Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[N:11]=[C:12]4[N:16]([CH:17]=3)[N:15]=[C:14]([O:18][CH3:19])[S:13]4)=[CH:7][C:6]2=[C:20]([OH:22])[CH:21]=1.[C:23]1([C:29]2[S:33][N:32]=[C:31]([CH2:34]O)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[CH3:19][O:18][C:14]1[S:13][C:12]2=[N:11][C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[C:20]([O:22][CH2:34][C:31]5[N:30]=[C:29]([C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=6)[S:33][N:32]=5)[C:6]=4[CH:7]=3)=[CH:17][N:16]2[N:15]=1
Reactant: OCc1nsc(-c2ccccc2)n1
Reactant: COc1cc(O)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(OCc2nsc(-c3ccccc3)n2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 1H, 8.25 mg, 0.026 mmol) and (5-phenyl-1,2,4-thiadiazol-3-yl)methanol (Example 7B, 5 mg, 0.025 mmol) were put in a flask and this was flushed with N2. Dry THF (4 mL) was added and to this resulting suspension was added tri-n-butylphosphine (0.017 mL, 0.065 mmol) and a solution of 1,1′-(azodicarbonyl)dipiperidine (16.57 mg, 0.065 mmol) in dry THF (2.5 mL) was added dropwise via a syringe pump over 2 h. The resulting being suspension was stirred for an additional 2 hours at RT, at which time LC showed that no starting material remained. The mixture was diluted with EtOAc, washed with 0.2N HCl, sat. aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (50% dichloromethane/hexanes to 100% dichloromethane to 1% EtOAc/CH2Cl2 to 7% EtOAc/CH2Cl2) and lyophilized in MeCN/water to give the title material (6.2 mgs, 49%). LC (Method B): 2.615 min. HRMS (ESI) calcd for C23H18N5O4S2 [M+H]+ m/z 492.0795. found 492.0828. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.00 (dd, J=8.02, 1.37 Hz, 2H), 7.85 (s, 1H), 7.50-7.56 (m, 3H), 7.14 (s, 1H), 6.71-6.75 (m, 1H), 6.51 (d, J=1.57 Hz, 1H), 5.51 (s, 2H), 4.21 (s, 3H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[S:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[OH:9]O>C(O)=O.C(OC(=O)C)(=O)C>[CH3:1][CH:2]1[S:7](=[O:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:8]
Reactant: OO
Reactant: CC1SCCNC1=O
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC1C(=O)NCCS1=O
Temperature: 0 °C

Procedure:
To a solution of 9 g of 2-methyl-3-thiamorpholinone in a mixture of 50 cm3 of formic acid and 10 cm3 of acetic anhydride, cooled to 0° C., 7 cm3 of H2O2 at 110 vol. are slowly added. After an 18 hour reaction period, the solution is concentrated under reduced pressure. The resulting product is dissolved in chloroform and the chloroform solution is deposited on a silica gel column.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(O)=O>C1COCC1>[C:26]1([CH2:25][C@H:16]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
A solution of dimethyl methylphosphonate (3.10 mL, 28.60 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.70 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 6 (1.00 g, 3.58 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded the compound dimethyl [(3S)-4-phenyl-3-[(tert-butyloxycarbonyl)amino]-2-oxobutyl]-phosphonate 7 as a clear oil (0.797 g, 59%), which crystallizes in hexane as a white solid; mp 78-81° C. (lit.1 mp 76-78° C.); Rf 0.38 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 1.38 (9H, s, (CH3)3), 2.84-3.32 (4H, m), 3.74 and 3.78 (6H, 2xs, 2xOMe), 4.55 (1H, q, J=8.4 Hz, —CH—), 5.28 (1H, d, J=8.4 Hz, —NH—), and 7.16-7.32 (5H, m, Ar—H).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH2:22][NH:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[O:12]=[C:13]1[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:21]=2[CH2:22][N:23]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1
Reactant: CCOC(=O)N1CCC(NCc2ccncc2NC(=O)OC(C)(C)C)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2Cc3ccncc3NC2=O)CC1
Reaction time: 8 h
Yield: 39.7 %

Procedure:
Trifluoroacetic acid (1.43 g) was added to a solution of the material from Step A (0.47 g, 1.24 mmol) in dichloromethane (10 mL). After stirring overnight, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.62 g, 3.73 mmol) was added at room temperature. After 2 d, the acetonitrile was evaporated in vacuo, the residue partitioned between 1N NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1 to 20% methanol in methylene chloride gradient elution), which gave the title compound (0.15 g). MS 305.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22].C[Si]([N:35]=[C:36]=[O:37])(C)C>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][C:36]([NH2:35])=[O:37])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[CH3:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: C[C@@H](Nc1cc(N2CCC(N3CCC(N)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@H](Nc1cc(N2CCC(N3CCC(NC(N)=O)C3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a stirred solution of 1-(1-(4-chloro-3-((R)-1-(2,4-dichlorophenyl)ethylamino)phenyl)piperidin-4-yl)pyrrolidin-3-amine (0.056 g, 0.12 mmol) in THF (1 mL) and acetic acid (1 drop) was added a solution of (trimethylsily)isocyanate (0.015 g, 0.13 mmol) in THF (0.5 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with diluted with aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude was purified by flash chromatography (SiO2, 2-10% methanol in dichloromethane) to afford the desired product as a white solid (0.016 g, 0.031 mmol, 26%). 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.16 (dd, J=2.2, 8.4 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.82 (br, 1H), 6.16 (dd, J=2.5, 8.8 Hz, 1H), 5.77 (br, 1H), 5.23 (br, 1H), 4.87 (q, J=6.6 Hz, 1H), 4.64 (d, J=5.2 Hz, 1H), 3.44-3.37 (m, 2H), 3.08-2.82 (m, 3H), 2.69-2.40 (m, 4H), 2.25-1.85 (m, 6H), 1.60-1.42 (m, 5H); MS: (ES) m/z calculated for C24H31Cl3N5O [M+H]+ 510.2. found 510.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])=[CH:20][CH:19]=1>C(O)C>[OH:13][C:11]1([CH2:12][N:25]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][OH:28])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=2)[CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: COc1ccc(CNC(CO)c2ccccc2)cc1
Solvent: CCO
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Yield: 82 %

Procedure:
A solution of tert-butyl-1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 3.42 mmol) and 2-[(4-methoxyphenyl)methylamino]-2-phenyl-ethanol (800 mg, 3.109 mmol) in ethanol (5 mL) was stirred at 60° C. for 72 hours. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography using 0 to 10% MeOH in DCM as eluent to yield tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.2 g, 82%). ESI-MS m/z calc. 470.6. found 471.5 (M+1)+; Retention time: 1.45 minutes (3 min run).
Reaction SMILES: [C:1]([O-:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[C@@H:48]1([N:86]2[C:95]3[N:94]=[CH:93][N:92]=[C:90]([NH2:91])[C:89]=3[N:88]=[CH:87]2)[O:85][C@H:57]([CH2:58][O:59][P:60]([O:63][P:64]([O:67][CH2:68][C:69]([C@H:72]([C:74]([NH:76][CH2:77][CH2:78][C:79]([NH:81][CH2:82][CH2:83][SH:84])=[O:80])=[O:75])[OH:73])([CH3:71])[CH3:70])([OH:66])=[O:65])([OH:62])=[O:61])[C@@H:51]([O:52][P:53]([OH:56])([OH:55])=[O:54])[C@H:49]1[OH:50]>>[C:1]([S:84][CH2:83][CH2:82][NH:81][C:79](=[O:80])[CH2:78][CH2:77][NH:76][C:74](=[O:75])[C@H:72]([OH:73])[C:69]([CH3:70])([CH3:71])[CH2:68][O:67][P:64]([OH:66])(=[O:65])[O:63][P:60]([OH:62])(=[O:61])[O:59][CH2:58][C@H:57]1[O:85][C@@H:48]([N:86]2[C:95]3[N:94]=[CH:93][N:92]=[C:90]([NH2:91])[C:89]=3[N:88]=[CH:87]2)[C@H:49]([OH:50])[C@@H:51]1[O:52][P:53]([OH:56])([OH:55])=[O:54])(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)[O-]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCS
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Product: CCCCCCCCCCCCCC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O

Procedure:
The compounds are then tested on the supernatant in competition with the peptide substrate Gly-Asn-(Ala)4 -(Arg)2 ("G8R") according to the conditions which follow, as described by TOWLER et al. (PNAS, (1987), 84, 2708-2711). Myristoylcoenzyme A is synthesized enzymatically immediately before use by incubation of myristate with ATP, Coenzyme A (lithium salt) and Pseudomonas Acyl-Coa synthetase (20 min at 30° C.). The peptide substrate and the biological source as obtained above are then added. The mixture is incubated for 10 min at 37° C.; the reaction is then stopped with 110 μl of methanol and 10 μl of trichloroacetic acid. The medium is left at 4° C. for 10 min and then centrifuged at 10,000 g for 5 min. An aliquot (30 μl) of the final supernatant is injected into an HPLC system equipped with a μBondapak column (Waters) and developed with a linear gradient as described by Towler et al. (PNAS, (1987), 84, 2708-11). Detection of the acylated peptide is performed using a radioactive line detector (Berthold) by means of the addition of 5 ml/min of scintillation fluid (Zinsser). The acylated peptide is eluted at 85% acetonitrile-TFA/15% H20-TFA.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]1=O.Cl>C1COCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CC1Cc2c(cccc2-c2cnc3ccccc3c2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2cccc(-c3cnc4ccccc4c3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
11.3 g (0.3 mol) of NaBH4 were added in portions at 0° C. to a solution of 64 g (0.23 mol) of 2-methyl-4-(3-quinolyl)-1-indanone in 600 cm3 of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 1000 g of ice, admixed with concentrated aqueous HCl to a pH of 1 and extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The solvent was removed under reduced pressure and the crude product was taken up in 1000 cm3 of toluene, admixed with 2 g of p-toluenesulfonic acid and heated under reflux for 2 hours using a water separator. The reaction mixture was washed 3 times with 150 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. Chromatography on silica gel (hexane/ethyl acetate 20:1) gave 45 g (76%) of 2-methyl-7-(3-quinolyl)indene as a colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(Cl)Cl>[I:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1c2ccccc2oc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1c2ccccc2oc2ccc(I)cc12
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A solution of xanthen-9-one (1.96 g, 10.0 mmol; Aldrich) in trifluoroacetic acid-CH2Cl2 (1:1, 40 mL) was chilled to 0° C. and treated with N-iodosuccinimide (NIS; 2.25 g, 10.0 mmol; Lancaster), added portionwise over 1 h. After an additional 1 h at 0° C., the ice bath was removed and stirring continued for 8 h. Residual oxidant was quenched with aq. NaS2O3 and the mixture was extracted with CH2Cl2. The organic phase was washed with NaHCO3, dried over MgSO4, and the residue purified by flash chromatography (120 g silica gel, 10-100% CH2Cl2-hexanes) to afford the title compound (1.75 g, 5.43 mmol; 54% yield): 1H NMR (300 MHz, CDCl3) δ ppm 8.66 (d, J=2 Hz, 1H), 8.34 (dd, J=8, 2 Hz, 1H), 7.98 (dd, J=9, 2 Hz, 1H), 7.75 (ddd, J=9, 7, 2 Hz, 1H), 7.50 (dd, J=8, 1 Hz, 1H), 7.40 (ddd, J=8, 7, 1 Hz, 1H), 7.28 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 323 (M+H)+, 340 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[I:11]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(C)s1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(I)c(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-methylthiophene-2-carboxylate (287 mg, 1.837 mmol) in MeOH (7 mL), was added silver sulfate (687 mg, 2.205 mmol) and I2 (513 mg, 2.021 mmol). The mixture was stirred at room temperature under N2 overnight. The reaction was quenched with sat. Na2SO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 10% EtOAc in hexanes over 1140 mL) to afford in order of elution methyl 4-iodo-5-methylthiophene-2-carboxylate. LCMS calc.=207.1. found=206.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 767 (s, 1H); 3.87 (s, 3H); 2.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=1>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[C:25]([F:33])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:41]=[CH:42][C:36]([F:35])=[CH:37][C:38]=2[C:43]([F:46])([F:44])[F:45])[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: COC(=O)C(CC(C)C)c1cc(Nc2ccc(F)cc2C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-(5′-fluoro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)) and 4-fluoro-2-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:14])[N:21]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 3.96 g (20 mmol) of 2-difluoromethyl-4-methoxy-1H-benzimidazole, 4.70 g (20 mmol) of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine, and 22 g (80 mmol) of powdered K2CO3 in 150 mL of DMF was stirred rapidly for 3 hrs, and then diluted with water. The resulting precipitate was collected, washed with water and then with cold ethanol, and dried to give 6.82 g (86%) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole: mp (CHCl3/EtOH) 263-266° C.; 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.4 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.82 (m, 4H); Anal. Calcd. for C16H15ClF2N6O2: C, 48.4; H, 3.8; N, 21.2. Found: C, 48.3; H, 3.8; N, 21.1%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]2[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:13]=3[N:12]=2)=[C:8]([OH:10])[CH:9]=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:11]2[N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:13]=3[N:12]=2)=[C:8]([O:10][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH:9]=1
Reactant: Clc1ccccc1CBr
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCc3ccccc3Cl)n(CC3CCCCC3)c2cc1F
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a suspension of sodium hydride (16 mg, 0.4 mmol, 60%) in dry N,N-dimethylformamide (10 ml) at 25° C. was slowly added a solution of 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (0.10 g, 0.275 mmol) in dry N,N-dimethylformamide (5 ml), and was allowed to stir for 0.5 h. A solution of 1-bromomethyl-2-chloro-benzene (82 mg, 0.4 mmol; CAS Reg. No. 611-17-6) in N,N-dimethylformamide (5 ml) was then added drop wise to the above solution, and further stirred for 16 h at 25° C. The reaction mixture was quenched with saturated aqueous solution of ammonium chloride. The solvents were removed under reduced pressure. The crude material dissolved in ethyl acetate, washed with water, and then with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel (10-20% ethyl acetate/n-hexane) to afford the title compound as a colorless powder (38%). MS (Turbo Spray): m/z=501.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[OH:12])[O:8][CH2:7][CH2:6][C:5]2=[O:14].N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[O:12][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[O:8][CH2:7][CH2:6][C:5]2=[O:14]
Reactant: Cc1cc2c(c(C)c1O)OCCC2=O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c(C)c1O[Si](C(C)C)(C(C)C)C(C)C)OCCC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6,8-dimethyl-7-hydroxychroman-4-one (the compound of Preparation 26, 0.50 g, 2.60 mmol), imidazole (0.35 g, 5.14 mmol), and triisopropylsilyl chloride (0.61 mL, 2.85 mmol) in dimethylformamide (10 mL) was stirred at ambient temperature overnight. The reaction was diluted with water and extracted with ether (2×). The combined organic phase was washed with 1N lithium chloride (2×) and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (1×4 inches packed in hexane) with elution proceeding as follows: 5% ethyl acetate/hexane (100 mL), nil; 5% ethyl acetate/hexane (100 mL) and 10% ethyl acetate/hexane (150 mL), 0.529 g (58%) of 6,8-dimethyl-7-triisopropylsilyloxychroman-4-one as a waxy lemon yellow solid which had: NMR δ 7.57 (s, 1 H), 4.52 (t, J=6.4 Hz, 2 H), 2.74 (t, J=6.4 Hz, 2 H), 2.21 (s, 3 H), 2.11 (s, 3 H), 1.40-1.26 (m, 3 H), 1.13 (d, J=7.2 Hz, 18 H); 13C NMR δ 191.60, 160.25, 159.93, 125.91, 122.55, 116.15, 115.29, 67.24, 37.52, 17.91, 17.69, 17.38, 14.24, 12.28, 9.97. A small silyl impurity was noted in the proton NMR at 1.06 ppm however, the material was found to be suitable for further transformations without additional purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(C)C=CC=CC=1>O>[Cl:3][CH2:22][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][CH:24]=1)[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Thionyl chloride (4.45 ml) was added dropwise to a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.0 g) and toluene (200 ml) at 0° C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (13.4 g, yield 84%) as pale-yellow crystals. m.p. 79-80° C.