific aldolase and pyruvate to form R-α-keto acid monatin (R-MP). R-MP then reacts with a broad specificity D-aminotransferase and D-alanine to produce R,R monatin and pyruvate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)(=O)=O)=CC=1>C(#N)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
A solution of 4-Hydroxybenzaldehyde (20.1 grams, 0.164 moles), potassium carbonate (67.9 grams, 0.492 moles) and t-butyl 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylate (70 grams, 0.197 moles) in acetonitrile (1000 mL) was stirred for 18 hours at 80° C. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was cooled to room temperature and quenched on to chilled water (1000 mL). The compound was extracted with dichloromethane (3×500 mL). The resulting dichloromethane layer was washed with 10% lye solution (100 mL), water (100 mL) and brine solution (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (50.3 grams).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:29]=[CH:28][S:27][C:7]=12.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[C:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][C:9]([C:18]([N:20]2[CH2:21][CH2:22][C:23](=[O:26])[CH2:24][CH2:25]2)=[O:19])=[C:8]2[N:3]1[CH2:4][CH2:5][C:6]1[CH:29]=[CH:28][S:27][C:7]=12
Reactant: O=C(c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CC2)N1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2sccc2CC3)CC1

Procedure:
A solution of 100 mg of 1-[(4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizin-10-yl)carbonyl]-4-piperidinol in 5 ml of methylene chloride was treated with 51 mg of pyridinium chlorochromate. After the reaction was completed, the solvent was evaporated in vacuo and the residue was chromatographed over silica gel. The product was recrystallized from diethyl ether and there was obtained 1-[(4,5-dihydro-7-oxo-8-phenyl-7H-thieno[2,3-a]-quinolizin-10-yl)carbonyl]-4-piperidinone of m.p. 218°-220°.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][C:10]2[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[C:7]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:6][C:5]=2[C:4](=[O:36])[CH2:3]1.CC(C)C(O)=O.[CH3:44][N:45]([CH3:48])[CH:46]=O>>[C:25]([O:24][C:23](=[O:29])[NH:22][C:18]1([C:15]2[CH:14]=[CH:13][C:12]([C:8]3[C:7]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:6][C:5]4[C:4](=[O:36])[C:3](=[CH:44][N:45]([CH3:48])[CH3:46])[C:2]([CH3:37])([CH3:1])[CH2:11][C:10]=4[N:9]=3)=[CH:17][CH:16]=2)[CH2:21][CH2:20][CH2:19]1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CN(C)C=O
Reactant: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2C1
Solvent: CC(C)C(=O)O
Product: CN(C)C=C1C(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2CC1(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Tert-butyl (1-(4-(7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (1 g, 2 mmol) was dissolved in 10 ml of anhydrous N,N-dimethylfomamide dimethylformamide dimethyl acetate. The resulting mixture was heated to 100° C. under a nitrogen atmosphere for 48 hours. TLC and LC-MS analysis showed complete consumption of the starting material. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was slurried in n-hexane (10 ml) for 1 hour. The suspension was filtered and the solid was dried until constant weigh to give the desired product as a bright yellow solid (420 mg, 76% yield). LCMS (Method A): RT=8.51 min, M+H+=552; RT=8.81 min, M+H+=525 (tert-butyl(1-(4-(6-(hydroxymethylene)-7,7-dimethyl-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)cyclobutyl)carbamate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([SiH2:15][O:16][C:17]([CH3:43])([CH3:42])[C@@:18]([NH:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([OH:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:23][CH:22]=1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([SiH2:15][O:16][C:17]([CH3:43])([CH3:42])[C@@:18]([NH:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:33])[F:34])=[CH:23][CH:22]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(O)CCCCC(F)(F)F)cc1)C(C)(C)O[SiH2]C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N[C@](C)(CCc1ccc(C(=O)CCCCC(F)(F)F)cc1)C(C)(C)O[SiH2]C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of oxalylchloride (0.15 mmol) in CH2Cl2 is added at −78° C. first DMSO (0.2 mmol) and then a solution of N-{(R)-1-(tert-Butyl-dimethyl-silanyloxymethyl)-1-methyl-3-[4-(6,6,6-trifluoro-1-hydroxy-hexyl)-phenyl]-propyl}-acetamide (0.1 mmol) in CH2Cl2. After stirring for 1 h at −78° C., triethylamine (0.7 mmol) is added and the mixture is warmed to RT. Quenching with water is followed by extraction with AcOEt. After drying (MgSO4), the solvent is evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7](Cl)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C-:17]#[N:18].[K+].[Cl-]>CC#N.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:17]#[N:18])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(Cl)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: COc1ccc(C(C#N)c2ccccc2)cc1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of p-methoxybenzhydryl chloride (27.00 g, 0.116 mol) in dry CH3CN (200 mL) was added dibenzo-18-crown-6 (2.12 g) followed by dry KCN (8.02 g, 0.123 mol), and the stirred mixture was refluxed for 66 h. After this time, the reaction mixture was cooled to room temperature and the solid was removed by filtration. The filtrate was evaporated under vacuum. The resulting solid was dissolved in CH2Cl2 (50 mL) and the solution flushed through a silica gel column (230-400 mesh, 60 g) using CH2Cl2. The eluent was evaporated and the residue was titurated with heptane to precipitate the product. The precipitate was collected and washed with heptane to give a solid. 1H--NMR analysis of this solid showed that it was a mixture of starting chloride and product. Therefore, the heptane filtrates were evaporated and the solids were recombined, giving a total of 25.03 g of material. This solid was reacted again as described above, except that the reflux period was extended 48 h. Afterwards, the reaction mixture was worked up as described above to give the title nitrile (18.56 g, 72%) as a yellowish white solid. The structure was confirmed by 1H--NMR in CDCl3.
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:10]1=[O:26]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1[C@H](N)C(=O)N1OCC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
(3S-trans) -[[3-[(t-Butyloxycarbonyl)amino]-4-methyl-2-oxo-1-azetidinyl]oxy]acetic acid. phenylmethyl ester (3.6g) was dissolved in 5 ml of dichloromethane and the solution was cooled to -10° C. Trifluoroacetic acid (25ml) was added dropwise and the mixture was stirred for 20 minutes at -10° C. After evaporation, the residue was treated with ether yielding 2.5 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)C.ClCCl>[C:15]1([CH2:14][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccc(O)cc1C(F)(F)F
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: OCc1ccc(OCc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(hydroxymethyl)-3-(trifluoromethyl)phenol (for a preparation see Intermediate 17)(3.86 g, 20.1 mmol) in ethanol (80 mL) was added benzyl bromide (2.4 ml, 20.2 mmol, Aldrich) and then 2 M sodium hydroxide (11 ml, 22 mmol). The mixture was stirred at ambient temperature overnight under nitrogen. The solvent was removed in vacuo to leave an aqueous suspension. The residue was partitioned between dichloromethane (100 ml) and water (100 ml). The phases were separated and the aqueous phase extracted with dichloromethane (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified on silica 100 g using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (4.68 g);
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:16]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:6]1[N:10]2[C:11]([CH2:15][Cl:16])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cnc2cccc(C)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cccc(CCl)n12
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
To a solution prepared by dissolving 430 mg (2.06 mM) of 3-carbethoxy-5-methylimidazo[1,2-a]pyridine in 10 ml of ethyl acetate was added 330 mg (2.67 mM) of N-chlorosuccinimide. Then, 1.03 ml (1.03 mM) of 1N-trifluoroacetic acid-ethyl acetate was added dropwise at room temperature. The mixture was stirred under argon gas at room temperature for 14 hours. After the reaction, the reaction mixture was poured in 30 ml of saturated aqueous NaHCO3 solution with ice-cooling and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 350 mg (yield 71.2%) of the title compound as yellow liquid.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[NH2:28]>>[F:26][C:24]1[C:23]([F:27])=[CH:22][C:21]2[NH:28][C:15]([CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)=[N:19][C:20]=2[CH:25]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)c(F)cc1N
Agent: [Na+]
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3cc(F)c(F)cc3[nH]2)[nH]1
Yield: 43.2 %

Procedure:
The product is prepared according to the procedure described in Stage 3 of Example 1, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 173 mg of 1,2-diamino-4,5-difluorobenzene in place of the 1,2-diamino-4-fluorobenzene. After purification by silica gel column chromatography, elution being carried out with a gradient of pure CH2Cl2 to CH2Cl2/MeOH: 85/15, 150 mg of 2-[(5,6-difluoro-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a light pink solid, the characteristics of which are the following:
Reaction SMILES: C([O:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([C:20]([O:22][CH3:23])=[O:21])=[N:12][C:11]=1[C:24]([O:26][CH3:27])=[O:25])(=O)C1C=CC=CC=1.C(N)C1C=CC=CC=1.C(OCC)C>CO>[OH:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]([C:20]([O:22][CH3:23])=[O:21])=[N:12][C:11]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1nc(C(=O)OC)c2cccnc2c1OC(=O)c1ccccc1
Solvent: CCOCC
Solvent: CO
Solvent: NCc1ccccc1
Product: COC(=O)c1nc(C(=O)OC)c2cccnc2c1O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Dimethyl 8-(benzoyloxy)-1,6-naphthyridine-5,7-dicarboxylate (2.0 g, 5.46 mmol, prepared as in Example 164) was dissolved in dry methanol (4.0 ml) in a pressure tube. Benzylamine (0.58 g, 5.46 mmol) was added and the reaction capped and heated to 80 degrees C. under nitrogen for 16 hours. LCMS analysis indicated that the reaction was complete. The reaction was transferred to an Erlenmeyer flask and then diethyl ether was added to precipitate the product. Filtered and dried the solid in vacuo to obtain the desired compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]([NH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=O)[C:16]([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:17][C:16]([C:15]1[O:24][C:23]([O:25][CH2:26][CH3:27])=[CH:22][N:21]=1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)CNC(=O)C(C)(C)C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOc1cnc(C(C)(C)C)o1

Procedure:
To a vigorously-stirred slurry of phosphorus pentoxide (163.8 g., 1.15 mole) in chloroform (600 ml.) maintained under a nitrogen atmosphere is added slowly a solution of ethyl N-pivaloylglycinate (107.8 g., 0.576 mole) in chloroform (350 ml.). Upon completing the addition, the reaction mixture is stirred and heated at reflux under a nitrogen atmosphere for 14 hours. The cooled reaction mixture is treated with 20% sodium hydroxide (800 ml.), vigorously stirred for 1/2 hour and allowed to separate into two phases. After discarding the aqueous phase, the organic phase is washed with water and saturated brine, dried over sodium sulfate and filtered. Distillation of the filtrate provides 2-(1,1-dimethylethyl)-5-ethoxyoxazole as a pale yellow liquid (64 g., 66%), b.p. 58°-64° C./0.7 mm.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([NH2:19])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(C2CCCCC2)c1)c1ccccc1
Yield: 48.1 %

Procedure:
This compound was prepared following the same procedure as described for Example 3 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (Example 8b) (100 mg, 0.36 mmol) and benzoic acid (40 mg, 0.33 mmol) as starting materials. The title compound (60 mg, 43.5%) was isolated as off white solid; MS (ESI): 379 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(N=NC(C#N)(C)C)(C#N)C.[Br:27]N1C(C)(C)C(=O)N(Br)C1=O.C(Br)C1C=CC=CC=1>ClCCCl.[W]>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:9]([CH2:12][Br:27])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)c1c(C)ccc(Br)c1OC
Agent: [W]
Agent: BrCc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COC(=O)c1c(CBr)ccc(Br)c1OC
Yield: 68.9 %

Procedure:
A solution of methyl 3-bromo-2-methoxy-6-methylbenzoate (Intermediate 91, 20 g) in 1,2-dichloroethane (400 ml) was stirred and illuminated with a 500 W tungsten filament lamp and treated with a catalytic amount of AIBN. Solid 1,3-dibromo-5,5-dimethylhydantoin (20 g) was gradually added over 3 hours until NMR analysis indicated complete conversion to the desired benzyl bromide. After cooling, the mixture was evaporated to dryness and the residue was triturated with cyclohexane and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of DCM and cyclohexane with a gradient of 1-25% to give methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (16.3 g) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH2:20])=[O:19])[CH2:13][CH2:12]1.CO.CN(C)C=O>[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH2:20])=[O:19])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: NC(=O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)CN1CCN(c2ccc(N)cc2F)CC1
Yield: 97.1 %

Procedure:
2-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-acetamide (0.558 g, 0.00198 mol) was combined with Methanol (60 mL, 1 mol) and N,N-Dimethylformamide (10 mL, 0.1 mol). The solution was passed through a 10% Pd/C CatCart (55×4 mm) in an H-cube hydrogenator at 10 bar, 30° C. for 3.5 hours. The reaction was concentrated to yield a yellow solid, 2-[4-(4-Amino-2-fluoro-phenyl)-piperazin-1-yl]-acetamide (485 mg, 97%). LCMS: m/z=253.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, 2H), 6.76 (m, 1H), 6.31 (m, 2H), 4.97 (br s, 2H), 2.87 (m, 6H), 2.52 (m, 4H).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][N:7]([CH3:25])[CH:8]=[C:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16](C=O)[CH:15]=1)[CH:10]=[N+](C)C.[OH-:26].[Na+]>>[CH3:6][N:7]([CH3:25])[CH:8]=[C:9]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH:10]=[O:26]
Reactant: CN(C)C=C(C=[N+](C)C)c1cn(C=O)c2ccccc12
Reactant: [OH-]
Agent: F[B-](F)(F)F
Agent: [Na+]
Product: CN(C)C=C(C=O)c1c[nH]c2ccccc12

Procedure:
The trimethinium salt obtained in Step A (990 mg., 3 mmole) is stirred with 1N sodium hydroxide solution at 70° C. for one hour. The solid is filtered off and washed with water yielding 564 mg. (88%) of compound, m.p. 188°-190° C. (dec.). Recrystallization of the crude product from alcohol (11.5 ml.) affords the pure compound crystallizing in cream-colored prisms, m.p. 191°-192° C. with slight darkening.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][CH2:17]OCC.C([Mg]Cl)=C.[Cl-].[NH4+]>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:16]=[CH2:17])([OH:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCOCC
Agent: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)(c1ccccc1)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of 20 g. of 4-hydroxy-benzophenone in 180 ml. of dry ether is added, within about 30 minutes, to a 0° C. solution of 184 ml. of a 3.4 molar tetrahydrofuran solution of vinyl magnesium chloride, and the reaction mixture is stirred at the same temperature for additional 1 hour. The mixture is allowed to stand at room temperature overnight. Thereafter the mixture is poured onto ice water containing ammonium chloride. The etheral phase is separated, washed with water until neutral, dried over anhydrous mganesium sulfate, and the solvent is evaporated. 22.6 g. of crude 4-hydroxy-α-vinyl-benzhydrol are obtained. After recrystallization from a mixture of ethyl acetate and n-hexane, the product melts at 104°-105° C.