Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.CCCCCC.C([Li])CCC.[C:21](#[N:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31]([CH3:37])([CH3:36])[C:32]2=O)=[CH:28][CH:27]=1>C1COCC1.O>[CH3:24][O:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][C:31]([CH3:37])([CH3:36])/[C:32]/2=[CH:22]/[C:21]#[N:23])=[CH:28][CH:27]=1
Reactant: CC#N
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)C2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc2c(c1)/C(=C\C#N)C(C)(C)C2
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a solution of 1,1,1,3,3,3-hexamethyldisilazane (4.13 ml, 19.6 mmol) in THF (80 ml) was added dropwise, under argon atmosphere at −78° C., a 1.56M solution of n-butyllithium hexane solution (12.5 ml, 19.6 mmol). The mixture was stirred for 10 minutes, to which was added acetonitrile (0.94 ml, 17.9 mmol), and the mixture was stirred for further 15 minutes. To the mixture was added a solution of 6-methoxy-2,2-dimethyl-1-indanone (3.00 g, 16.3 mmol) in THF (10 ml), which was stirred for 15 minutes. To the reaction mixture was added water so that the temperature was gradually reverted to room temperature. The reaction mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was dissolved in toluene (100 ml). To the solution was added 10-camphor sulfonic acid (0.5 g), and the mixture was heated for 1.5 hours under reflux. The reaction mixture was cooled, to which was added water. The mixture was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (hexane/ethyl acetate, 97:3→9:1) to give 1.03 g (yield 30%) of (Z)-(6-methoxy-2,2-dimethylindan-1-ylidene)acetonitrile as an oily product.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([OH:40])=O)=[CH:34]3)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[CH2:41]([CH2:43][NH2:44])[OH:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:33]3[CH:37]=[CH:36][C:35]([C:38]([NH:44][CH2:43][CH2:41][OH:42])=[O:40])=[CH:34]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCCO)c3)ccc2n1CC1CCOCC1
Yield: 70.2 %

Procedure:
Following the same procedure in Example 33, step A, using DIPEA (47 uL, 35 mg, 0.27 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (60 mg, 0.14 mmol) (see following step B for preparation), ethanolamine (17 mg, 0.27 mmol) and HATU (103 mg, 0.27 mmol) in DMF (5 mL). The crude product was purified by MPLC using EtOAc/MeOH (9:1) on silica gel to give 48 mg (72%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.42-1.58 (m, 4H), 1.61 (s, 9 H), 2.23-2.36 (m, 1 H), 3.25-3.34 (m, 2 H), 3.38 (t, J=5.76 Hz, 2 H), 3.61 (t, J=5.76 Hz, 2 H), 3.86-3.94 (m, 2 H), 4.44 (d, J=7.42 Hz, 2 H), 6.67 (dd, J=3.32, 1.76 Hz, 1H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.82-7.85 (m, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.98 (d, dd, J=8.7, 1.5 Hz, 1 H), 8.28 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=489.3.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1.[OH:19]O>C(O)=O>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:19])=[O:16])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Reactant: OO
Solvent: O=CO
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Reaction time: 36 h
Yield: 69 %

Procedure:
Procedure C′: 2′-trifluoromethyl-biphenyl-4-carbaldehyde (Array 4PNL-S04-0) (0.63 g, 2.5 mmol) is suspended in formic acid (3.5 mL), and the solution is placed in an ice bath. Hydrogen peroxide is added (0.875 mL, 7.5 mmol), and the reaction vessel is placed in the refrigerator and is allowed to stand for 1-2 days. The yellow solid that precipitates out is filtered, washed with cold water and dried in a vacuum oven to give the title compound (0.45 g, 69%). MS (ES−) 265.1
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O-2].[Mg+2].O.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1[CH2:24][O:23][CH2:22]C1>>[CH3:22][O:23][CH2:24][O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: NCCCCO
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C1CCOC1
Agent: [Mg+2]
Agent: [O-2]
Solvent: O
Product: COCOCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Aminobutanol (700 mg) was dissolved in THF (12.5 mL). To the solution, magnesium oxide (1.58 g), water (3.2 mL), and benzenesulfonyl chloride (1.15 mL) were added, and the mixture was stirred at room temperature for 2 hours. The precipitate was removed by filtration, and washed with chloroform (50 mL). Then, the combined filtrate was concentrated under reduced pressure. To the residue, water (20 mL) was added, and the resultant mixture was then extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate). The obtained colorless oil (1.48 g) was dissolved in dichloromethane (7.5 mL). To the solution, N,N-diisopropylethylamine (3.43 mL) and chloromethyl methyl ether (1.0 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (50% ethyl acetate/hexane) to obtain the title compound (1.36 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(OC3CCOCC3)ccc2CCC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 95.5 %

Procedure:
To methyl 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (406 mg, 1.34 mmol) dissolved in a mixed solvent of methanol (7 ml) and THF (7 ml) was added a 1N aqueous solution of sodium hydroxide (4.0 ml), and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.0 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-[(tetrahydropyran-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (307 mg, 1.28 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:22]([F:25])([F:24])[F:23])/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([CH3:21])[CH:13]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:26][C:27]([F:31])([F:30])[CH2:28][NH2:29].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([CH:9]([C:22]([F:25])([F:24])[F:23])/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:29][CH2:28][C:27]([F:31])([F:30])[F:26])=[O:18])=[C:14]([CH3:21])[CH:13]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a stirred solution of (E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic acid in DMF was added 2,2,2-trifluoroethylamine, 1-hydroxybenzotriazole hydrate (HOBt.H2O), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and DIPEA, and the reaction mixture was stirred at 25° C. for 18 h. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with hexane:EtOAc afforded a white semi-solid (110 mg, 50%): 1H NMR (400 MHz, CDCl3) 7.40 (m, 2H), 7.26 (m, 3H), 6.56 (d, J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 5.82 (br s, 1H), 4.08 (m, 3H), 2.52 (s, 3H); ESIMS m/z 468.40 ([M−H]−); IR (thin film) 1657, 1113, 804 cm−1.
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:24])[C:9]([O:11][CH2:12][O:13][C:14](ON1C(=O)CCC1=O)=[O:15])=[O:10]>>[CH3:2][N:1]([C:14]([O:13][CH2:12][O:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])=[O:15])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CNCC(=O)O
Reactant: CC(C)C(=O)OCOC(=O)ON1C(=O)CCC1=O
Product: CC(C)C(=O)OCOC(=O)N(C)CC(=O)O
Yield: 53.8 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.123 g, 1.3 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)methyl 2-methylpropanoate (0.300 g, 1.1 mmol) were reacted to provide 0.138 g (51.3% yield) of the title compound (46) as a colorless semi-solid material after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=5.78 (d, 2H), 4.12 (d, 3H), 3.02 (d, 3H), 2.62 (m, 1H), 1.2 (t, 6H). MS (ESI) m/z 256.05 (M+Na)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:13]([O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:22][CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To 20 mL of a chloroform solution containing 2.17 g of 1,4-benzodioxane-6-carbaldehyde and 2.67 g of tert-butyl(piperidin-4-yl)carbamate, 0.76 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 4.27 g of sodium triacetoxyborohydride, and stirred overnight. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60 manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate:hexane=5:1] to obtain 2.96 g of tert-butyl(1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-piperidin-4-yl)carbamate.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:16][F:17])([CH3:15])[CH:3]=1.Cl.[CH3:19][N:20](C)C=O>>[C:19]([C:2]1[C:7]2[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:16][F:17])([CH3:15])[CH:3]=1)#[N:20]
Reactant: CC1(CF)C=C(Br)c2cc([N+](=O)[O-])ccc2O1
Reactant: CN(C)C=O
Agent: Cl
Product: CC1(CF)C=C(C#N)c2cc([N+](=O)[O-])ccc2O1

Procedure:
A mixture of 5.6 g of 4-bromo-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran, 1.84 g of cuprous cyanide and 50 ml of N,N-dimethylformamide was refluxed with heating for 5 hours under a nitrogen atmosphere. When aqueous HCl solution was added to the mixture under ice-cooling, crystals were separated out. The crystals were collected by filtration, washed with water and dissolved in methylene chloride. After it washed with water and dried, the solvent was evaporated off. The resultant residue was purified with silica gel column chromatography (developing solution: CH2Cl2) to obtain 3.27 g of 4-cyano-2-fluoromethyl-2-methyl-6-nitro-2H-1-benzopyran with a melting point of 169°-171° C.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16](S(N4CCC(O)CC4)(=O)=O)=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][C:34](=[O:44])[N:35](C1C=CC(N)=CC=1)[CH3:36]>>[CH:1]1([NH:5][C:6]2[C:7]3[CH:31]=[CH:30][NH:29][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:35]([CH3:36])[C:34](=[O:44])[O:33][CH3:32])=[CH:15][CH:14]=3)[N:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)N(C)c1ccc(N)cc1
Reactant: O=S(=O)(c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1)N1CCC(O)CC1
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1

Procedure:
According to the general procedure for synthesis of 1-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenylsulfonyl)piperidin-4-ol, methyl-4-aminophenyl(methyl)carbamate and 2-Chloro-N-cylclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine gave methyl 4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl(methyl)carbamate (MS calcd for C19H22N6O2 366.2, found [MH] 368.0; UV 209.8, 271.2, 304.5 nm).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.IC.[CH3:16]N1C=CC(C2C=CC=CC=2)=N1>C1COCC1.O>[CH3:16][N:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:13][CH:12]=[N:11]1
Reactant: Cn1ccc(-c2ccccc2)n1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nccc1-c1ccccc1
Yield: 95 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.83 g, 20.8 mmol) is suspended in THF (45 ml) and stirred under a nitrogen atmosphere. 3-Phenyl pyrazole (2.5 g, 17.3 mmol dissolved in THF, 15 ml) is added slowly, stirred for 30 minutes then iodomethane (1.3 ml, 20.8 mmol) added and stirred for 3 hrs. The reaction is added to water and extracted twice with ethyl acetate. The combined organic extracts are ished with brine, dried over Na2SO4, filtered and concentrated. The crude product is purified by chromatography using a hexane-ethyl acetate gradient (100% hexane to 40% ethyl acetate in hexane) to elute the title compound. Obtained is a mixture of 1-methyl-3-phenyl-1H-pyrazole and 1-methyl-5-phenyl-1H-pyrazole (2.6 g, 95% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][OH:12])([O-:3])=[O:2].CN1CCOCC1.O=C(Cl)[O:23][C:24](Cl)(Cl)[Cl:25]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH3:13])[CH2:11][O:12][C:24]([Cl:25])=[O:23])([O-:3])=[O:2]
Reactant: CC(CO)c1ccccc1[N+](=O)[O-]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A solution consisting of 7.2 g 2-(2-nitrophenyl)propanol (39.7 mmol) and 4.4 ml N-methylmorpholine (39.7 mmol) in 15 ml absolute THF are slowly added to 5 ml diphosgene (41.4 mmol) in 10 ml absolute THF at 0° C. in a nitrogen atmosphere through a needle. Having stirred for 1 hour at 0° C., some of the precipitate is sucked off and the filtrate is withdrawn at the high vacuum. 6.91 g of (1) is obtained in the form of a brown oil (71%).
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([O:11][C:12]1[C:13]([Br:25])=[C:14]([OH:24])[CH:15]=[C:16]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.C(OCC)C>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]2[O:19][C:20]([CH3:23])=[CH:21][N:22]=2)[CH:15]=[C:14]([O:24][CH2:2][CH3:3])[C:13]=1[Br:25])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cnc(-c2cc(O)c(Br)c(OCc3ccccc3)c2)o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1cc(-c2ncc(C)o2)cc(OCc2ccccc2)c1Br
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Iodoethane (111 uL, 1.37 mmol) was added to a mixture of 3-(benzyloxy)-2-bromo-5-(5-methyloxazol-2-yl)phenol (412 mg, 1.14 mmol) and potassium carbonate (632 mg, 4.58 mmol) in DMF (2.8 mL). After stirring for two hours, the solution was diluted with 1:1 ethyl acetate/diethyl ether, washed with water (5×), brine, dried over magnesium sulfate and concentrated to provide 2-(3-(benzyloxy)-4-bromo-5-ethoxyphenyl)-5-methyloxazole as a white crystalline solid (421 mg). MS (M+1)=388.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52 (d, J=7.07 Hz, 2H), 7.36-7.43 (m, 2H), 7.28-7.35 (m, 2H), 7.23 (d, J=1.52 Hz, 1H), 6.86 (d, J=1.52 Hz, 1H), 5.24 (s, 2H), 4.21 (q, J=6.74 Hz, 2H), 2.41 (d, J=1.01 Hz, 3H), 1.50 (t, J=6.82 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(F)c1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (2.03 g, 0.011 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (6.38 g, 0.049 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-fluoro-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 0.010 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.40 g, 35%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][N:14]=1>CN(C)P(=O)(N(C)C)N(C)C>[O:11]1[CH2:10][CH:9]1[CH2:7][O:12][C:13]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:15][N:14]=1
Reactant: ClCC1CO1
Reactant: Oc1cc(-c2ccccc2)on1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1ccc(-c2cc(OCC3CO3)no2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
10.28 g of anhydrous potassium carbonate and 6.89 g of epichlorohydrin were added to a solution of 10.00 g of 3-hydroxy-5-phenylisoxazole in 50 ml of hexamethylphosphoric triamide, and the mixture was stirred at room temperature for 24 hours. At the end of this time, insoluble materials were removed by filtration from the reaction mixture, and 200 ml of ethyl acetate were added thereto. The mixture was then washed twice, each time with 200 ml of a 10% w/v aqueous solution of sodium chloride. The organic layer was then dried over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, eluted with a 4:1 by volume mixture of cyclohexane and ethyl acetate, to give 11.00 g (yield 82%) of the title compound as colorless needles, melting at 98°-99° C.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=2[CH:12]=1.Cl[CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21].C(N(CC)CC)C.[I-].[Na+]>CN(C)C=O.O>[CH3:14][O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Naproxen (1.07 g, 5 mmole) and 2-chloro-N,N-diethyl-acetamide (0.90 g, 6 mmole) were dissolved in 7 ml of N,N-dimethylformamide and triethylamine (1.4 ml, 10 mmole) and sodium iodide (76 mg) were added. The mixture was refluxed for 2 h, cooled and poured into 35 ml of water. The precipitate formed after standing overnight at 4° C. was collected by filtration, washed with water and recrystalized from 95% ethanol, yielding 1.5 g (92%) of the title compound. Mp 89°-89.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>O>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][NH:21][C:2]2[CH:7]=[C:6]([C:8]3[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=4)[N:11]=[C:10]([CH3:20])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccnc(Cl)c2)n(-c2cccc(F)c2)n1
Reactant: NCc1cccnc1
Solvent: O
Product: Cc1cc(-c2ccnc(NCc3cccnc3)c2)n(-c2cccc(F)c2)n1
Temperature: 190 °C
Yield: 60 %

Procedure:
A mixture of 2-chloro-4-[1-(3-fluorophenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 47; 0.48 g, 0.0017 mol) and 3-(aminomethyl)pyridine (10 mL) was heated at 190° C. overnight (about eighteen hours). The reaction mixture was cooled, treated with copious amount of water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/triethylamine, 99:1) to give 0.35 g (60% yield) of product as a yellow oil: Anal. Calc'd. for C21H18FN5: C, 70.18; H, 5.05; N, 19.49. Found: C, 69.78; H, 5.35; N, 18.87.