Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][C@H:35]1[CH2:39][NH:38][C@@H:37]([C:40]([OH:42])=[O:41])[CH2:36]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:38]5[CH2:39][CH:35]([OH:34])[CH2:36][CH:37]5[C:40]([OH:42])=[O:41])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: OC1CCNC1
Product: O=C(O)C1CC(O)CN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with cis-4-hydroxy-D-proline. A yellow solid 130 was obtained (0.038 g, 74%). 1H-NMR (CDCl3, 400 MHz) δ 2.34–2.42 (m, 1H), 2.64–2.68 (m, 2H), 3.73–3.82 (m, 1H), 3.94–4.00 (m, 1H), 4.28–4.34 (m, 4H), 4.68–4.74 (m, 1H), 6.92–7.12 (m, 6H), 7.52 (br, 1H), 7.80 (s, 1H), 8.04 (br, 1H); MS (APCI) m/z 519 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si:30]([O:47][C@@H:48]([CH3:52])[C:49](O)=[O:50])([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:30]([O:47][C@@H:48]([CH3:52])[C:49]([N:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[S:12][C@@:11]1([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:50])([C:43]([CH3:45])([CH3:46])[CH3:44])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 3-(5-(3-fluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazol-2-yl)propylcarbamate (0.54 g, 1.30 mmol) and (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid (0.64 g, 1.95 mmol) in DMF (10 mL) was added PyBOP (1.01 g, 1.95 mmol) followed by DIEA (0.34 g, 2.60 mmol). After stirring at room temperature for 14 hours, the reaction mixture was partitioned between 10% Na2CO3 (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (40 mL). The combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed (1:9 to 1:4 ethyl acetate/hexanes) to provide the less polar diastereomer product (180 mg, 19%) as a yellow syrup.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:32])[C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:14]=[C:13]([O:28][CH:29]([CH3:31])[CH3:30])[CH:12]=2)=[N:7][CH:8]=1.P(Br)(Br)Br.[CH2:37]([O:39][P:40]([O:44]CC)[O:41][CH2:42][CH3:43])[CH3:38]>ClC(Cl)C.C(Cl)Cl>[CH:29]([O:28][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[CH:14]=1)[C:10]([NH:9][C:6]1[CH:5]=[N:4][C:3]([CH2:2][P:40](=[O:44])([O:41][CH2:42][CH3:43])[O:39][CH2:37][CH3:38])=[CH:8][N:7]=1)=[O:32])([CH3:30])[CH3:31]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2cnc(CO)cn2)c1
Agent: BrP(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OC(C)C)c2)cn1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.4 %

Procedure:
To a solution of N-(5-hydroxymethyl-pyrazin-2-yl)-3-isopropoxy-5-(4-methanesulfonyl-phenoxy)-benzamide (130 mg, 0.28 mmol) in 2.8 mL of dichloroethane was added 0.56 mL of a 1 M solution of PBr3 in CH2Cl2 and the solution stirred for 4 h at rt. Then triethylphosphite (0.5 mL, 2.8 mmol) was added and the resulting solution microwave heated at 120° C. for 5 min. Then the mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3, brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 and subjected to MPLC on a 12 g SiO2 column eluting with % EtOAc in hexanes (time): 65-95 (30 min ramp) to provide 33 mg (20%) of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 6H, J=6 Hz), 1.30 (d, 6H, J=6 Hz), 3.22 (s, 3H), 3.50 (d, 2H, J=21 Hz), 4.02 (m, 4H), 4.78 (septet, 1H, J=6 Hz), 6.97 (t, 1H, J=2 Hz), 7.25 (d, 2H, J=8 Hz), 7.35 (t, 1H, J=2 Hz), 7.51 (t, 1H, J=2 Hz), 7.95 (d, 2H, J=8 Hz), 8.41 (dd, 1H, J=1, 2 Hz), 9.29 (d, 11-1, =1 Hz). 11.17 (s, 1H); LCMS (m/z): 578.6 [C26H32N3O3PS+H]+.
Reaction SMILES: C1(=O)N([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])C(=O)C2=CC=CC=C12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:6][CH2:7][C:8]([NH2:35])=[O:9])=[CH:12][C:13]=1[O:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCC(N)=O)ccc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A mixture of 3-phthalimido-3-(4-benzyloxy-3-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated ammonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-,3-(4-benzyloxy-3-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6)δ 7.84 (m, 4H, Ar), 7.60-7.25 (m, 5H), 7.53 (br s, 1H, CONH), 7.15-6.8 (m, 4H), 5.67 (t, 1H, J=7.8 Hz), 5.04 (s, 2H, OCH2), 3.75 (s, 3H, OMe), 3.19 (d, 2H, J=9, 16.5 Hz);13C NMR (DMSO-d6)8 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.BrC(OC)=O.[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>O1CCCC1>[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CC1CCC(N)CC1
Agent: COC(=O)Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To tetrahydrofuran (50 ml) are added 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) and pyridine (50 mmole), and thereto is added dropwide with stirring methyl bromoformate (50 mmole) with keeping the inner temperature at 5°-15° C. by ice-cooling, and thereafter, the mixture is stirred at room temperature for one hour. To the mixture is added 4-methylcyclohexylamine (55 mmole), and the mixture is further stirred for 3 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is dissolved in chloroform. The chloroform layer is washed with dilute aqueous sodium hydroxide solution, diluted hydrochloric acid and water in order, and dried over sodium sulfate. Inorganic materials are filtered off and the mother liquor is concentrated. The resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-(4-methylcyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 45%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19].[CH2:22]([O:24][C:25](=[O:28])[NH:26][NH2:27])[CH3:23].CC1C=CC(S(N)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[N:27][NH:26][C:25]([O:24][CH2:22][CH3:23])=[O:28])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: CCOC(=O)NN
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)NN=C(C)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 40 h
Yield: 40.5 %

Procedure:
In a round bottom flask fitted with a Dean-Stark, a solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.384 g, 7.86 mmol) in toluene (16 mL) was treated with ethylcarbazate (2.61 g, 25 mmol) followed by p-toluenesulfonamide (103 mg, 0.60 mmol). The reaction was stirred at 150° C. for 40 h. The solvent was removed by distillation and the residue was purified by flash column chromatography (silica gel, 1:1 EtOAc/hexanes) to give the title compound (1.24 g, 40%). API-ES: m/z 390.1 [M+H]+, rt 4.14 min, 4.20 min: mixture of cis and trans.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 66.7 %

Procedure:
A mixture of 2.05 g of 2-(R)-hydroxy-4-methylpentanoic acid, 2.01 g of benzyl alcohol and 0.251 g of p-toluenesulfonic acid monohydrate in 40 ml of benzene was heated to reflux for 1.5 hours. The reaction mixture, after being allowed to cool, was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure to yield the title compound as a colorless oil (2.30 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[OH:8][C:3]1[C:2]([NH:1][C:9](=[O:10])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccnc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1cccnc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 3-aminopyridin-2-ol (8.05 g, 73.0 mmol) in DCM (20 mL) was added CbzCl (13.2 mL, 93.0 mmol) and Na2CO3 (18.0 g, 170 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added and the mixture was washed with NaHCO3 (50 mL). The organic phase was dried over MgSO4, filtered and concentrated. The crude product was purified by combi-flash (ISCO, 40 g silica, MeOH/DCM from 3% to 5%, UV254) to afford benzyl (2-hydroxypyridin-3-yl)carbamate (16.2 g, 90% yield): MS (ES) m/z 245 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][OH:12])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:6](=[O:21])[CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[C:6](=[O:21])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(CO)C21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Reaction time: 1 h

Procedure:
To a solution of 5-acetyl-2-(4-fluorobenzyl)-7-(hydroxymethyl)-2,5-diazabicyclo[4.1.0]heptane-3-one (1.3 g, 4.45 mmol) in 40 mL anhydrous THF under nitrogen, sodium hydride (60% in mineral oil, 231 mg, 5.78 mmol) was added. After stirring for 1 h, benzyl bromide (0.58 ml, 4.89 mmol) in THF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with chloroform three times. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel using hexanes and ethyl acetate as eluents to give the title product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46]Br)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]>O1CCOCC1.C(OC(=O)C)C>[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 41 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (500 mg, 2.25 mmol), CsF (865.83 mg, 5.70 mmol) in Dioxane (9.5 mL), (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.07 g, 1.90 mmol, Intermediate 2) and Pd(PPh3) (173.3 mg, 0.15 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (450 mg, 41.3%) as off-white solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:17][CH:16]=1)=[O:29]
Reactant: Nc1ccc(-c2coc(-c3ccccc3)n2)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2coc(-c3ccccc3)n2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
to a solution of 4-(2-phenyloxazol-4-yl)benzenamine (299 mg, 1266 μmol) and pyridine (500 μl, 6131 μmol) dissolved in 4 mL dichloromethane at room temperature was added 2,4-dichlorobenzoyl chloride (177 μl, 1266 μmol) all at once. The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure, taken up in heptane and concentrated again under reduced pressure to afford a yellow solid. The solid was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic extract was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow solid. The product was purified by preparative reversed phase HPLC. Combination of fractions containing product were concentrated under reduced pressure to afford a colorless solid (100 mg, 19%). ESI+ m/z=409.0 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:17])[N:6]([CH2:13][C:14]([OH:16])=[O:15])[C:7]2=[O:12].[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[CH:20]=[N+:21]([O-:44])[CH:22]=[C:23]([Cl:43])[C:24]=1[CH2:25][C@@H:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH2:39][CH:40]2[CH2:42][CH2:41]2)[CH:29]=1)[O:15][C:14](=[O:16])[CH2:13][N:6]1[C:5](=[O:17])[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[C:7]1=[O:12]
Reactant: COc1cccc2c1C(=O)N(CC(=O)O)C2=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cccc2c1C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Yield: 41.4 %

Procedure:
To a solution of 2-(4-methoxy-1,3-dioxoisoindolin-2-yl)acetic acid (30 mg, 0.128 mmol) in DCM (3 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (53.6 mg, 0.128 mmol), EDC (73.4 mg, 0.383 mmol) and DMAP (15.58 mg, 0.128 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was removed, and the resulting crude was purified by flash chromatography on silica gel (DCM:MeOH=98:2) recovering the title compound (33.7 mg, 0.053 mmol, 41% yield). MS/ESI+ 637.34 [MH]+; [αD]=−12.96, c=0.25 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.46 (dd, 1H), 7.18 (d, 1H), 7.06 (d, 1H), 6.95 (dd, 1H), 7.08 (t, 1H), 5.99 (dd, 1H), 4.36 (s, 2H), 3.99 (s, 3H), 3.94 (dd, 1H), 3.90 (dd, 1H), 3.38 (dd, 1H), 3.22 (dd, 1H), 1.07-1.36 (m, 1H), 0.50-0.68 (m, 2H), 0.24-0.45 (m, 2H).
Reaction SMILES: [OH-].[Na+].[Br:3]Br.[C:5]1([C:11]#[CH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.C(COC)OC>[C:5]1([C:11]#[C:12][Br:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrBr
Reactant: C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: BrC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (31.4 g) in water (160 ml) was cooled to 6° C. and bromine (18 ml) was added dropwise, the temperature being kept below 20° C. Phenylacetylene (20 g) in dimethoxyethane (80 ml) was added over 15 minutes and the mixture was stirred at room temperature for 5 hours. Water (200 ml) was added, and the mixture was extracted with ether (4×60 ml), dried (MgSO4) and the solvents removed at room temperature to yield phenylbromoacetylene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(S)c(C)c1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Product: Cc1ccc(Sc2ccc(C(F)(F)F)cc2Br)c(C)c1

Procedure:
Prepared from 2,4-dimethyl-benzenethiol and 2-bromo-1-iodo-4-trifluoromethyl-benzene.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:8]1([CH2:14]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].C(OCC)C>O>[C:8]1([CH2:14][O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCCCCO
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: OCCCCCOCc1ccccc1
Yield: 56.8 %

Procedure:
A stirred solution of 107.0 grams (1.0 mole) of 1,5-pentanediol, 30 ml (0.25 mole) of phenylmethyl bromide and 33.0 grams of 85% potassium hydroxide in 40 ml of xylenes was heated at 110° C. for 18 hours. After this time the reaction mixture was cooled and shaken with diethyl ether and water. The organic layer was washed in turn with water, aqueous 5% hydrochloric acid, water, and with an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 0.5-50% diethyl ether in hexanes. The appropriate fractions were combined and concentrated under reduced pressure yielding 27.6 grams of 7-phenyl-6-oxaheptan-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].O[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:23]2[CH:24]=[CH:25][C:20]([C:17]3[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=3)=[CH:21][CH:22]=2)[CH:9]=1)=[O:4]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1 g) in anhydrous tetrahydrofuran (20 mL) was cooled to 0° C. under a nitrogen atmosphere. 4-Hydroxybiphenyl (3 g) and triphenylphosphine (4.61 g) were added and the mixture was treated with di-isopropylazodicarboxylate (3.46 mL) dropwise. The mixture was stirred at 0° C. for 10 min then cooling was removed and the mixture stirred for a further 3 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (100 mL). The organic phase was separated, dried and evaporated. The residue was purified by flash chromatography, eluting with pentane/ethyl acetate 9:1 by volume to give a mixture of the title compound and 4-hydroxybiphenyl (1.8 g). This material was purified further by flash chromatography eluting with dichloromethane/methanol 99:1 by volume to give compound 17 as a white solid (200 mg). LCMS System A: Rt=4.2 mins.