Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.[O:13]([CH2:20][CH2:21]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:21][CH2:20][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: COC(=O)c1nc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: ClCCl
Product: COC(=O)c1nc(Br)ccc1OCCOc1ccccc1
Reaction time: 48 h
Yield: 71.3 %

Procedure:
A mixture of methyl 6-bromo-3-hydroxypicolinate (26B) (308 mg, 1.33 mmol) and 2-phenoxyethanol (183 mg, 1.33 mmol) were stirred in dry DCM (10 mL). PPh3-polystyrene bound (665 mg, 2.0 mmol) was added, followed by the dropwise addition of DIAD (0.387 mL, 2.0 mmol). The mixture was stirred for 48 hours, then filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE/EtOAc 9:1-7:3 to provide 334 mg (72%) of the desired compound methyl 6-bromo-3-(2-phenoxyethoxy)picolinate (27A): 1H NMR (300 MHz, CDCl3) δ7.58-6.90 (7H, m), 4.43 (2H, m), 4.34 (2H, m), 3.91 (3H, s).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:5]([O:2][CH3:1])=[CH:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:7]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ncc(C(F)(F)F)cc2OC)ccc1Cl
Temperature: 0 °C

Procedure:
33.5 g of a 30% strength methanolic solution of sodium methoxide were added to a solution of 3.0 g (9.3 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine in 100 ml of methanol. The mixture was refluxed for 20 h and then poured into about 500 ml of ice-water. The product was extracted from the aqueous phase with 3×100 ml of methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The oily residue was induced to crystallize by trituration with n-hexane. Yield: 1.3 g of colorless crystals; melting point: 62°-63° C. (purity about 85%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[O:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: C[Mg]Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde (1.32 g, 5.16 mmol) and 50 mL tetrahydrofuran is stirred at 0° C. Methyl magnesium bromide (2.2 mL, 6.71 mmol, 3M) is added dropwise and the resulting mixture is allowed to stir at room temperature 30 min. The reaction is not complete, so an additional amound of methyl magnesium bromide (1 mL, 3 mmol) is added and the reaction stirred an additional 1 hr at room temperature. The mixture is cooled on an ice/water bath and aqueous ammonium chloride (10 mL) is added. The product is extracted with three 75 mL portions of ethyl acetate, the combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The crude product is purified by silica gel chromatography eluting with a mixture of 1:1 hexanes:ethyl acetate to afford 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol as an ivory solid, 1.12 g, 80%. MS (M++1) 272.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid (4.5 g) and 4-nitrophenol (2.75 g) in 35 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.4 g) and the mixture was stirred at room temperature for 4 hours. After the normal work up, crystallization of the crude ester from 2-propanol yielded 4.9 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester, mp 75°-76° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[CH:6]1)[CH3:2].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc(CO)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOCn1cnc(CO[Si](CC)(CC)CC)c1
Reaction time: 17 h

Procedure:
The compound (520 mg) obtained in (2) was dissolved in dichloromethane (30 mL), followed by addition of triethylsilyl chloride (1.12 mL), TEA (1.16 mL) and DMAP (catalytic amount) under stirring, and the stirring was continued for 17 hours. The reaction solution was diluted with water, and extracted with chloroform. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→80%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (665 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[CH2:25]([Mg]Cl)[CH2:26][CH3:27]>>[OH:21][C:18]1([CH2:25][CH2:26][CH3:27])[CH2:17][CH2:16][C:13]2([C:12](=[O:22])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=3)[CH2:15][CH2:14]2)[CH2:20][CH2:19]1
Reactant: CCC[Mg]Cl
Reactant: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Product: CCCC1(O)CCC2(CCN(c3ccc(OCC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2-aza-spiro[4.5]decane-1,8-dione (obtained in example 86, step 1) by reaction with propylmagnesium chloride (2M in diethyl ether). MS (m/e): 368.2 [(M-H2O)H+].
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].O>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH:2]2[C:8](=[O:9])[NH:7][C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:3]2)[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: O=C1Nc2ccccc2OCC1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2OCC1N1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 0.989 g of 3-chloro-2,3-dihydro-1,5-benzoxazepin-4(5H)-one and 1.0 g of potassium phthalimide in 5 ml of dimethylformamide is warmed to 90° overnight. The reaction mixture is poured into 20 ml of water and stirring is continued for 1 hr. Isolation by vacuum filtration and drying at 60° in vacuo affords 3-phthalimido-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; m.p. 188°-193°; NMR (DMSO, d6) δ 7.95 (s, 4), 6.61-7.40 (m, 5), 4.92 (d of d, 1), 4.01 (d, 2).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:42]=[CH:41][C:40](F)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:21][CH2:20]4)=[CH:9][CH:8]=1>CN1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]3[CH:18]=[C:19]4[C@:24]([C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[O:27])([CH2:25][C:16]=3[CH:15]=[N:14]2)[CH2:23][N:22]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH2:21][CH2:20]4)=[CH:11][CH:12]=1
Reactant: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(F)cc1)C2
Reactant: C1CCNC1
Agent: CN1CCCC1
Product: O=C(c1ccccn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCCC3)cc1)C2
Yield: 34.1 %

Procedure:
A solution of pyrrolidine (0.065 mL, 0.783 mmol) and (R)-(1-(4-fluorophenyl)-6-((4-fluorophenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (183 mg, 0.261 mmol) in N-methylpyrrolidine (2 mL) was stirred in a sealed vial at 100° C. for 22 hours. The cooled reaction mixture was then purified directly by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 5-95% acetonitrile in water) to afford (R)-(1-(4-fluorophenyl)-6-((4-(pyrrolidin-1-yl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as an off-white solid (52 mg). LCMS (Method F, ES-API): RT 2.78 min, m+H=584.3; 1H NMR (400 MHz, CDCl3): δ 8.63-8.62 (1H, m), 7.89 (1H, dt, J=8.0, 1.2 Hz), 7.81 (1H, td, J=7.5, 1.8 Hz), 7.51-7.47 (2H, m), 7.46-7.41 (3H, m), 7.28 (1H, s), 7.18-7.12 (2H, m), 6.48-6.45 (3H, m), 5.41 (1H, dd, J=12.2, 2.1 Hz), 4.31 (1H, d, J=16.9 Hz), 3.80-3.76 (1H, m), 3.33-3.30 (4H, m), 2.88 (1H, d, J=16.9 Hz), 2.85-2.76 (1H, m), 2.61 (1H, d, J=12.1 Hz), 2.45-2.35 (2H, m), 2.07-2.01 (4H, m).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[NH:14])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:16](=[CH:19]OC(C)C)[CH:17]=[O:18].C([O-])([O-])=O.[K+].[K+].C(Cl)(Cl)Cl>O>[CH:1]1([N:4]2[C:16]([CH:17]=[O:18])=[CH:19][N:14]=[C:5]2[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)OC=C(Br)C=O
Reactant: COc1ccc(C(=N)NC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2ncc(C=O)n2C2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
N-cyclopropyl-4-methoxy-benzamidine (0.90 g, 4.75 mmol), 2-bromo-3-isopropoxy-propenal (1.37 g, 7.12 mmol) and K2CO3 (0.98 g, 7.12 mmol) were mixed with chloroform (10 ml) and water (1.2 ml), followed by stirring at r.t. for 24 h. After drying of the reaction mixture (Na2SO4), filtration and concentration of the filterate in-vacuo, the crude residue was purified via flash chromatography (40% EA in hex.) to isolate the title compound (973 mg, 85%). 1H-NMR: 9.83 (s, 1H), 7.82 (m, 3H), 7.02 (d, 2H), 3.89 (s, 3H), 3.58 (m, 1H), 1.13 (m, 2H), 0.64 (m, 2H).
Reaction SMILES: [CH2:1]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[C:15]1([S:21]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)(Cl)Cl.[Fe]>[CH2:1]([C:10]1[S:11][C:12]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: ClSc1ccccc1
Reactant: COc1ccc(Cc2cccs2)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Cc2ccc(Sc3ccccc3)s2)cc1
Reaction time: 192 h
Yield: 27.5 %

Procedure:
A solution of 34 g (0.179 mole) of 2-p-anisylthiophene in 500 ml of carbon tetrachloride was treated with 23 ml (28.5 g, 0.197 mole) of benzenesulfenyl chloride and 0.1 g of iron powder. The mixture was allowed to stand at room temperature for eight days. The mixture was filtered to remove a small amount of solid. The filtrate was evaporated to give 67 g of crude solid product. Recrystallization from 220 ml of ethyl acetate gave 15.4 g (29%) of 2-p-anisyl-5-(phenylthio)thiophene, m.p. 92°-93° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.[NH2:15][OH:16]>CO.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10](=[N:15][OH:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1
Reactant: NO
Reactant: CC1(C)CC(=O)c2ccccc2O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC1(C)CC(=NO)c2ccccc2O1
Temperature: 82.5 °C
Reaction time: 2 h

Procedure:
A reaction mixture prepared from 10 mmol of 2,2-dimethyl-4-chromanone, 12 mmol of hydroxylamine hydrochloride in 5 ml of methanol and 5 ml of pyridine is heated with stirring over the course of 2 hours to 80-85° C., the solvent is distilled off on a rotary evaporator and the oily residue is crystallized under water.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[CH3:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:36]
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Reactant: COc1ccccc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccc1OC

Procedure:
1-(2-Methoxybenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-methoxybenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CC(OC)(C)C>[Si:47]([O:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (190 mg, 0.40 mmol) in dry DMF (5 mL) was added K2CO3 (160 mg, 1.16 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (92 mg, 0.38 mmol) at 0° C. The mixture was allowed to warm to room temperature and heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C., diluted with MTBE and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient 10 to 30% ethylacetate/hexane) to provide the title compound (144 mg, 54%). 1H NMR (CD3OD) 8.66 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.38-7.29 (m, 5H), 5.20 (s, 2H), 3.99 (s, 3H), 3.83-3.82 (m, 2H), 3.77 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.49 (br s, 2H), 1.70-1.55 (m, 4H), 1.45-1.26 (m, 4H), 1.05-0.85 (m, 6H), 0.83 (s, 9H), 0.03 (s, 6H); MS(ESI+) m/z 650.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O.ClCCl>[CH2:24]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[N:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][CH:7]=2)[N:3]=[CH:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(-c2ncc(-c3c[nH]cn3)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc(Cn2cnc(-c3cnc(-c4ccccc4)nc3)c2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 36.5 %

Procedure:
To a solution consisting of 5-(1H-imidazol-4-yl)-2-phenylpyrimidine (Step B, 0.050 g, 0.193 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.133 g, 0.965 mmol) at room temperature under dry conditions. After heating the reaction mixture in an 80° C. oil bath for one hour, benzyl bromide (Aldrich, 0.039 g, 0.231 mmol) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was diluted with dichloromethane (100 mL) and washed with saturated aqueous ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica. Elution through an 8-g Silicycle® flash silica cartridge with gradient of 100% dichloromethane to 5% methanol in dichloromethane afforded the title compound as a white solid (22 mg, 36%). Rf 0.56 with 95:5 v/v dichloromethane-methanol; melting point 195° C; 1H-NMR (400 MHz; DMSO-d6) δ 9.25 (s, 2H), 8.44-8.42 (m, 2H), 8.03 (s, 2H), 7.56-7.54 (m, 3H), 7.45-7.36 (m, 5H), 5.38 (s, 2H); MS (ESI+) m/z 313.1 (M+1); H-PGDS FPBA IC50: 4 μM.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:21])[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18].Cl.Cl[C:24](OC(Cl)(Cl)Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:21]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]([F:19])([F:18])[F:20])=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=1)=[C:24]=[O:25]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Yield: 70.4 %

Procedure:
A solution of 3-benzoxazol-2-yl-4-trifluoromethoxyphenylamine (210 mg, 0.71 mmol) in 5 mL of dry toluene was stirred while 1.15 mL of 3.1N hydrochloric acid in ethyl acetate was added. The precipitate was concentrated by evaporation. Another 5 mL of toluene was added followed by evaporation. This procedure was repeated 3 times to remove excess of hydrochloric acid. The amine hydrochloride was dissolved in 5 mL of toluene and trichloromethyl chloroformate (0.853 mL, 7.1 mmol) was added. The mixture was refluxed overnight under a nitrogen atmosphere, evaporated at 70° C. followed by stripping with dry toluene. 2-(5-Isocyanato-2-trifluoromethoxyphenyl)benzoxazole (160 mg, 70%) was obtained as crystals and used immediately to synthesize the title compound.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15].I[CH3:18]>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:18])[C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: CI
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
Sodium hydride (4.22 g, 60%, 106 mmol) was added portionwise to a solution of N-(4-fluoro-3-nitrophenyl)acetamide (13.9 g, 70 mmol) in THF (200 mL) at 0° C. Stirring for 20 min, iodomethane (18.5 g, 130 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated NaHCO3 (30 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with saturated NaCl (2×50 mL). After filtration and concentration, 13.1 g (88%) of the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.92 (s, 3 H), 3.30 (s, 3 H), 7.38 (s, 1 H), 7.52 (s, 1 H), 7.95 (s, 1 H).
Reaction SMILES: [NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([O:46]C)=O)[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].O.[NH2:59][NH2:60]>CO>[NH:1]([C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])[C@H:2]([C:7]([NH:9][C@H:10]([C:23]([NH:25][C@H:26]([C:34]([NH:36][C@H:37]([C:44]([NH:59][NH2:60])=[O:46])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1)=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
3.97 g of Z-Asn-Lys(BOC)-Phe-His-OMe are dissolved in 20 ml of boiling methanol. 2.5 ml of hydrazine hydrate are added to the solution whilst it is still at about 30° C. and the mixture is allowed to stand for 20 hours at room temperature. The peptide-hydrazide is precipitated by adding water, filtered off and washed with water until free of hydrazine. The product is reprecipitated from dimethylformamide-water.
Reaction SMILES: [OH:1][C:2]([CH3:11])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O>[CH3:11][C:2]([O:1][Si:23]([CH3:26])([CH3:25])[CH3:24])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)C(=C)CCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C#CCC(C)(O[Si](C)(C)C)C(=C)CCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 25.77 g. of 4-hydroxy-4-methyl-5-methylene-1-octyne and 28.6 g. of imidazole in 50 ml. of dimethylformamide is added 22.9 g. of chlorotrimethylsilane. The mixture is stirred at room temperature for 40 minutes, poured into cold water and extracted with petroleum ether. The extract is washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent is removed. The residue is distilled and the desired product recovered at 85°-87° C. (0.45 mm.) as a colorless liquid.