Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][NH:23][C:24](=O)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:26]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]3)[CH:9]=2)=[CH:6][C:5]([CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:26]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNCc4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A solution of N-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]-3-(4-piperidinylmethyl)benzamide (100 mg, 0.194 mmol) in THF (2.0 mL) was added to lithium aluminum hydride (1.0 N in THF, 2 mL, 2 mmol). The mixture was heated in a microwave reactor at 80° C. for 60 minutes. After cooling to room temperature, the reaction mixture was carefully quenched with saturated Na2SO4, filtered through celite, dried over K2CO3 and concentrated under vacuum to give a crude oil. Further purification by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), gave the title compound (80 mg, 82%) as an oil. LC/MS: m/z, 502 (M+H), 1.29 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@:11]1([NH:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[C@@H:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:14]=[C:13]([CH2:27][OH:28])[C:12]1=[O:29])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[OH:37].C(Cl)Cl.OO.[OH-].[Na+]>CCOCC>[Si:1]([O:8][C@H:9]([C@@:11]1([NH:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[C:12](=[O:29])[C@@:13]2([CH2:27][OH:28])[C@H:14]([O:37]2)[C@@H:15]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:10])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CO
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)C(CO)=C[C@@H]1NC(=O)OCc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@]1(NC(=O)N(C)C)C(=O)[C@]2(CO)O[C@@H]2[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 200-mL round-bottomed flask was charged with enone 10 (1.1 g, 2.2 mmol, 1.0 equiv) and MeOH:CH2Cl2 (7:1, 32 mL). The resulting solution was cooled to 0° C., and a cooled solution of H2O2 (30% aq., 20 mL) and NaOH (20% aq., 5 mL) was added dropwise. The reaction was stirred at 0° C. for 2 h, and diluted with Et2O (30 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×15 mL). The combined organics were washed with H2O (3×30 mL), brine (20 mL), dried with magnesium sulfate, and concentrated in vacuo. The crude product was purified via flash chromatography (70:30 petroleum ether:acetone) affording the title compound as a clear, viscous oil with >20:1 diastereoselection (0.91 g, 81%). Analytical data: [α]D19 −22.4 (c=1.00, CHCl3); 1H NMR (600 MHz, CDCl3): δ 7.32-7.26 (m, 5H), 5.66 (d, J=9.6 Hz, 1H), 5.20 (d, J=12.0 Hz, 1H), 4.93 (d, J=12.6 Hz, 1H), 4.68 (s, 1H), 4.68-4.66 (m, 1H), 4.07-4.04 (m, 2H), 4.02-3.98 (m, 2H), 2.64 (s, 6H), 1.15 (d, J=6.6 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 204.4, 156.9, 156.0, 136.6, 128.3, 128.1, 128.0, 74.0, 69.3, 66.4, 65.9, 60.7, 56.0, 52.3, 36.1, 25.5, 18.2, 17.7, −3.9, −4.8; LRMS (ESI+) Calcd. for C25H39N3O7Si+, 522.26. Found, 522.23. IR (thin film, cm−1) 3402, 2954, 2857, 2359, 2249, 2125, 1650, 1519, 1227, 830, 732; TLC (70:30 petroleum ether/acetone): Rf=0.30.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[Br:35].O.[OH-].[Na+].Cl>CO>[Br:35][C:7]1[CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][C:23]=3[CH2:31][CH2:32][CH2:33][CH3:34])=[O:21])=[CH:16][CH:17]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:36])=[O:2]
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc(-c2ccc(OCC(=O)OC)c(Br)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc(-c2ccc(OCC(=O)O)c(Br)c2)cc1
Yield: 88.3 %

Procedure:
Methyl{[3-bromo-4′-({[(2-butyl-1-benzofuran-3-yl)carbonyl]amino}methyl)[1,1′-biphenyl]-4-yl]oxy}acetate (314 mg, 0.57 mmol), prepared in the previous step, in 100 mL of methanol and 10 mL of water was warmed to dissolve the solid. While still warm 1 N NaOH (684 μL, 0.68 mmol) was added and the mixture stirred, with no additional heat, until the reaction was complete by TLC. The reaction was acidified by the addition of 715 μL of 1 N HCl and then concentrated under reduced pressure to remove the methanol. The solid that formed was collected by filtration and dried under reduced pressure to give the title compound as a light tan solid (270 mg, 87%), mp 175-190° C. Elemental Analysis for C28H26BrNO5.0.40 H2O. Calc'd: C, 61.87; H, 4.97; N, 2.58. Found: C, 61.35; H, 4.54; N, 2.51.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]([O-:15])=[O:14])[N:7]=1.[K+]>CO>[NH2:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](=[N:4][O:3][CH3:2])[C:13]([OH:15])=[O:14])[N:7]=1
Reactant: CON
Reactant: Nc1ccnc(C(=O)C(=O)[O-])n1
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C(=O)O)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of O-methylhydroxylamine hydrochloride (0.25 g.) in methanol (6 ml.) was added a mixture of potassium 2-(4-aminopyrimidin-2-yl)glyoxylate and its monohydrate with stirring at ambient temperature, and the mixture was stirred for 4 hours. The reaction mixture was allowed to stand overnight at ambient temperature, filtered, and the filtered precipitates were washed with ethanol. After the filtrate and washings were combined together, the solvents were distilled off. The resultant oily substance was pulverized in acetone (15 ml.) and collected by filtration. This obtained powder was washed successively with acetone and diethyl ether and then dried to give a pale brown powder of 2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (290 mg.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6](B(O)O)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:42])[C:29]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([C:36]2[CH2:40][CH2:39][CH2:38][C:37]=2Br)[CH:30]=1)[CH3:26].O>C1(C)C(CCO)=CC=CC=1>[CH2:25]([O:27][C:28](=[O:42])[C:29]1[CH:30]=[C:31]([C:36]2[CH2:40][CH:39]=[CH:38][C:37]=2[C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:32]=[CH:33][C:34]=1[CH3:35])[CH3:26]
Reactant: CCOC(=O)c1cc(C2=C(Br)CCC2)ccc1C
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cc(C2=C(c3cc(Cl)ccc3OCc3ccccc3)C=CC2)ccc1C
Yield: 61 %

Procedure:
(5-chloro-2-benzyloxyphenyl)boronic acid (150 mg, 0.5 mmol), Pd(0)[PPh3]4 (25 mg, 0.021 mmol), potassium carbonate (483 mg, 3.36 mmol) and (3-(2-bromo-cyclopent-1-enyl)-6-methylbenzoic acid ethyl ester (130 mg, 0.42 mmol) in toluene-ethanol (1:1 10 mL) were stirred at 90° C., under nitrogen, for 2 hrs. Upon cooling, the reaction mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (MgSO4), filters and concentrated. The residue was purified on a Biotage® using 5% of ethyl acetate in iso-hexane to give the required product as white solid (114 mg, 61%). 1HNMR (CDCl3):1.27(3H,t, J=12 Hz), 2.01–2.08(2H, m), 2.51(3H, s), 2.83(2H, t, J=6 Hz), 2.90(2H, t, J=6 Hz), 4.94(2H, s), 6.80(1H, d, J=Hz), 6.97–7.70 (9H, m), 7.70(1H, s). LC/MS; Rt=4.22 [M+H] 447 (1 Cl)
Reaction SMILES: Br[C@@:2]1([O:40][C@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[C@H:14]([O:15][CH:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:4]1[O:5][C:6](=[O:8])[CH3:7])O.CC1C=C(C)C=C(C)N=1.[Br:55][CH2:56][CH2:57][OH:58]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:6]([O:5][C@@H:4]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:14]([O:15][C@H:16]2[O:33][C@H:32]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[C@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]2[O:18][C:19](=[O:21])[CH3:20])[C@@H:39]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[O:40][C@H:2]1[O:58][CH2:57][CH2:56][Br:55])(=[O:8])[CH3:7]
Reactant: OCCBr
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)OC[C@H]1O[C@H](O[C@@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OCCBr)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 23 h
Yield: 76.2 %

Procedure:
A solution of the crude acetobromo sugar 49 (20.5 g; 29.3 mmol) in dry methylene chloride (100 ml) was added dropwise (ca 20 min) to a cold (-78°) solution of silver trifluoromethanesulfonate (nonpurified, commercial material; 10.3 g; 40 mmol), 2,4,6-tri-methylpyridine (3.6 g; 30 mmol) and 2-bromoethanol (17.5 g; 140 mmol) in methylene chloride (250 ml) under nitrogen. The reaction mixture was stirred in the dark for 23 h during which time it had reached room temperature. The yellowish-white precipitate, that had formed, was removed and the resulting colorless solution was washed consecutively with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water. Drying (sodium sulfate), filtration and evaporation gave a residue which crystallized spontaneously. Recrystallization from ethyl acetate, followed by evaporation of the mother liquor and recrystallization from methanol, gave a total of 16.6 g (77%) of the title compound 15. Melting point and optical rotation are shown in Table 1 and the 13C- and 1H-NMR data are shown in Table 2 and 3 , respectively.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C#N)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (253 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (218 mg, 91%) as a pale-yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[O:18][CH2:17][CH2:16][N:15]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)C2CNCCO2)no1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(NC(=O)C2CN(C(=O)c3ccc(C(F)(F)F)cc3)CCO2)no1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a cold (0° C.) solution of morpholine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (75 mg; 0.259 mmol), 4-(trifluoromethyl)benzoic acid (49.2 mg; 0.259 mmol) and N,N-diisopropylethylamine (0.099 mL; 0.57 mmol) in anhydrous acetonitrile (2 mL) is added phosphorous oxychloride (0.023 mL; 0.259 mmol). The reaction mixture is left stirring at room temperature for 3.5 hours. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/methylene chloride then trituation from hot methanol provides the title compound, m/z 426 [M+H+].
Reaction SMILES: [C:1]([C:4]1[C:9]([NH:10][C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=2)=O)=[C:8]([CH3:22])[C:7]([O:23][CH3:24])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1N=C(C2C=C(O)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH3:24][O:23][C:7]1[C:8]([CH3:22])=[C:9]2[C:4]([C:1]([OH:3])=[CH:2][C:11]([C:13]3[S:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=3)=[N:10]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1C
Agent: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(O)cc(-c3nc(C(F)(F)F)cs3)nc2c1C
Yield: 73 %

Procedure:
Compound 65b was synthesized from compound 64b as a yellow powder in 73% yield, following the procedure as described for compound 43a. MS (ESI, EI+) m/z=341 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[S:24][CH2:25][CH2:26][C:27](O)=[O:28])=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH2:36]([N:38]([CH2:39][CH3:40])[C:27](=[O:28])[CH2:26][CH2:25][S:24][CH:8]1[C:9]2[C:10]([O:22][CH3:23])=[C:11]3[C:16](=[C:17]([OH:21])[C:18]=2[C:19](=[O:20])[N:7]1[CH2:6][C:5]1[CH:30]=[CH:31][C:2]([F:1])=[CH:3][CH:4]=1)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH3:37]
Reactant: CCNCC
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2SCCC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)CCSC1c2c(c(O)c3ncccc3c2OC)C(=O)N1Cc1ccc(F)cc1

Procedure:
A solution of 24 (10.7 mg, 0.024 mmol) in CH2Cl2 (0.24 mL) was stirred with EDC (14 mg, 0.73 mmol) and diethyl amine (10 μL, 0.097 mmol) for 1 day at ambient temperature. The product 25 was purified by reverse phase HPLC using 5-95% A. Buffer A contained CH3CN—1% HOAc and B contained H2O—1% HOAc. 1H NMR (300 MHz, CDCl3) δ 0.984 (t, 3H, J=6 Hz), 1.05 (t, 3H, J=7 Hz), 2.23-2.45 (m, 4H) 3.04 (q, 2H, J=7 Hz), 3.29 (q, 2H, J=8 Hz), 4.06 (s, 3H), 4.47 (d, 1H, J=14 Hz), 5.31 (d, 1H, J=15 Hz), 5.50 (s, 1H), 7.05 (t, 2H, J=9 Hz), 7.36-7.44 (m, 2H), 7.55-7.62 (m, 1H), J=9 Hz), 8.95-9.00 (m, 1H); EI MS (m/z) 520.2 [MH+], 1016.9 [2M+Na].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][C@H:30]2[O:32][CH2:31]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:29][C@@H:30]2[CH2:31][O:32]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
4-Benzyloxyphenol (15.00 g, 74.91 mmol) in anhydrous N,N-dimethylformamide (50 mL) was added to a solution of sodium hydride (60% dispersion in oil) (2.88 g, 74.9 mmol) in N,N-dimethylformamide (50 mL). The solution was stirred for 30 minutes and (S)-(+)-glycidyl 4-methylbenzenesulfonate (17.12, 75.0 mmol) was added. The mixture was heated to 80° C. for 2 hours. The solvent was removed and the residue partitioned between diethyl ether and water. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent evaporated to dryness in vacuo. To yield the title compound as a white solid (13.6 g, 53.3 mmol). MS (El, m/z): 256 [M]+
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9](=[O:11])[O-:10])[CH2:3][N+:4]([CH3:7])([CH3:6])[CH3:5].[CH2:12]([S:20](O)(=[O:22])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([S:20]([O:1][C@H:2]([CH2:8][C:9](=[O:10])[O-:11])[CH2:3][N+:4]([CH3:7])([CH3:5])[CH3:6])(=[O:22])=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCS(=O)(=O)O
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Product: CCCCCCCCS(=O)(=O)O[C@H](CC(=O)[O-])C[N+](C)(C)C

Procedure:
The carnitine inner salt solution is mixed with the octanesulphonic acid solution at ambient temperature under agitation for 20 minutes, and the homogeneous solution obtained is lyophilised.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:34])([F:33])[F:32])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([C:27]([F:30])([F:29])[F:28])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:70][N:71]1[CH2:76][CH2:75][CH2:74][N:73]([CH2:77][C:78]([F:81])([F:80])[F:79])[C:72]1=[O:82]>O.CN(C)C=O>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C:13]2([C:31]([F:32])([F:33])[F:34])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:70][N:71]4[CH2:76][CH2:75][CH2:74][N:73]([CH2:77][C:78]([F:79])([F:81])[F:80])[C:72]4=[O:82])=[O:23])=[C:20]([C:27]([F:28])([F:29])[F:30])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: NN1CCCN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NN1CCCN(CC(F)(F)F)C1=O)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 25-mL round-bottom flask, was placed 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (100 mg, 0.19 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL), HATU (141 mg, 0.37 mmol, 2.00 equiv), DIEA (96 mg, 0.74 mmol, 4.00 equiv), 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one (40 mg, 0.20 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×20 mL of brine. The mixture was dried over anhydrous sodium sulfate. The residue was purified by preparative TLC (EtOAc/ether=1:2). This resulted in 34.3 mg (26%) of 4-[5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-N-[2-oxo-3-(2,2,2-trifluoroethyl)-1,3-diazinan-1-yl]-2-(trifluoromethyl)benzamide as a white solid; (ES, m/z): [M+H]+ 719.00, 1H NMR (300 MHz, DMSO): δ 10.72 (s, 1H), 8.37 (s, 1H), 8.23 (s, 2H), 8.16-8.14 (d, J=6 Hz, 1H), 8.08 (s, 1H), 7.74-7.72 (d, 1H), 4.70-4.49 (dd, J=21 Hz, J=45 Hz, 2H), 4.17-4.11 (q, J=9 Hz, 2H), 3.58-3.54 (t, J=6 Hz, 2H), 3.48-3.45 (t, J=5.1 Hz), 2.07-2.05 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]3)=[CH:11][C:2]=2[O:1][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]
Reactant: N#Cc1cc2ccccc2cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3ccccc3cc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a stirred solution of 3-hydroxy-naphthalene-2-carbonitrile from step 2 (200 mg, 1.18 mmol) and 2,2′,4′-trichloroacetophenone (317 mg, 1.42 mmol, 1.2 eq) in anhydrous N,N-dimethylformamide (4.7 mL) was added potassium carbonate (326.7 mg, 2.36 mmol, 2.0 eq), and the orange reaction mixture was stirred at 80° C. for 16 h. The resulting dark wine colored reaction was diluted with ethyl acetate and water. The organic layer was washed with saturated aqueous ammonium chloride, water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure and the crude product was purified on the MPLC (biotage) eluted with 15% ethyl acetate-hexane. Crystallization from ether-hexane afforded 243 mg (57.7%) of the desired benzofuran. 1H-NMR (DMSO-d6) δ 8.66 (s, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.72 (broad s, 2H), 7.63 to 7.42 (m, 4H); LC-MS (ES MH+=356).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7](F)(F)F)=O.[N+:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=C2)([O-:16])=[O:15].O>CN(C)C=O>[N+:14]([C:17]1[CH:25]=[C:24]2[C:23](=[CH:19][CH:18]=1)[NH:22][CH:21]=[C:7]2[C:6]([OH:5])=[O:11])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C

Procedure:
Trifluoroacetic anhydride (21.37 g) was added dropwise to a chilled solution of 5-nitro-1H-indole (15.0 g) in dry dimethylformamide (150 ml) under a dry N2 atmosphere. The solution was allowed to warm to room temperature, and was then heated at reflux for 24 hours. The reaction mixture was cooled and poured into water (500 ml) and the resulting dark brown precipitate was filtered, suspended in water (200 ml) containing sodium hydroxide (50.0 g), and heated at reflux for 3 hours. The dark brown solution was cooled to room temperature, extracted with ether (4×100 ml), acidified to pH2 and the title compound filtered and dried (19 g), m.p. 256°-258° C. δH (360 MHz, DMSO-d6) 7.71 (1H, d, J=7.2 Hz, H-7), 8.9 (1H, dd, J=7.2, 1.0 Hz), 8.27 (1H, s, H-2), 8.89 (1H, d, J= 1.0 Hz, H-4); m/z 206 (M+, 70), 163 (10), 138 (20), 123 (100, 106 (15), 81 (10%).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[S:8][C:9]([CH2:21][CH3:22])=[CH:10][C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:5]([CH2:23][NH:24][C:25]([C:27]2[N:28]([CH2:36][C:37]([O:39]CC)=[O:38])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[N:4][N:3]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[Br:1][C:2]1[N:6]([C:7]2[S:8][C:9]([CH2:21][CH3:22])=[CH:10][C:11]=2[C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:5]([CH2:23][NH:24][C:25]([C:27]2[N:28]([CH2:36][C:37]([OH:39])=[O:38])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[N:4][N:3]=1
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(Br)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(Br)nnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1
Reaction time: 1 h

Procedure:
Ethyl 2-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethylcarbamoyl)indole-1-acetate and a 2M aqueous sodium hydroxide solution are added to ethanol, and the mixture is refluxed with stirring for 1 hour. An aqueous citric acid solution is added to adjust the reaction mixture to pH 3 to give 2-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethylcarbamoyl)indole-1-acetic acid.