Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH2:26][CH2:27][O:28][CH2:29][CH:30]=1)CCC.[Cl-].[Li+].O1CCOCC1>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.[Cu]I>[CH2:18]([O:17][C:15]([C:4]1[S:3][C:2]([C:25]2[CH2:30][CH2:29][O:28][CH2:27][CH:26]=2)=[N:6][C:5]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(C2=CCOCC2)nc1Cc1ccc(Cl)cc1
Yield: 38.7 %

Procedure:
A mixture of ethyl 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (289 mg, 0.802 mmol), tributyl(3,6-dihydro-2H-pyran-4-yl)stannane (332 mg, 0.890 mmol), tetrakis(triphenylphosphine)palladium(0) (46.4 mg, 0.0401 mmol), lithium chloride (1.20E2 mg, 2.82 mmol) and copper(I) iodide (45.8 mg, 0.241 mmol) in dry 1,4-dioxane (6.26 mL, 80.2 mmol) was degassed by vacuum and backfilling with argon four times, and then heated under argon at reflux for 3 hours. The mixture was filtered thru Celite, washing with 10% MeOH in DCM. Volatiles were removed in vacuo, and the residue was adsorbed to silica gel by concentrating a DCM solution to which silica gel had been added. Column chromatography (gradient elution, 0 to 20% EA in hexanes) afforded ethyl-4-(4-chlorobenzyl)-2-(3,6-dihydro-2H-pyran-4-yl)-1,3-thiazole-5-carboxylate (113 mg, 38.9%) as a white solid. 1H NMR (300 MHz, DMSO) δ 7.35-7.31 (m, 2H), 7.27-7.23 (m, 2H), 6.86-6.83 (m, 1H), 4.40 (s, 2H), 4.29 (q, J=6.9, 2H), 4.25-4.22 (m, 2H), 3.78 (t, J=5.4, 2H), 2.51-2.46 (m, 2H), 1.27 (t, J=6.9 Hz, 3H).
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:24])=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[N+:21]([O-])=O)[CH3:6]>[Fe].O>[CH2:5]([O:7][C:8](=[O:25])[C:9]([CH3:24])=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[NH2:21])[CH3:6]
Reactant: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)=Cc1cc(OC)c(OC)cc1N
Yield: 73.2 %

Procedure:
Into 250 ml of glacial acetic acid, 19.0 g of 3-(4,5-dimethoxy-2-nitrophenyl)-2-methyl-2-propenoic acid ethyl ester were dissolved; and, with 15.0 g of iron powder and 20 ml of ion-exchanged water being added thereto, the mixture was refluxed under heating for 40 minutes. The resulting reaction liquid was filtered out, the filtrate was concentrated under a reduced pressure, and thus obtained residue was dissolved in ethyl acetate. The resulting product was successively washed with water, a 5% aqueous sodium hydrogencarbon ate solution, and a saturated aqueous sodium chloride solution; and then was left on sodium sulfate anhydride for one night so as to be dried. Ethyl acetate was evaporated under a reduced pressure from this solution, and the resulting crude product was recrystallized from hexane/ethanol, whereby 12.5 g of the aimed product were obtained (yield: 78%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH3:16])=[O:14])[C:9]([CH3:18])([CH3:17])[CH2:8]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:17][C:9]1([CH3:18])[CH2:8][CH:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1CCC(O)CC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(OS(C)(=O)=O)CC1(C)C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (1.69 mL, 21.7 mmol) was added at −20° C. to a solution of racemic methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate (3.11 g, 16.7 mmol) and triethylamine (4.65 mL, 33.4 mmol) in dichloromethane (67 mL). The reaction was stirred for 3 hours. Saturated aqueous sodium bicarbonate was added to the mixture and extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexanecarboxylate. 1H NMR (500 MHz, CDCl3) δ 4.92-4.72 (m, 1H), 3.64 (s, 3H), 2.99 (s, 3H), 2.29-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.71 (m, 2H), 1.63-1.59 (m, 1H), 1.49-1.32 (m, 1H), 1.01 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1>Cl>[Cl:1][C:2]1[C:7]([C:8]([OH:15])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(O)c1cccnc1Cl
Agent: Cl
Product: CC(O)(C(=O)O)c1cccnc1Cl

Procedure:
A solution of ethyl 2-(2-chloropyridin-3-yl)-2-hydroxypropanoate (0.2 g, 0.871 mmol) in hydrochloric acid, 37% (Sigma Aldrich, 2.75 ml, 33.5 mmol) was heated in a sealed tube at 60° C. overnight. Reaction mixture was rotovapped and dried by vacuum pump. The residue containing 2-(2-chloropyridin-3-yl)-2-hydroxypropanoic acid was advanced to next step. M: 201.9.
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[OH-].[Na+].O>C(O)C.C(OCC)(=O)C>[Cl:12][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]([OH:13])=[O:2])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CNc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CNc1cccc(Cl)c1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
(3-Chloro-phenylamino)-acetic acid methyl ester (4 g, 20.0 mmol) and sodium hydroxide (4.00 g, 100 mmol) were combined in ethanol (60.0 mL) and water (10 mL) to give a light yellow solution which was heated at 60° C. for 4 hours. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with 1M aqueous hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (3-chloro-phenylamino)-acetic acid as a brown solid (3.20 g, 86%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33].O>CN(C)C=O>[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([O:7][C:8]2[C:9]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:23][C:22]=1[NH:31][C:32](=[O:34])[CH3:33]
Reactant: COC(=O)COc1ncccc1O
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(NC(C)=O)c(F)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
2.08 g of potassium carbonate was added to a solution of 3.0 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine and 2.95 g of N-(2,5-difluoro-4-nitrophenyl)acetamide in 40 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours at temperature from 60 to 70° C. Then, the mixture was cooled to room temperature, poured into water, extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated to obtain crude crystal. The crude was washed with diisopropyl ether to obtain 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitrophenyl]acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1.C=C1CCOC(C2C=CC=CC=2)C1.C(=O)C1C=CC=CC=1.CC(CCO)=C>C(O)C.[Pd]>[CH3:1][CH:2]1[CH2:7][CH2:6][O:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: CC1=CC(c2ccccc2)OCC1
Agent: [Pd]
Agent: C=C(C)CCO
Agent: C=C1CCOC(c2ccccc2)C1
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: CC1CCOC(c2ccccc2)C1

Procedure:
In an autoclave, 10 g of a mixture of 5,6-dihydro-4-methyl-2-phenyl-2H-pyran and tetrahydro-4-methylene-2-phenyl-2H-pyran (prepared from benzaldehyde and isoprenol as described in Swiss Pat. No. 655 932) in 50 ml of ethyl alcohol were hydrogenated in the presence of 0.1 g of 10% Pd on charcoal to yield 9.7 g of pure tetrahydro-4-methyl-2-phenyl-2H-pyran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:28])([CH3:27])[CH2:9][C:10]([NH2:26])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:14])([F:13])[F:12])[CH:7]=1.C=O.[C:33](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]([CH3:27])([CH3:28])[CH2:9][C:10]([NH:26][CH3:33])([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:11]([F:12])([F:14])[F:13])[CH:7]=1
Reactant: CC(=O)O
Reactant: COc1ccc(F)cc1C(C)(C)CC(N)(Cc1ccnc2ccccc12)C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CNC(Cc1ccnc2ccccc12)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A solution of 3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine (42.0 mg, 0.1 mmol) and formaldehyde (8 μL, 0.1 mmol) in dichloroethane (2 mL) was stirred for 30 min at room temperature in the presence of 4A molecular sieves (200 mg). The reaction mixture was acidified with acetic acid (57 μL, 1.0 mmol), stirred for 16 h and treated with sodium triacetoxy borohydride (42.4 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 3 h and quenched with NaHCO3 (sat. 6 mL). Phases were separated and the aqueous layer was extracted with CHCl3 (2×4 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on SiO2 (20%–40%, EtOAc:Hexanes) to give 24.0 mg (55%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:35](CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:27])[NH2:35])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(Cc1ccc(-c2ccc(CCC(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
Acid compound 46 (1.2 g, 2.73 mmol) was dissolved in DCM (30 mL). Triethylamine (0.46 mL, 3.27 mmol) and BOP reagent (1.33 g, 3.0 mmol) were added and the reaction mixture stirred at room temperature for 15 min under an atmosphere of argon. Ammonia gas was then bubbled gently through the solution for 15-20 min to complete the reaction. Excess ammonia was degassed, the solvent was removed under reduced pressure and the residue was suspended in EtOAc (75 mL). The organic layer was washed with 0.5 N NaOH (2×10 mL), water (2×25 mL), and brine (1×30 mL), dried and concentrated under reduced pressure to yield the amide compound 51 (1.1 g, 92%). 1H NMR (DMSO-d6): 7.54 (d, J=8.0 Hz, 4H), 7.31 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.77 (br, 1H), 4.56 (m, 1H), 2.93 (s, 3H), 2.75-2.90 (m, 7H), 2.74 (t, J=8.4 Hz, 2H), 1.30 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:16]([O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:28][C:27]1[CH:26]=[CH:25][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)c1ccccc1
Product: Nc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 88.4 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948:360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-benzyloxyaniline (999 mg, 5 mmol) and N,N-dimethylaniline (1.209 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL), and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-benzyloxyanilino)quinazoline hydrochloride (1.675 g, 82%) as a mustard yellow solid; mp 246°248° C. Calculated for C21H16N4O3.HCl: C, 61.69; H, 4.19; N, 13.71%. Found: C, 61.72; H, 4.22; N; 13.52%. 1H NMR (DMSO-d6): δ11.98 (1 H, brs), 9.85 (1 H, d, J=2.2 Hz), 8.94 (1 H, s), 8.76 (1 H, dd, J=2.3, 9.1 Hz), 8.15 (1 H, d, J=9.3 Hz), 7.65 (2 H, d, J=9.0 Hz), 7.48 (2 H, d, J=7.0 Hz), 7.41 (2 H, t, J=7.4 Hz), 7.31 (1 H, t, J=7.4 Hz), 7.15 (2 H, d, J=9.1 Hz), 5.16 (2 H, s). Mass spectrum (APCI) 373 (100 MH+).
Reaction SMILES: ClCCl.[CH:4]1([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[C:16]([C:26]([NH2:28])=O)=[CH:17][N:18]3[CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][C:12]=2[F:30])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH:4]1([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15](=[O:29])[C:16]([C:26]#[N:28])=[CH:17][N:18]3[CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:13][C:12]=2[F:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: NC(=O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.6 %

Procedure:
To a 30 ml dichloromethane suspension of 3.69 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide were added at −78° C. 7.0 ml of triethylamine and a 10 ml dichloromethane solution of 4.0 ml of trifluoroacetic anhydride. After gradually rising the temperature, it was stirred at room temperature for 2 days. After adding water, it was extracted with chloroform, followed by drying over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by silica gel column chromatography. After adding a mixed solvent of 30 ml of THF, 30 ml of methanol and 10 ml of water to the resulting solid, 2.3 g of potassium carbonate was added thereto under ice-cooling. After stirring at room temperature for 15 hours, 1.0 g of potassium carbonate was added thereto, followed by stirring at room temperature for 4 days. After evaporating the solvent under a reduced pressure, water was added, followed by extraction with chloroform. After drying over anhydrous sodium sulfate and subsequent filtration, the solvent was evaporated under a reduced pressure. By washing the resulting residue with ethyl acetate, 2.62 g of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonitrile was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9]([CH:12]=O)[CH:8]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][CH:10]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[CH:8]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1csc(-c2cnccn2)c1
Product: O=C/C=C/c1csc(-c2cnccn2)c1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 5-pyrazinyl-3-thiophenecarboxaldehyde (prepared as described in Reference Example 95) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 217 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:46])([CH3:45])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)=[CH:35][CH:34]=2)([OH:32])[CH3:31])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:46])([CH3:45])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)=[CH:35][CH:34]=2)([OH:32])[CH3:31])[NH:8][CH:9]=1
Reactant: Cn1cc(-c2ccc(C(C)(O)Cc3nc(CC(C)(C)C)cn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)cn1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C(C)(O)Cc3nc(CC(C)(C)C)c[nH]3)cc2)cn1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (5.25 mL, 21 mmol) was added to an ambient temperature solution of 1-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propan-2-ol (250 mg, 0.42 mmol) in methanol (10 mL). After stirring at 70° C. for 1 h, volatiles were removed. The residue was partitioned between diethyl ether and 1 N hydrochloric acid. The aqueous phase was washed with diethyl ether, basified with 2.5 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found 339.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.C[O:21]B(OC)OC.[OH-].[Na+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>C1COCC1.CCCCCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([OH:21])=[CH:3][C:4]=1[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ncc(Br)cc1CC(C)(C)C
Reactant: COB(OC)OC
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ncc(O)cc1CC(C)(C)C
Reaction time: 0.08 h

Procedure:
Under an argon atmosphere, to a solution of 5-bromo-2-methoxy-3-neopentylpyridine (4.38 g) in THF (40 mL) was added a 1.6 M solution of n-butyllithium in hexane (12.7 mL) at −78° C., and the mixture was stirred for 5 min. Trimethoxyborane (2.31 mL) was added at −78° C., and the mixture was stirred at room temperature for 14 hr. 8N Aqueous sodium hydroxide solution (2.54 mL) and 38% aqueous hydrogen peroxide (5.20 mL) were added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution at 0° C., and the mixture was neutralized with 2N hydrochloric acid (23.4 mL). The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.56 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([CH3:15])=[CH2:14])[CH:9]=2)[CH:4]=1.[Se](=O)=[O:17]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[CH2:15])[CH2:14][OH:17])[CH:7]=[CH:6]2
Reactant: C=C(C)c1ccc2cc(OC)ccc2c1
Reactant: O=[Se]=O
Solvent: ClCCl
Product: C=C(CO)c1ccc2cc(OC)ccc2c1

Procedure:
A solution of 0.20 g 2-methoxy-6-isopropenylnaphthalene and 0.12 g selenium dioxide (SeO2) in 10 ml methylene chloride was heated at reflux for 22 hours. The cooled solution was then washed with 10 ml 20% (by weight) sodium hydroxide (NaOH) after adding 40 ml ethylene dichloride (EDC). The organic layer was dried over MgSO4, filtered, and concentrated to give an oil which was purified on a 2×17 cm silica (SiO2) column using a 5 to 1 by volume solution of heptane and ethyl acetate. The product containing fractions were combined and concentrated to give 2-(6-methoxy-2-naphthyl)prop-2-en-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].C1N=[CH:18][N:17](C(N2C=NC=C2)=O)[CH:16]=1.CNC>ClC1CC(C(C)C)CCC1(Cl)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:12])[N:17]([CH3:18])[CH3:16])[CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: CNC
Product: CN(C)C(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,6-dichloroterephthalic acid (100 mg, 0.46 mmol) in dichloromenthane was added CDI (62 mg, 0.46 mmol) in one portion. The reaction mixture was stirred at room temperature for 1.5 hours and then dimethyl amine (1.0 M in THF, 2 mL, 2.0 mmol) was added. The reaction was concentrated under reduced pressure to give the crude 2,6-dichloro-4-(dimethylcarbamoyl)benzoic acid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6): δ 14.35 (s, 1H), 7.56 (s, 2H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[C:10]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:9][N:8]=[C:7]([CH2:16][C:17]([O:19]C)=[O:18])[CH:6]=1.Cl>O.O1CCCC1>[CH3:4][C:5]1[C:10]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:9][N:8]=[C:7]([CH2:16][C:17]([OH:19])=[O:18])[CH:6]=1
Reactant: COC(=O)Cc1cc(C)c(-n2cnnn2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)ncc1-n1cnnn1
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (19.2 mg, 0.458 mmol) was dissolved in 5 mL water then added to a methyl 2-(4-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate in tetrahydrofuran (15 mL). The reaction was stirred for 1 h then acidified with 1 N HCl to pH ˜3. The mixture was extracted with a mixture of THF/ethyl acetate (4×.). Dried over Na2SO4, filtered and evaporated concentrated to yield 2-(4-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetic acid.
Reaction SMILES: [P:1]([O:10][CH:11]([CH3:13])[CH3:12])([O:6][CH:7]([CH3:9])[CH3:8])[O:2]C(C)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.P([O-])([O-])[O-].[CH2:32](Cl)[C:33](=[CH2:35])[CH3:34]>>[CH:11]([O:10][P:1]([CH2:34][C:33](=[CH2:32])[CH3:35])(=[O:2])[O:6][CH:7]([CH3:8])[CH3:9])([CH3:12])[CH3:13]
Reactant: C=C(C)CCl
Reactant: CC(C)OP(OC(C)C)OC(C)C
Agent: [O-]P([O-])[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)CP(=O)(OC(C)C)OC(C)C

Procedure:
208 parts of triisopropyl phosphite, 1.5 parts of phenothiazine and 3.4 parts of Ni(CO)4 (corresponding to 2 mol %, based on the phosphite) are heated to 120°-130° C in a nitrogen atmosphere. 99 parts (corresponding to a 10% excess) of methallyl chloride are added dropwise over a period of 5 hours. 68 parts of isopropyl chloride (Bp: 35°-36° C) are distilled off through a column. The product is fractionated in vacuo through a column. Boiling point: 58°-63° C/0.25 Torr; Yield: 155 parts (70.5% of the theoretical): nD20 : 1.4312 Purity according to GC: 97.3%
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br)#[N:23]>>[C:22]([C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])#[N:23]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: N#Cc1ccccc1CBr
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2C#N)c1
Yield: 57.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-cyanobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (231 mg, yield: 57.5%).