Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH-:28].[Na+]>C(O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@H:18]([CH2:19][CH2:20]2)[OH:28])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
Feces (day 14) (25 mg) were weighed and placed in a test tube (15 mL) equipped with a screw cap, and an internal standard substance (5β-cholestane) (0.1 μmol) and a 90% ethanol solution containing 1N sodium hydroxide (1 mL) were added thereto. The mixture was heated at 80° C. by means of a block heater. One hour after, distilled water (0.5 mL) was added, and neutral sterols were taken through two rounds of extraction by use of petroleum ether (2.5 mL). The resultant extract was washed with distilled water (7.5 mL), dehydrated over sodium sulfate, and dried to solid under nitrogen gas flow. The recovered neutral sterols were trimethylsilylated, and analyzed through gas chromatography under the following conditions (Table 28).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][P:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:13][CH:12]=1)(=O)C>CO>[P:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1)([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]
Reactant: CC(=O)Oc1ccc(CCOP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=P(OCCc1ccc(O)cc1)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (62.8 mg, 0.454 mmol) was added to a stirred solution of 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)phenyl acetate (100 mg, 0.227 mmol) in MeOH (20.5 mL) at 25° C. The reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford dibenzyl 2-(4-hydroxyphenyl)ethyl phosphate, as an oil. LCMS calc.=399.1; found=398.9 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 8.05 (1 H, s); 7.41-7.30 (m, 10 H); 6.99 (d, J=8.2 Hz, 2 H); 6.86 (d, J=8.3 Hz, 2 H); 5.02 (s, 2 H); 5.00 (s, 2 H); 4.18 (q, J=7.1 Hz, 2 H); 2.86 (t, J=7.1 Hz, 2 H).
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:6]=1[C:7]([NH:9][CH:10]([C:12]1[N:13]=[N:14][N:15]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:16]=1[CH2:17][CH:18]=C(C)C)[CH3:11])=[O:8].[BH4-].[Na+]>CO>[Cl:4][C:5]1[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:6]=1[C:7]([NH:9][CH:10]([C:12]1[N:13]=[N:14][N:15]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:16]=1[CH2:17][CH2:18][OH:1])[CH3:11])=[O:8]
Reactant: O=[O+][O-]
Reactant: CC(C)=CCc1c(C(C)NC(=O)c2cccc(C(F)(F)F)c2Cl)nnn1-c1ncccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NC(=O)c1cccc(C(F)(F)F)c1Cl)c1nnn(-c2ncccn2)c1CCO
Temperature: 25 °C
Yield: 70 %

Procedure:
A stream of O3 generated from an ozonator was passed though the solution of Intermediate 238 (200 mg, 0.43 mmol, 1.0 equiv.) in MeOH (30 mL) at −78° C. until the color of the reaction solution became blue (˜10 min). NaBH4 (49 mg, 1.3 mmol, 3.0 equiv.) was added at −78° C. The reaction solution was warmed to room temperature and partitioned between EtOAc and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography with EtOAc/hexanes as eluents to afford the title compound (140 mg, 0.30 mmol, 70% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.95-8.88 (d, J=4.9 Hz, 2H), 7.81-7.73 (dd, J=7.8, 1.7 Hz, 1H), 7.67-7.58 (dd, J=7.7, 1.6 Hz, 1H), 7.50-7.44 (t, J=4.9 Hz, 1H), 7.43-7.36 (t, J=7.8 Hz, 1H), 6.95-6.83 (d, J=8.1 Hz, 1H), 5.62-5.44 (m, 1H), 4.06-3.89 (m, 2H), 3.66-3.56 (ddd, J=14.7, 6.1, 4.6 Hz, 1H), 3.44-3.34 (ddd, J=14.7, 7.7, 4.9 Hz, 1H), 3.20-3.14 (t, J=5.9 Hz, 1H), 1.88-1.71 (d, J=7.0 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 165.5, 159.0, 155.5, 147.4, 138.3, 133.1, 132.2, 129.2, 129.1 (q, JC—F=31.5 Hz), 128.5 (q, JC—F=5.2 Hz), 126.8, 122.5 (q, JC—F=273.4 Hz), 120.7, 61.1, 41.4, 27.3, 20.7. HRMS-ESI (m/z): [M+H]+ calcd for C18H17ClF3N6O2, 441.1048. found, 441.1038.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:19][C:11]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([NH:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)=[N:7][CH:6]=1)=[O:20]
Reactant: NCCN1CCOCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(I)nc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(NCCN2CCOCC2)nc1
Temperature: 70 °C

Procedure:
N-(2-iodopyrimidin-5-yl)-2-methyl-5-nitrobenzamide (60 mg, 0.156 mmol), 2-morpholinoethanamine (˜200 mg, 1.5 mmol), and DIEA (0.041 mL, 0.234 mmol) were taken up in IPA (2.5 mL) in a 16×100 mm resealable pyrex tube and heated at 70° C. for 4 h. The mixture was concentrated and purified by preparative TLC (2.5% MeOH/CH2Cl2) to afford 2-methyl-N-(2-(2-morpholinoethylamino)pyrimidin-5-yl)-5-nitrobenzamide.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: COc1cccc(CBr)c1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: COc1cccc(Cn2c(Oc3cc(C)cc(C)c3)c(C(C)C)c(=O)[nH]c2=O)c1
Yield: 55 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (217 mg, yield: 55.0%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([N:19]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Solvent: CCO
Product: COc1ccc(N=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
1.00 g (5.4 mmol) of 4-methylsulfonylbenzaldehyde and 0.67 g (5.4 mmol) of 4-methoxyaniline were dissolved in 15 ml of ethanol, and the solution was heated under reflux for 1 hour. At the end of this time, the reaction solution was cooled to room temperature, and the crystals which precipitated were collected by filtration and washed with ethanol, to give 1.48 g (yield 95%) of the title compound as slightly yellow prismatic crystals.
Reaction SMILES: [CH2:1]([P:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.N>>[N+:15]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][P:8]2(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=P1(Cc2ccccc2)CCCCC1
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 1-benzylphosphorinane-1-oxide (5.39 g) were added nitric acid (1.94 ml) and sulfuric acid (15 ml) at 0° C., and the mixture was stirred at 50-60° C. for 2hours. The reaction mixture was added to crushed ice-water, neutralized with ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-(4-nitrobenzyl)-phosphorinane-1-oxide (2.47 g) as pale yellow crystals.
Reaction SMILES: [Na].[CH3:2][CH2:3][OH:4].[F:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1>CCOC(C)=O>[CH2:3]([O:4][CH2:14][CH:12]([OH:13])[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([F:5])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCO
Reactant: Fc1ccc(OCC2CO2)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCOCC(O)COc1ccc(F)cc1
Yield: 86.3 %

Procedure:
Slowly add sodium (1 g, 43.5 mmol) to absolute EtOH (80 mL) and stir the mixture at ambient temperature for 2 hours. Add 2-[(4-fluorophenoxy)methyl]oxirane (2.0 g, 11.89 mmol) in a single portion and stir for 16 hours at ambient temperature. Add 30 mL EtOAc; wash with H2O (10 mL) three times; then dry the organic layer over Na2SO4; filter; and concentrate the filtrate under reduced pressure to give the title compound (2.55 g, 86.3%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 7.15 (m, 2H), 6.95 (m, 2H), 5.05 (m, 1H), 3.95 (m, 3H), 3.49 (m, 4H), 1.05 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](O)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(CC(O)c2ccc(F)c(F)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CSc1ccc(/C=C/c2ccc(F)c(F)c2)cc1
Temperature: 25 °C

Procedure:
The alcohol from step 3 (3.78 g) was dissolved in toluene (45 mL) and p-TsOH (260 mg) was added. The mixture was refluxed with azeotropic removal of water for 18 hr, cooled to r.t., washed with saturated NaCHO3 sol., brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (95:5)) to give the title product as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2([CH3:16])[CH3:15].[Li]CCCC.CN([CH:25]=[O:26])C.O>O1CCCC1>[CH3:15][C:5]1([CH3:16])[C:4]2[C:9](=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:11]=[C:2]([CH:25]=[O:26])[CH:3]=2)[O:8][CH2:7][CH2:6]1
Reactant: CN(C)C=O
Reactant: CC(C)c1cc(Br)cc2c1OCCC2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C=O)cc2c1OCCC2(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-4,4-dimethyl-8-(propan-2-yl)-3,4-dihydro-2H-chromene (154 mg, 0.54 mmol) in tetrahydrofuran (5.44 mL) was cooled to −78° C. and n-BuLi (261 μL, 0.65 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 30 minutes, and then DMF (168 μL, 2.17 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature, and stirred for 30 minutes before water was added. It was then extracted with EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to obtain the desired product as a colorless oil.
Reaction SMILES: [C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3]Cl.[I-:12].[Na+].O>C(#N)C>[C:1](=[O:11])([O:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10])[O:2][CH2:3][I:12]
Reactant: [I-]
Reactant: COCCCOC(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COCCCOC(=O)OCI
Temperature: 55 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Chloromethyl [3-(methoxy)propyl] carbonate (3.7 g) was dissolved in acetonitrile (12 ml), and sodium iodide (12.0 g) was added. The mixture was stirred at 55° C. for 4 hours under an argon atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with an aqueous 5% sodium thiosulfate solution (50 ml×2), water (50 ml) and a saturated sodium chloride aqueous solution (50 ml). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain iodomethyl [3-(methoxy)propyl] carbonate (5.0 g) as a pale yellow liquid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:20]([OH:22])=[O:21])[NH2:8])=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-tert-Butoxycarbonyl-O-ethyl-L-tyrosine (III, EXAMPLE 2, 195 g, 632 mmol) is suspended in THF (1200 mL), p-toluenesulfonic acid monohydrate (240 g, 1.26 mol) is added at 20-25°. The resulting mixture is heated at reflux for 2 hr. The mixture is neutralized with sodium hydroxide (2N, about 700 mL) to pH between 5 and 6 at 20-25°. The resulting mixture is stirred at 5° for 2 hr before it is filtered. The cake is washed with THF/water (4/1, 50 mL×3). The precipitate is dried to give the title compound. The filtrate is removed of all volatile, adjusted pH again to give more precipitate. The precipitate is dried to give additional title compound, NMR (D2O/NaOH) δ7.14, 6.88, 4.02, 3.40, 2.88, 2.73 and 1.30; CMR (D2O/NaOH) δ182.8, 157.0, 131.4, 131.0, 64.8, 57.8, 40.3 and 14.3.
Reaction SMILES: [CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([CH:30]([CH3:34])[C:31](O)=[O:32])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:38])=O>>[CH:1]1([C:4]([N:6]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([CH:30]([CH3:34])[C:31]([Cl:38])=[O:32])[CH:21]=2)[CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)O)cc(C(F)(F)F)c1)C(=O)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C(=O)Cl)cc(C(F)(F)F)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 218, Step 3, using the following starting materials: 2-{2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-5,4′-bis-trifluoromethyl-biphenyl-3-yl}-propionic acid and oxalyl chloride.
Reaction SMILES: C(C(NC(C1C=C(C)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35](C)[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr.[C:41](#N)C>ClCCl>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:32]=[CH:33][C:34]([CH3:41])=[CH:35][C:36]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: CC#N
Reactant: Cc1cccc(C(=O)N(SSc2ccc(C)cc2C(=O)NC(CC(C)C)C(=O)O)C(CC(C)C)C(=O)O)c1
Agent: BrBr
Solvent: ClCCl
Product: Cc1ccc2c(=O)n([C@@H](CC(C)C)C(=O)O)sc2c1

Procedure:
Following the general method of Example 3, a slurry of [s-(R*,R*)]-2-[-[2-(1-carboxy-3-methyl-butylcarbamoyl)-4-methylphenyldisulfanyl)-5-methylbenzoylamino]-4-methyl-pentanoic acid (1.8 g, 3.2 mmol) (from Preparation 22) in 5 mL acetonitrile and 20 mL dichloromethane was reacted with bromine (0.6 g, 3.7 mmol) in 10 mL dichloromethane. The crude product was recrystallized from methanol/water to afford 1.3 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:5]([C:7]1[CH:8]=[CH:9][C:10](F)=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:6].O.[NH2:21][NH2:22].Cl>O1CCCC1>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([C:5]([C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[O:6])[CH:14]=2)[NH:22][N:21]=1
Reactant: NN
Reactant: N#Cc1cc(C(=O)c2cc(F)cc(F)c2)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1n[nH]c2ccc(C(=O)c3cc(F)cc(F)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(3,5-difluoro-benzoyl)-2-fluoro-benzonitrile (2.05 g, 7.84 mmol) and hydrazine hydrate (0.73 mL, 15.7 mmol) in dry tetrahydrofuran (100 mL) was stirred at room temperature for 2 hours. The reaction mixture was treated with 37% hydrochloric acid (1.3 mL, 15.7 mmol) for 30 min and then the volatiles were partially evaporated. The reaction mixture was then diluted with water (100 mL) and aqueous NH3 was added to reach neutral pH. The resulting solid was filtered, washed thoroughly with water and dried under vacuum at 60° C. The title compound was obtained as yellow solid (1.75 g, 80% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[S:6](=O)(=[O:9])([OH:8])[OH:7]>>[S:6]([OH:9])([O:5][CH:3]([CH3:4])[CH2:2][NH2:1])(=[O:8])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CC(O)CN
Product: CC(CN)OS(=O)(=O)O

Procedure:
FIG. 5 shows another synthetic reaction scheme for preparation of an mPEG-DTB-ligand compound in accord with the invention. The details of the reaction procedure are given in Examples 3A-3B. Briefly, cold 1-amino-2-propanol was reacted with sulfuric acid to form 2-amino-1-methylethyl hydrogen sulfate. This product was reacted with carbon disulfide and sodium hydroxide in aqueous ethanol to yield 5-methylthiazolidine-2-thione. An aqueous solution of hydrochloric acid was added to the 5-methylthiazolidine-2-thione and heated. After refluxing for one week, the product, 1-mercapto(methyl)ethyl ammonium chloride, was crystallized and recovered. This product was reacted with methoxy carbonylsulfenyl chloride to yield 2-(methoxycarbonyldithio)ethaneamine. Reaction of the 2-(methoxycarbonyldithio)ethaneamine with mPEG-chloroformate using the procedure described above with respect to FIG. 2 yields the desired mPEG-DTB-nitrophenyl compound suitable for reaction with a selected amine-containing ligand to form a compound in accord with the invention.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60]CCCCCC=C)[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:72])[C:68]([F:71])([F:70])[F:69])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate prepared in Example 8, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][C:23]([F:26])([F:25])[F:24])[N:7]=1)(=[O:4])=[O:3].C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1>CO.[Pd]>[CH3:1][S:2]([O:5][C:6]1[N:7]=[C:8]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][C:23]([F:26])([F:25])[F:24])[C:32]([OH:33])=[N:12][C:9]2=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(Nc2ccccc2OC(F)(F)F)n1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Oc1ccc2nc(O)n(-c3ccccc3OC(F)(F)F)c2n1
Reaction time: 2 h
Yield: 61.7 %

Procedure:
5-Nitro-6-(2-(trifluoromethoxy)phenylamino)pyridin-2-yl methanesulfonate (1.8 g, 4.58 mmol) was dissolved in MeOH (45 mL) and catalytic amount of 10% Pd/C was added. The reaction flask was purged with nitrogen and placed under an atmosphere of hydrogen for 2 h. The reaction mixture was filtered through Celite® and the solvent was removed under reduced pressure. The residue was immediately dissolved in THF (35 mL) and CDI (1.8 g, 11.0 mmol) added. The mixture was stirred overnight and concentrated under reduced pressure. The residue was added EtOAc, washed with water and 1 M HCl, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.1 g). LCMS m/z=390.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Li]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: [Li]c1ccccc1F
Solvent: C1CCOC1
Product: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (500 mg, 2.32 mmol, Example 3) was dissolved in anhydrous tetrahydrofuran (14 mL) and cooled to −78° C. A solution of 2-fluorophenyl lithium (4-6 equiv, freshly prepared following the same procedure as in Example 4) was added. The reaction was stirred at −78° C. for 1-3 hrs and quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The product was then purified on silica gel to give (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone as a white solid (445.5 mg, 77% yield). HRMS, observed: 250.0306, Calcd for M+: 250.0309.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:6]=1[CH:7]=[O:8])[CH:2]=[CH2:3].[BH4-].[Na+]>O>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:6]=1[CH2:7][OH:8])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1ccc(Br)cc1CO
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 2-allyloxy-5-bromobenzaldehyde (5.27 g, 21.9 mM) was treated with sodium borohydride, (0.415 g, 10.9 mM). The reaction was stirred at ambient temperature for 2½ hours, water was added and the solvent removed at reduced pressure. The residue was acidified to pH 1 and extracted with ethyl acetate twice. The organic layers were combined, dried (MgSO4) and evaporated to give 2-allyloxy-5-bromobenzyl alcohol (5.12 g, 96%) as a white solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][N:30]=1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([CH3:28])=[N:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cn1

Procedure:
The title compound, white solid (30 mg, 27%), MS (ISP) m/z=450.3 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 6-methyl-nicotinic acid.