Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:13]([N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[C:13]([N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([OH:12])[C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc2c(O)cc(Cl)cn2n1
Reactant: CC(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2c(O)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a mixture 6-chloro-2-methylpyrazolo[1,5-a]pyridin-4-ol 6.59 (17 mg), 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19 mg), Cs2CO3 (76 mg) and PEPPSI-IPr (6 mg) was added DME and water (2:1, 3 mL) and the reaction mixture was heated to 80° C. for 2 h. The mixture was then extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 10 mg of 6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-ol. LCMS [M+H]+: 271.12.
Reaction SMILES: [Mg].[CH3:2]I.[F:4][C:5]([F:15])([F:14])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl>CCOCC.O>[OH:11][CH:10]([C:9]1[CH:12]=[CH:13][C:6]([C:5]([F:14])([F:15])[F:4])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CI
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
Magnesium (3.71 g/0.153 mol) was placed into a flask of the egg-plant type, followed by the replacement of air by nitrogen and addition of 30 ml of ether. While gently stirring the mixture, a solution of methyl iodide (24.4 g/0.172 mol) in ether (20 ml) was slowly added dropwise to the mixture, and the resulting mixture was refluxed with heating for 30 minutes. The mixture was cooled to room temperature, and a solution of 4-trifluoromethylbenzaldehyde (25.1 g/0.144 mole) in ether (20 ml) was slowly added dropwise to the mixture. The mixture was refluxed with heating for 2 hours, 30 ml of water was added dropwise to the mixture with ice cooling, and hydrochloric acid (2N) was further added until the aqueous layer became transparent. The aqueous layer was separated from an ethereal layer, the aqueous layer was subjected to extraction with ether, and the ethereal layers were combined, and the combined layer was washed with an aqueous solution of common salt three times. After removal of ether, the layer was distilled at a reduced pressure, giving 1-(1-hydroxylethyl)-4-trifluoromethylbenzene [compound (I)] represented by the formula CF3C6H4CH(OH) CH3, b.p. 53°~55° C. (50.5 Pa), colorless transparent liquid, yield 98.3%.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:32])([F:31])[C:8]1[CH:9]=[C:10]([S:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([NH:27][C:28]([NH2:30])=[O:29])=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:30][C:28](=[O:29])[NH:27][C:21]1[CH:20]=[CH:19][C:18]([O:17][S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:31])([F:6])[F:32])[CH:9]=2)(=[O:16])=[O:15])=[CH:23][C:22]=1[N+:24]([O-:26])=[O:25])(=[O:35])[CH3:34]
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
1 ml of concentrated sulfuric acid is added, with stirring, to 60 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidonitrobenzene in 200 ml of acetic anhydride. A clear solution is initially produced, and the temperature rises to about 40° C. The mixture is stirred for a further four hours, and the precipitate produced is filtered off with suction and washed with diisopropyl ether and petroleum ether, melting point 196° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1OC(=O)C)=[O:5])[CH3:2].[ClH:22]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH:9]=[CH:8][CH:7]1[Cl:22])=[O:5])[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)C1(c2ccccc2)CCC=CC1OC(C)=O
Solvent: CCO
Product: CCOC(=O)C1(c2ccccc2)CCC=CC1Cl

Procedure:
200 g of 1-phenyl-2-acetoxy-cyclohex-3-ene-1-carboxylic acid-ethyl-ester are dissolved in 1 liter of 96% ethanol. The solution is charged with 190 g of HCl gas and heated under reflux for 2 hrs. The solvent is removed and the residue directly fractionated in the vacuum. b.p.°,1 130° C. Yield: 169 g.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH2:35])=[CH:26]1>>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][NH:35][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([C:15]3[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=3)[CH:18]=2)=[CH:26]1
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Reactant: NCc1csc2ccccc12
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3csc4ccccc34)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-benzothien-3-ylmethylamine gave the title compound as an oil. M+(LC/MS(ESI)): 476.3. HPLC (Condition A), Rt: 4.79 min (HPLC purity: 86.7%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:8]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=2)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[S:3][C:4]([S:8]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=[C:14]([CH3:26])[CH:13]=3)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(Br)nc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 80 °C
Yield: 33.1 %

Procedure:
A solution of tert-butyl (6-{[(2-bromo-4-methyl-1,3-thiazol-5-yl)sulfonyl]amino}-4-methylpyridin-2-yl)carbamate (0.96 g, 2.08 mmol, 1 equiv), 4-cyanophenylboronic acid (0.336 g, 2.29 mmol, 1.1 equiv), and cesium carbonate (2.03 g, 6.24 mmol, 3 equiv) in 2:1 dimethoxyethane/water (30 mL) was purged with nitrogen for 15 minutes. Dichloro[1,1′-bis(diphenylphosphine)ferrocene] palladium (II) chloride (0.068 g, 0.08 mmol, 0.04 equiv) was then added, and the resulting mixture was purged with nitrogen for another 15 minutes. The reaction was heated to 80° C. for 1 h. After cooling to 24° C., the solution was concentrated in vacuo (˜25 mm Hg). The resulting aqueous mixture was extracted ethyl acetate (60 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→10% ethyl acetate in hexanes) provided the intermediate (0.334 g, 33%). 1H NMR (400 MHz, CDCl3), δ: 7.97 (d, J=8.3 Hz, 2H), 7.73 (d, J=8.3 Hz, 2H), 7.63 (br s, 1H), 7.43 (s, 1H), 6.90 (s, 1H), 2.65 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H); LRMS (ESI) m/z: 486.1.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[N:3]=[CH:2]1.[CH2:11]([O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[C:16](/[O:10][C:9]1[C:4]2[N:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)\[CH3:17])[CH3:12]
Reactant: Oc1cccc2ocnc12
Reactant: CC#CC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc2ocnc12
Temperature: 80 °C
Yield: 100.1 %

Procedure:
A stirred mixture of benzooxazol-4-ol (0.388 g, 2.87 mmol), ethyl-2-butynoate (1.93 g, 17.2 mmol) a catalytic amount of 4-dimethylaminopyridine and potassium carbonate (0.595 g, 4.30 mmol) in tetrahydrofuran (20 mL) was placed in a sealed tube and heated at 80° C. for 2 h. The reaction mixture was filtered and the filtrate was collected and concentrated in vacuo. The resulting residue was purified by ISCO column chromatography (Silicycle 40 g, 2% to 15% ethyl acetate/hexanes) which afforded (E)-3-(benzooxazol-4-yloxy)-but-2-enoic acid ethyl ester (710 mg, 100%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH:14]([C:18](=O)[CH3:19])[C:15](=[O:17])[CH3:16]>C(Cl)(Cl)Cl>[C:15]([C:14]1[N:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]2=[N:1][C:18]=1[CH3:19])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:12])(=[O:17])[CH3:16]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Nc1nccc2c(Cl)cccc12
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)nc2c3cccc(Cl)c3ccn12
Yield: 9 %

Procedure:
To a suspension of 1-amino-5-chloroisoquinoline (10 g) in chloroform (150 ml) was added dropwise 3-chloro-2,4-pentanedione (11.3 g). The mixture was refluxed for 6 hours and then allowed to stand at room temperature over night. The mixture was washed successively with aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g) with chloroform as an eluent to afford a solid. This solid was recrystallized from ethyl acetate to give 3-acetyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:24][NH2:25])=[C:4]([C:16]2C=C(Cl)C=CC=2Cl)[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1.C[C:27]1[CH:31]=[CH:30][S:29][C:28]=1C=C(C#N)C#N>>[NH2:1][C:2]1[C:3]([CH2:24][NH2:25])=[C:4]([C:16]2[S:29][CH:28]=[CH:27][C:31]=2[CH3:30])[C:5]2[C:10](=[O:11])[N:9]([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:15]=1
Reactant: Cn1c(=O)c2c(-c3cc(Cl)ccc3Cl)c(CN)c(N)nc2n(C)c1=O
Reactant: Cc1ccsc1C=C(C#N)C#N
Product: Cc1ccsc1-c1c(CN)c(N)nc2c1c(=O)n(C)c(=O)n2C
Yield: 17.1 %

Procedure:
The title compound was prepared using the procedures described in the preparation of Compound 8 (Example 7). The only difference was that after the synthesis of 2-(3-methyl-thiophen-2-ylmethylene)-malononitrile, the reaction was carried onto the next step without further work-up or purification, and propanol was used instead of ethanol. Furthermore, after the hydrogenation using BH3.THF, the reaction mixture was concentrated. An ample amount of MeOH was added until there was no more bubbling. The mixture was dried in vacuo, and purified by prep. HPLC. After washing the product with EtOAc, an amount of 82.4 mg (17.1% yield) of the title compound was collected. 1H NMR (400 MHz, d6-DMSO): δ ppm 7.80 (br s, 3H), 7.53 (d, J=4.0 Hz, 1H), 7.36 (br s, 2H), 6.96 (d, J=4.0 Hz, 1H), 3.80 (m, 2H), 3.51 (s, 3H), 3.10 (s, 3H). MS [m+H] calc'd for C15H17N5O2S, 332.0, 333.2. found 332.0, 333.2.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])O.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:7]=1[CH3:17])[CH2:3][C:2]([CH3:19])([CH3:18])[CH3:1]
Reactant: Cc1oc(-c2ccccc2)cc1C(O)CC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 3,3-dimethyl-1-(2-methyl-5-phenylfuran-3-yl)butan-1-ol (1.1 g) in toluene (15 mL) was added thionyl chloride (0.6 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 100%) as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([OH:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22]Cl)[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>CC(=O)CC>[CH2:18]([N:20]([CH2:25][CH3:26])[C:21](=[O:24])[CH2:22][O:17][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH3:19]
Reactant: Oc1nc(-c2ccccc2)cc2ccccc12
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCN(CC)C(=O)COc1nc(-c2ccccc2)cc2ccccc12

Procedure:
The procedure is as in Example 47, starting with 3-phenyl-1-isoquinolinol (5.1 g), N,N-diethylchloroacetamide (3.8 g), sodium carbonate (4.8 g) and cuprous iodide (1.15 g) in 2-butanone (100 cc). After 2 chromatographic separations on silica gel with chloroform as eluant and crystallization of the product in petroleum ether, N,N-diethyl-(3-phenyl-1-isoquinolyl)oxyacetamide (0.5 ), m.p. 102° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=1.[Cl:12][C:13]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:14]=1[CH:15]=[C:16]([C:20](=O)[CH3:21])[C:17]([NH2:19])=[O:18]>C(O)(C)C>[C:17]([C:16]1[CH:15]([C:14]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:13]=2[Cl:12])[N:3]2[CH:4]=[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[N:6]=[C:2]2[NH:1][C:20]=1[CH3:21])(=[O:18])[NH2:19]
Reactant: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Reactant: COC(=O)Cc1c[nH]c(N)n1
Solvent: CC(C)O
Product: COC(=O)Cc1cn2c(n1)NC(C)=C(C(N)=O)C2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of methyl 2-(2-amino-1H-imidazol-4-yl)acetate (986 mg, 6.4 mmol) and 2-(2,4-dichlorobenzylidene)-3-oxobutanamide (Example 158, Step 2, 1.64 g, 6.4 mmol) in isopropyl alcohol (40 mL) was placed as a slurry in a 100° C. oil bath. The mixture became a clear solution within 2 min and a precipitate formed during heating for 14.5 h. Upon cooling to room temperature, the tan solids were isolated by filtration with hexanes wash (2×15 mL) to provide methyl 2-(6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidin-2-yl)acetate (1.14 g, 45%) as a tan solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][S:4][CH:3]1[C:8]([O:10]C)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([NH2:18])=[NH:17]>C(O)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[N:17]=[C:8]([OH:10])[C:3]3[S:4][CH2:5][CH2:6][CH2:7][C:2]=3[N:18]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: COC(=O)C1SCCCC1=O
Solvent: CCO
Product: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Temperature: 25 °C

Procedure:
A 100-mL round bottomed flask was charged with methyl 3-oxotetrahydrothiopyran-2-carboxylate (1.5 g, 8.6 mmol, 1.47 eq.), 3-chlorobenzamidine (HCl salt, 1.1 g, 5.75 mmol, 1 eq.) and ethanol (20 ml). The resulting mixture was stirred under reflux for 48 hrs. After cooling to room temperature, the volatile material was removed under reduced pressure and the residue was treated with hydrochloric acid (2N, 10 ml) and water (20 ml). The precipitate was collected by filtration and washed with water (3×10 ml) followed by ether (3×10 ml). After drying, the title compound was obtained as white solid (1.15 g, 72% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(Cl)Cl>CN(C=O)C>[N:19]([C:12]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][C:16]=2[N:15]=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: Clc1ccnc2c1CCN(Cc1ccccc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 70 °C
Yield: 55.1 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.417 mmol) was treated with 5 equiv. of NaN3 (135 mg) in DMF (0.5 ml) and heated to 70° C. for 4 h. The residue was dissolved on 50 ml of DCM and washed with brine. The organic layer was concentrated to afford a black oil, which was purified by column chromatography to afford the desired azide (61 mg), which was used directly in the next step.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.FC1C=CC=C(I)C=1>>[F:33][C:29]1[CH:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(F)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Fc1cccc(I)c1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cccc(F)c2)o1
Yield: 98 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-Phenylheptyl)-5-(3-fluorophenyl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (75 mg, 0.113 mmol) and 1-fluoro-3-iodobenzene following General Procedure A. Flash chromatography (2% EtOAc/hexanes) yielded the title compound as a clear oil (53 mg, 98%): 1H NMR (CDCl3, 400 MHz) 7.43-7.33 (m, 3H), 7.29-7.25 (m, 3H), 7.18-7.15 (m, 3H), 7.04-7.00 (m, 1H), 4.83 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.6 Hz), 1.96-1.88 (m, 2H), 1.63-1.59 (m, 2H), 1.47-1.35 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 170.4, 167.3 (d, J=245 Hz), 155.1, 147.9, 135.6 (d, J=8.4 Hz), 135.2 (d, J=8.5 Hz), 133.5, 133.3, 130.7, 127.7, 124.9 (d, J=3.0 Hz), 120.2 (d, J=21.1), 116.2 (d, J=23.5), 73.8, 41.5, 41.0, 36.5, 34.3, 34.3, 30.8, 30.2, 23.3, 0.2, 0.0.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH2:25][OH:26])[CH:21]=2)[CH:17]=[CH:18][CH:19]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([C:20]2[O:24][N:23]=[C:22]([CH2:25][O:26][S:9]([CH3:8])(=[O:11])=[O:10])[CH:21]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: OCc1cc(-c2cccc(Cl)c2)on1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(-c2cccc(Cl)c2)on1
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Triethyl amine (965 mg, 9.5 mmol) and methanesulfonyl chloride (820 mg, 7.2 mmol) were added to a solution of [5-(3-chloro-phenyl)-isoxazol-3-yl]-methanol (1.0 g, 4.8 mmol) in dichloromethane (50 mL) at 0° C. After 1 hour, the reaction mixture was quenched with cold saturated sodium bicarbonate and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (1.4 g, 100%, light brown solid). 1H NMR (CDCl3) δ (ppm): 7.80 (s, 1H), 7.70 (m, 1H), 7.45 (m, 2H), 6.73 (s, 1H), 5.37 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [N:1]1([C:7](OCC)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]C.CC(=O)CC>O>[CH2:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCCCCCN1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
A mixture of 2.02 g of ethyl 1-piperazinecarboxylate, 1.92 g of anhydrous potassium carbonate, 3.08 g of decyl bromide and 20 ml of 2-butanone was stirred overnight at 80° C. After addition of water, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was extracted with 3N hydrochloric acid. The extract was made alkaline with potassium carbonate and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure Ethanol (20 ml) and ml of 10% aqueous sodium hydroxide were added to the residue, and the mixture was stirred overnight at 100° C. The reaction mixture was cooled and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.38 g of 1-decylpiperazine as an oil.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:40]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:48]3[CH2:47][CH2:46][CH:45]([N:41]4[CH2:42][CH2:43][CH2:44][CH:39]([OH:38])[CH2:40]4)[CH2:50][CH2:49]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OC1CCCN(C2CCNCC2)C1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC(O)C2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 3-hydroxy-[1,4′]bipiperidine (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H49N6O3Cl2 [(M+H)+] 707.3238, observed 707.3232.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:18]Br)=[CH:8][C@@H:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:20]([O:29]C(C)C)([O:25][CH:26]([CH3:28])[CH3:27])[O:21][CH:22]([CH3:24])[CH3:23]>>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:18][P:20]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:29])=[CH:8][C@@H:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](C=C(CBr)CCOC(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)[C@@H](C=C(CCOC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h
Yield: 32.3 %

Procedure:
21.2 g (63.1 mmol) of ethyl 6-acetoxy-4-bromomethyl-2(R)-formylamino-hex-3-enoate and 69.1 ml (252.2 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by flash chromatography on silica gel with ethyl acetate/ethanol (19:1), giving 8.6 g of ethyl 6-acetoxy-2(R)-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate a yellowish-orange oil. ee=92.5%; αD -90.2°±0.4° (c=2.84 CH2Cl2).
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]([CH3:14])([CH3:13])[C:10](=S)[NH:11][C:6]=2[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[Si]([N:22]=[N+:23]=[N-:24])(C)(C)C>C1COCC1.[Hg](OC(C)=O)OC(C)=O.CCOC(C)=O>[CH3:13][C:9]1([CH3:14])[O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]=2[N:11]2[N:22]=[N:23][N:24]=[C:10]12
Reactant: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2NC1=S
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)Oc2c(F)cc([N+](=O)[O-])cc2-n2nnnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of 8-fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-thione (1.0 g, 3.9 mmol) in THF, Hg(OAc)2 was added at 0° C. TMS-N3 was added to the reaction mixture at 0° C. and stirred for 1 hour. Reaction mixture was allowed to warm to room temperature and stirred for 3 hours. LCMS analysis of the reaction mixture indicated completion of the reaction. After 3 hours, the reaction mixture was diluted with 100 ml of EtOAc and partitioned with saturated aqueous NH4Cl (100 ml). Layers were separated and the aqueous layer was washed twice with EtOAc (50 ml). Combined EtOAc layers were dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to give the product in 57% yield (0.57 g). LCMS (m/z) 266 (MH+).