Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[CH:9]=[C:8]([O:18][CH3:19])[C:7]=12)#[CH:2].I[C:21]1[CH:22]=[N:23][N:24]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:25]=1[CH3:26].C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:19][O:18][C:8]1[C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[C:2][C:21]2[CH:22]=[N:23][N:24]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)[C:25]=2[CH3:26])[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[CH:9]=1
Reactant: Cc1c(I)cnn1-c1cccs1
Reactant: C#Cc1cnn2cc(-c3cnn(C)c3)cc(OC)c12
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3cnn(-c4cccs4)c3C)c12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-ethynyl-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (20 mg, 0.08 mmol), 4-iodo-5-methyl-1-(2-thienyl)-1H-pyrazole (23 mg, 0.08 mmol), copper (I) iodide (4.5 mg, 0.024 mmol), and tetrakis(triphenylphosphine)palladium (0) (9.1 mg, 0.008 mmol) in N,N-dimethylformamide (2 ml), was added triethylamine (0.022 ml, 0.16 mmol). The mixture was sparged with argon for 3 minutes and heated to 70° C. After 1 h, reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)-3-{[5-methyl-1-(2-thienyl)-1H-pyrazol-4-yl]ethynyl}pyrazolo[1,5-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[CH:25]([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:25]
Reactant: COC(=O)Cc1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Yield: 34 %

Procedure:
[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.25 mmol) is dissolved in anhydrous tetrahydrofuran (200 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (6.63 mL of 2M soln., 13.25 mmol) is slowly added to the solution at room temperature. This is allowed to stir under nitrogen for 6 hours at room temperature. Hexamethylphosphor-amide (9.2 mL, 53 mmol) is added to the reaction followed by methyl iodide (1.74 mL, 26.5 mmol), added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester (1.6 g, 4.51 mmol) is isolated in 34% yield after column chromatography. The racemic 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester is resolved on a Chiralpak AD column (4.6×150 mm). Eluted with 15% 3A alcohol in heptane with 0.2% dimethy-ethylamine at 0.6 mL per minute with detection at 260 nm and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 98.9% ee; isomer 2, 96.4% ee).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[C:21]2[CH2:34][CH2:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37].C(=O)([O-])[O-].[K+].[K+].CO>CC(C)=O.C(OCC)(=O)C>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH2:2][N:41]2[CH2:42][CH2:43][N:38]([C:36](=[O:37])[CH2:35][CH2:34][C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[C:18]([Cl:17])[CH:19]=4)[NH:23][C:22]=3[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:39][CH2:40]2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
1-(Bromomethyl)-3,5-bis(trifluoromethyl)benzene (83 mg) was added to a mixture of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}piperazine (Description 30, 35 mg) and potassium carbonate (36 mg) in acetone (3 mL) and the mixture was stirred at room temperature for 2 h. Methanol (1 mL) and ethyl acetate (10 mL) were added and the mixture was washed with water. The organic fraction was filtered through a plug of silica in a Bond Elut™ cartridge, eluting with hexane/EtOAc (80:20 increasing to 60:40), to give the title compound as a colorless solid (49 mg, 89%). 1H NMR (360 MHz, CDCl3) δ2.16-2.19 (2H, m), 2.33-2.36 (2H, m), 2.59-2.63 (2H, m), 3.15-3.20 (2H, m), 3.28-3.30 (2H, m), 3.53 (2H, s), 3.58-3.61 (2H, m), 7.13 (1H, dd, J 8.7, 1.8 Hz), 7.25 (1H, d, J 8.3 Hz), 7.36-7.53 (6H, m), 7.77 (2H, s), and 8.51 (1H, s). m/z (ES+) 628, 630 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14](OS(C)(=O)=O)[C@H:13]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:28].[Li+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([Cl:28])[C@H:13]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@H]2OS(C)(=O)=O
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of compound 12e (550 mg, 1.37 mmol) in DMF (30 mL) was added lithium chloride (721 mg, 13.7 mmol). After stirring for 120 minutes at 120° C. the reaction was concentrated in vacuo. The residue was diluted with CH2Cl2 (50 mL) washed with water (1×20 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-66% isohexane:EtOAc) to give the title compound (330 mg, 72%) as a yellow oil. MS M+H 342, 344.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13](OC)[CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=[O:24].[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([O:34][C:13]1[CH:12]=[C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([OH:1])=[N:3][CH:4]=[N:5][C:6]=23)[CH:16]=[CH:15][CH:14]=1)(=[O:24])[CH3:33]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1
Reactant: COc1cccc(-c2cnn3c(O)ncnc23)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)Oc1cccc(-c2cnn3c(O)ncnc23)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 4-hydroxy-8-(3-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine (242 mg), aluminum chloride (799 mg) and nitrobenzene (3 ml) is stirred at 80°-90° C. for 5 hours. To the reaction mixture is added acetyl chloride (0.12 ml). After reacting for 45 minutes, the reaction mixture is cooled and poured into ice water. The resulting precipitate is separated by filtration, washed with water and dried to give the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([CH3:22])=[N:9][N:10]2[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=12.[Br:23]N1C(=O)CCC1=O>ClCCl>[Br:23][C:5]1[S:4][C:3]([C:7]2[C:8]([CH3:22])=[N:9][N:10]3[C:15]([CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:14][C:13]([CH3:21])=[N:12][C:11]=23)=[C:2]([Cl:1])[CH:6]=1
Reactant: CCC(CC)c1cc(C)nc2c(-c3sccc3Cl)c(C)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(-c3sc(Br)cc3Cl)c(C)nn12
Reaction time: 2 h

Procedure:
Dissolve 3-(3-chloro-thiophene-2-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (1.16 g, 3.5 mmol) in dichloromethane (15 mL) and add N-bromosuccinimide (0.69 g, 3.85 mmol) in one aliquot. Stir 2 h under an inert atmosphere and confirm the reaction is complete using TLC. Dilute the reaction with dichloromethane (50 mL), wash with water (75 mL), brine (50 mL), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to give a yellow solid (1.56 g, quantative yield). 1H NMR (400 MHz, DMSO): 7.39 (s, 1H), 6.88 (s, 1H), 3.48-3.44 (m, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 1.80-1.73 (m, 4H), 0.76 (t, J=7.0 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2>CC(N(C)C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH3:39])[CH:34]=[CH:33]2
Reactant: Cn1ccc2cc(O)ccc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4c(ccn4C)c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Nitrogen was bubbled through a mixture of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (400 mg, 1.24 mmol), (prepared as described for the starting material in Example 9), potassium carbonate (500 mg, 3.62 mmol), 5-hydroxy-1-methylindole (231 mg, 1.57 mmol), (prepared as described for the starting material in Example 291), and DMA (5.0 ml) for 5 minutes. The mixture was then stirred at 90° C. for 3 hours under an atmosphere of nitrogen and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by column chromatography, gradient elution, with dichloromethane/methanolic ammonia (7M), (100/0 to 90/10) to give 6-methoxy-4-(1-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (247 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH3:73])[CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][NH:68]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:68]1[CH2:69][CH2:70][CH2:71][CH2:72][CH:67]1[CH2:66][N:65]([CH2:63][CH3:64])[CH3:73])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(C)CC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-ethyl-N-methyl-N-(piperidin-2-ylmethyl)-amine in DMSO at ambient temperature.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C.S(Cl)(Cl)=[O:25].C[N:29](C)[CH:30]=[O:31].Cl>C(Cl)Cl.CCOCC>[C:30]([NH:29][OH:25])(=[O:31])[CH2:20][CH2:19][CH2:18][C:17]#[C:16][CH2:15][C:14]#[C:13][CH2:12][C:11]#[C:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCC#CCC#CCC#CCC#CCCCC(=O)O
Reactant: CN(C)C=O
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCC#CCC#CCC#CCC#CCCCC(=O)NO
Reaction time: 3 h

Procedure:
Heneicosa-5,8,11,14-tetraynoic acid (130 mg) was dissolved in methylene chloride (3 ml) and a solution of thionyl chloride (104 mg) and dimethylformamide (5 mg) in methylene chloride (2.6 ml) was added. After 3 hours at 25° C., the solution was evaporated. To the residue was added a solution of hydroxylamine hydrochloride (58 mg) and sodium bicarbonate (70 mg) in water (0.4 ml) and methanol (0.4 ml) to which had been added normal aqueous potassium hydroxide sufficient to obtain a pH of 9. After 10 minutes ether (20 ml) and 1.0N hydrochloric acid (10 ml) were added. The organic solution was dried and evaporated, and the residue was chromatographed on silica gel, eluting with methylene chloride/methanol/ammonium hydroxide, (40/4/0.3;v/v/v) so as to afford the title compound as a solid, m.p.: 85°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(CCCCCCCl)NCCO
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1)NCCO
Yield: 92.2 %

Procedure:
1-[Bis(4-chlorophenyl)methyl]piperazine (642.5 mg, 2.00 mmol) and N-(2-hydroxyethyl)-6-chlorohexanesulfonamide (487.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-6-[4-[bis(4-chlorophenyl)methyl]-1-piperazinyl]hexanesulfonamide (975.0 mg) as a pale brown oil (92.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O.[CH:13]([NH2:15])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:15][CH:13]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cc(F)ccc12

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g) in formamide (30 ml) was heated to 150° C. for 6 hours. The reaction mixture was poured onto a 1:1 mixture of ice and water (250 ml) and the precipitated solid was collected, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g)
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:32]1([NH:36][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NC1CCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), cyclobutanamine (4.95 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.17 min) to provide (R/S)-N-cyclobutyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (7 mg, 0.011 mmol, 23.93% yield): LCMS=485.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.53-7.73 (7 H, m), 5.09 (1 H, s), 4.15-4.42 (1 H, m), 2.28 (2 H, dddd, J=10.07, 4.90, 4.62, 2.86 Hz), 1.98-2.13 (2 H, m), 1.70-1.79 (2 H, m); HPLC peak RT=10.4 min (Method A).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH2:11]([O:18][NH:19][CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[CH2:11]([O:18][N:19]([CH2:20][C:21]1([C:29]([OH:31])=[O:30])[CH2:26][C@H:25]([CH3:27])[CH2:24][C@H:23]([CH3:28])[CH2:22]1)[CH:1]=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CO
Reactant: C[C@@H]1C[C@H](C)CC(CNOCc2ccccc2)(C(=O)O)C1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: C[C@@H]1C[C@H](C)CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a cold solution of formic acid (15.5 mL, 0.40 mol) in dichloromethane (75 mL) at 0° C. under a nitrogen atmosphere was added acetic anhydride (5.9 mL, 62 mmol). After 1 h, a solution of (3S,5R)-1-(Benzyloxyamino-methyl)-3,5-dimethyl-cyclohexanecarboxylic acid (1.8 g, 6.2 mmol) in dichloromethane (75 mL) was added. The reaction was stirred at room temperature for 18 h and was concentrated in vacuo. Water (150 mL) was added and the mixture was extracted with dichloromethane (75 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a yellow solid (1.59 g, 80%). MH+320.
Reaction SMILES: FC(F)(F)C[O:4]C1C=CC(OCC(F)(F)F)=CC=1.C[C:20]([C:22]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:23]=1[O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:21].C(C1C=CC=CC=1)(=O)C>>[F:37][C:36]([F:39])([F:38])[CH2:35][O:34][C:23]1[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:27][C:22]=1[C:20]([OH:21])=[O:4]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
In another aspect of the invention, a method of preparing a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide is provided which comprises the following steps. The compound 1,4-dibromobenzene is contacted with an alkali metal 2,2,2-trifluoroethoxide in the presence of cuprous or cupric ion and in a strongly polar solvent comprising 2,2,2-trifluoroethanol to yield 1,4-bis(2,2,2-trifluoroethoxy)benzene. Then, in the presence of a Lewis acid catalyst, the 1,4-bis(2,2,2-trifluoroethoxy)benzene is treated with an acetylation agent under conditions to create 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The methyl moiety of the acetophenone function of said 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is thereafter replaced to yield 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid. The 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid is then treated with an inorganic chloride to provide 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride. Subsequently, the resultant 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid chloride is contacted with 2-aminomethylpyridine, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide. Finally, the 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide is treated with an agent capable of hydrogenation of the aromatic bond in the heterocyclic ring, whereby there is formed a 2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzamide.
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1.[CH3:16][C:17]([CH3:40])([CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:27]2[C:28]([CH3:30])=[CH:29][C:24]([O:23][CH2:22][C:17]([CH3:16])([CH3:40])[C:18]([O:20][CH3:21])=[O:19])=[N:25][CH:26]=2)=[CH:8][C:9]=1[F:15])#[N:12]
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(C#N)c(F)c2)cn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 104.8 %

Procedure:
N,N-dimethylformamide (30 mL) was added to 4-bromo-2-fluorobenzonitrile (2000 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxy}propanoate (4191 mg) and palladium chloride (dppf) methylene chloride complex (408 mg), and after adding 2N aqueous sodium carbonate solution (15 mL) to the mixture, the atmosphere was replaced with nitrogen and the resulting mixture was stirred at 60° C. for 7 hours. Ethyl acetate and water were added to the reaction mixture, and the liquids were separated. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating the mixture under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain methyl 3-{[5-(4-cyano-3-fluorophenyl)-4-methylpyridin-2-yl]oxy}-2,2-dimethylpropanoate (3587 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[N-:14]=[N+]=[N-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:13])[NH:14][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)NC(=O)CCC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Combined 7-Methoxy-1-tetralone (5.0 g, 0.028 mol;) with Polyphosphoric acid (80 g, 0.7 mol;) in 2-neck 500 ml Flask fit with overhead mechanical stirrer and septa under nitrogen flow. Sodium azide (2.2 g, 0.034 mol;) added portionwise over 5 min and the reaction was heated to 55° C. Continue stirring overnight. The mixture was poured into water and a white precipitate ensued. The mixture was filtered and washed with water then hexane and dried over 60 h. 8-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one obtained as a white solid (3.34 g, 62%). MP: 103-104° C.; 1H-NMR (CDCl3, 400 MHz) δ 7.45 (broad s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.72-6.69 (m, 1H), 6.54 (d, J=2.1 Hz, 1H), 3.81 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.3 Hz, 2H), 2.25-2.18 (m, 2H); LC/MS: 192.07 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)CCCN=C=NCC.[C:24](O)([CH3:27])([CH3:26])[CH3:25]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[C:24]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[CH3:11])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(I)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(I)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 5-iodo-2-methylbenzoic acid (760 mg, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (670 mg, 3.5 mmol), 4-dimethylaminopyridine (425 mg, 3.5 mmol), and t-butanol (1.07 g, 14.5 mmol) in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 5% NaHCO3, 1M HCl, water and, brine. The organic phase was dried and evaporated to give a pale yellow solid 600 mg 65%.