Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([OH:31])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:2][CH3:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[C:33]([O:31][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)([CH3:40])[CH3:39])[CH3:38]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCc1cc(O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A mixture of 3-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/Dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ8.04 (dd, J 8.3 Hz, 2H) 7.67 (d, J 3.4 Hz, 1H), 7.65 (dd, J=6.8, 2.0 Hz,7.62 (d, J=2.9 Hz, 1H), 7.45 (t, J=6.6 Hz, 2H), 7.37 (t, J=7.8 Hz, 2H), 6.72-6.61 (m, 3H), 4.25 (q, J=7.1 Hz, 2H), 4.20 (t, J=6.6 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.48, (t, J=7 Hz, 1H), 2.38 (s, 3H), 1.53-1.48 (m, 8H), 1.25 (t, J=7 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); MS (FIA) m/e 528 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30]>C(Cl)(Cl)Cl.CO>[CH3:32][C:28]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH:7][C:5](=[O:6])[C:4]3[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=3[O:2][CH3:1])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1)([CH3:33])[C:29]([OH:31])=[O:30]
Reactant: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(Br)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(OC(C)(C)C(=O)O)cc2)cc1

Procedure:
0.5 gm (1.4 millimols) of 4-[2-(2-methoxy-benzamido)-ethyl]-4'-hydroxy-biphenyl were heated at 90°-130° C for 90 minutes with 0.025 gm of 2-bromo-2-methyl-propionic acid. The reaction product was isolated by chromatography on silicagel with chloroform/methanol (9:1) as the eluant. M.P. 133° C. M + H = 433;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.C(OC([N:28]1[C:36]2[N:31]([C:32](=[O:38])[N:33]=[C:34](Cl)[CH:35]=2)[CH2:30][C@@H:29]1[CH3:39])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)[CH2:19][O:20][C:34]1[CH:35]=[C:36]2[NH:28][C@@H:29]([CH3:39])[CH2:30][N:31]2[C:32](=[O:38])[N:33]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C(=O)OC(C)(C)C
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4ccnc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and (S)-tert-butyl-7-chloro-2-meth yl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:17])[C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:17])[C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OCC(O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3d (2.2 g, 1.0 equiv) and EtOH (11 mL) at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (304.1 mg, 0.8 equiv) in H2O (4 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed complete as determined by TLC. 1N HCl aqueous solution (32 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (200 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4d. The diastereomeric ratio of crude 4d was determined to be 72/28 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4d (2.20 g, 83% yield) as a yellow solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]2O.O=P(Cl)(Cl)[Cl:26]>>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([S:21][CH3:22])[N:15]=[C:14]2[Cl:26]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)c2cc(Br)ccc2n1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (0.65 ml, 3.69 mmol) was added to a suspension of 6-bromo-2-(methylthio)-quinazolin-4-ol (500 mg, 1.85 mmol) in POCl3 (6.5 ml). The reaction was heated at reflux for 6 hours and then cooled to room temperature. The POCl3 was removed under reduced pressure. The residue was diluted with EtOAc (30 ml) and poured onto ice. The organic layer was washed twice with brine (2×30 ml), then dried over sodium sulfate and concentrated. The product thus obtained was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10][C:11]([CH3:13])=[CH2:12].FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[C:11]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])([CH3:13])([CH3:12])[CH3:10]
Reactant: C=C(C)C
Reactant: OCc1ccccc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Oc1ccccc1CO
Temperature: -78 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
The procedure was adopted from the previously published literature (J. Org. Chem. 1986, 51, 113-114). To a flame-dried flask, 2-hydroxy benzyl alcohol (10 g, 80 mg) and 400 mL CH2Cl2 was added. The reaction mixture was cooled to −78° C. by use of a dry ice/acetone bath. Following the addition of liquefied 2-methylpropene (40 mL), trifluoromethanesulfonic acid (2 mL, 22 mmol) was added. The reaction mixture was stirred for 5 hr while maintaining the temperature at −78° C. The reaction was quenched with triethylamine and then allowed to warm to room temperature. The solvent was removed by distillation under reduced pressure and the oily product was triturated with 500 mL petroleum ether several times. Petroleum ether was then evaporated and the crude product was purified by silica gel column with the following eluents: 20% EtOAc/80% Hexane. The product was isolated as pale yellow oil (30% yield). 1H NMR (CDCl3) δ 7.286 (dd, 1H, Ar), 7.195 (ddd, 1H, Ar), 7.063 (d, 1H, Ar), 7.003 (ddd, 1H, Ar), 4.669 (s, 2H, —CH2—), 1.447 (s, 9H, —C(CH3)3—). Mass Spec.=180.24 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:28]=[CH:27][C:26]([C:29]([NH:15][CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[N:9][CH:10]=3)=[O:30])=[CH:25][C:24]2=[O:32])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2ccc(CN)cn2)ccn1
Reactant: O=C(O)c1ccn(-c2cccc(F)c2)c(=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc(CNC(=O)c3ccn(-c4cccc(F)c4)c(=O)c3)cn2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-methyl-[2,4′-bipyridin]-5-yl)methanamine 18-2 (14 mg, 0.07 mmol), 1-(3-fluorophenyl)-2-oxo-1,2-dihydropyridine-4-carboxylic acid 89-3 (16 mg, 0.07 mmol), and HATU (29 mg, 0.076 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.098 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and subjected to reverse phase preparative HPLC separation to yield 1-(3-fluorophenyl)-N-((2′-methyl-[2,4′-bipyridin]-5-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide 89. MS m/z 415.2 (M+1).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5](O)=[O:6].[NH2:14]C(N)=O>CO>[C:1]1(=[O:13])[NH:14][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: NC(N)=O
Solvent: CO
Product: O=C1Cc2ccccc2C(=O)N1
Temperature: 180 °C
Yield: 34.2 %

Procedure:
A mixture of homophthalic acid (200 g, 1.09 mol) and urea (80 g, 1.31 mol) was ground to a fine powder then heated at 175-185° C. until it had melted then resolidified. The mixture was cooled to ambient temperature, methanol (500 ml) was added, then the mixture was heated under reflux for 20 minutes, filtered, and allowed to cool to ambient temperature. The resulting solid was collected by filtration, washed with methanol and dried in vacuo to give homophthalimide (60 g, 34%) as a solid; m.pt. 235-240° C.; δH 4.0 (2H, s), 7.3-7.75 (3H, m), 8.10 (1H, d), 11.20 (1H, br s).
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH2:8][CH:3]([CH2:4][CH2:5][CH:6]=C)[O:2]1.CC[O:13]CC.I([O-])(=O)(=O)=O.[Na+].I([O-])(=O)(=O)=O>[Os](=O)(=O)(=O)=O.O>[CH2:1]1[CH2:10][O:9][CH2:8][CH:3]([CH2:4][CH2:5][CH:6]=[O:13])[O:2]1
Reactant: CCOCC
Reactant: C=CCCC1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=CCCC1COCCO1
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A mixture of 5-ethylenedioxy-1-hexene (6.0 g.), osmium tetroxide (0.5 g.), ether (150 ml.) and water (150 ml.) is treated portionwise with sodium metaperiodate (19.3 g.) so that the reaction temperature does not exceed 30°. After the addition of the periodate, a voluminous white solid precipitates out. The mixture is stirred 2.5 hrs. at room temperature, then filtered, and the solid portion is washed with more aqueous ether. The aqueous portion of the filtrate is separated and extracted with three portions of methylene chloride. The combined organic phases are dried with magnesium sulfate, filtered, and evaporated in vacuo. Distillation of the residue yields 4-ethylenedioxy-pentanal (65% yield) b.p. 56°-58°/10.5 m nmr (CDCl3) δ: 1.27 (s, CH3), 2.04-2.80 (m, --CH2 --CH2 --); 3.9 (s, --OCH2 --CH2 --O), 9.73 (t, O=C--H). IR (film) μ: 3.66; 3.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Mg].C(O[CH2:21][C:22]([F:34])=[CH:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]2([CH:23]=[C:22]([F:34])[CH2:21][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:4]=3)[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Yield: 0 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.5 g), tetrahydrofuran (2 ml) and magnesium (38.6 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-chlorophenyl)cyclopropane (Example 17) (0.34 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: Nitrile; solvent: methanol; flow rate: 2 ml/min) to afford 1-(4-chlorophenyl)-1-(2-fluoro-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)cyclopropane (0.11 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[C:6]([CH:10]=1)[C:7]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[O:27][CH3:26])=[O:8]
Reactant: O=C(Cl)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: COc1ccccc1CN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1CNC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
5-Bromo-2-(4-trifluoromethoxy-benzenesulfonylamino)-benzoyl chloride (5.124 g, 11.6 mmol) was dissolved in tetrahydrofuran (100 mL) and the mixture was cooled in an ice bath below 5° C. 2-Methoxy-benzyl amine (1.8 mL, 13.8 mmol, 1.2 equivalents) and triethyl amine (1.9 mL, 13.6 mmol, 1.2 equivalents) were added to the mixture keeping the temperature below 10° C. The mixture was warmed to room temperature and the solvent was removed to dryness. The residue was partitioned between aqueous HCl (1M, 50 mL) and ethyl acetate (100 mL). The organic solvent was collected and concentrated to dryness. The resulting solid was dissolved in ethyl acetate and the solvent removed (2×25 mL). The resulting mixture was purified by column chromatography on silica with an eluent of 20% ethyl acetate in hexane. The solid was suspended in a mixture of 5% ethyl acetate in hexane (90 mL). The mixture was centrifuged and the solid dried at 40° C. overnight in vacuum oven. Recovery=4.85 g (75% yield). M/Z of [M−H]−=557, 1H NMR (CDCl3) δ=3.85 (s, 3H), 4.5 (sd, 2H), 6.5–6.6 (1H), 6.9–7.05 (4H), 7.3–7.4 (2H), 7.45 (1H), 7.5 (1H), 7.6 (1H), 7.8 (2H), 10.8 (br, 1H).
Reaction SMILES: C[O-].[Na+].CS(C)=O.CO[C:10](=[O:24])[CH2:11][CH2:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[O:14]>C1(C)C=CC=CC=1>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:10](=[O:24])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: COCCOCCCCC(=O)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCCOCCCC1C(=O)CCC1=O
Yield: 82.5 %

Procedure:
In a 5 L 3-neck round bottom flask fitted with mechanical stirrer, a distillation system, a 2 L dropping funnel, and an argon inlet, was poured sodium methoxide solution (25 wt. % solution in methanol, 200 mL). Toluene (1.0 L) was added and methanol was removed off by distillation with an heating mantle. To the sodium methoxide suspension, methyl sulfoxide (13.4 mL, 0.4 eq) was added and a solution of 44 (121.0 g, 0.46 mol) in toluene (2.0 L) was slowly added over a period of 2 h. The distillation was continued during the addition and additional 30 minutes (until 0.5 L residual toluene). The reaction mixture was cooled and water (1 L) was added. Toluene was extracted and thrown away. The aqueous phase was acidified with 10% HCl until pH 1 and extracted with dichloromethane (4×800 mL). The combined organic phase was washed with brine, dried over magnesium sulfate, and rotary evaporated to give the cyclopentanedione 45 (81.3 g, 75%) as a brown heavy oil. 1H NMR (400 MHz, CD3OD) δ 2.42 (t, J=7.1 Hz, 2H), 2.51 (s, 4H), 3.38 (s, 3H), 3.55-3.61 (m, 4H), 3.67 (m, 2H), 4.68 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[Cl-].[CH:47]1([C:53]2([CH2:59][N:60]3[C:64]([CH3:66])([CH3:65])[CH2:63][O:62][C:61]3=[O:67])[CH2:58][CH2:57][NH2+:56][CH2:55][CH2:54]2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]2[C:14]([N:56]2[CH2:57][CH2:58][C:53]([CH2:59][N:60]3[C:64]([CH3:65])([CH3:66])[CH2:63][O:62][C:61]3=[O:67])([CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[CH2:54][CH2:55]2)=[O:16])=[CH:6][CH:7]=1
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CC[NH2+]CC1
Reactant: O=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@@H]2CC(=O)C[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 0.412 g (1.73 mmol) of the product of Step D dissolved in 6 mL of methylene chloride. To the reaction mixture was added 0.451 g (2.35 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.318 g (2.35 mmol) of 1-hydroxybenzotriazole, 0.518 μL (4.71 mmol) of N-methylmorpholine, followed by 0.520 g (1.57 mmol) of 4-cyclohexyl-4-[(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)methyl]piperidinium chloride. The resulting clear yellow solution was stirred at room temperature for 48 h, then was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The organic layer was separated, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, brine, then dried (Na2SO4), filtered and evaporated in vacuo. The residual oil was purified on a Biotage Flash 40i chromatography apparatus (40 g Flash 40S silica gel cartridge) eluted sequentially with hexane for 2 min, 30% ethyl acetate-hexanes for 2 min and finally 75% ethyl acetate-hexanes for 20 min. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: C([O:8][P:9]([O:12][CH2:13][C@@H:14]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:30]=[N:31][C:32]([NH:44][C:45](=[O:49])[NH:46][CH2:47][CH3:48])=[CH:33][C:34]=3[C:35]3[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=3)=[CH:26][N:27]=2)[C:22](=[O:50])[C:21]([C:51]([OH:53])=[O:52])=[CH:20]1)[CH2:15][CH:16]([CH3:18])[CH3:17])([OH:11])=[O:10])C1C=CC=CC=1.C[Si](Br)(C)C>ClCCl>[CH2:47]([NH:46][C:45]([NH:44][C:32]1[N:31]=[CH:30][C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[N:27][CH:26]=2)[N:19]([C@@H:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][O:12][P:9]([OH:11])([OH:10])=[O:8])[CH:20]=[C:21]([C:51]([OH:53])=[O:52])[C:22]3=[O:50])=[C:34]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[N:39]=2)[CH:33]=1)=[O:49])[CH3:48]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3[C@H](COP(=O)(O)OCc2ccccc2)CC(C)C)cn1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cnc3c(c2)c(=O)c(C(=O)O)cn3[C@H](COP(=O)(O)O)CC(C)C)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
1-[(2S)-1-{[(Benzyloxy)(hydroxy)phosphoryl]oxy}-4-methylpentan-2-yl]-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (Example 24, 700 mg, 0.90 mmol) was dissolved in dry dichloromethane (30 mL), then the reaction mixture was cooled to 0° C. Trimethylsilyl bromide (TMS-Br) (0.55 g, 3.61 mmol) was added and the mixture was stirred for 2 h at room temperature. A solid formed on the walls of the round bottom flask, and the solvent was decanted. The solid was washed with ethyl acetate (20 mL) then dissolved in methanol (20 mL) and water (50 mL) was added to precipitate a solid which was filtered and dried to give crude compound (380 mg). The crude compound was purified by preparative HPLC to afford 220 mg (25.9%) of 6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-1-[(2S)-4-methyl-1-(phosphonooxy)pentan-2-yl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[O:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:17])=[O:26]
Reactant: CN=C=O
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=O)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.40 g (6 mmol) of methylisocyanate are added and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete the precipitation, and the precipitate is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][C@H:26]([NH:34][C:35]([CH2:37][CH2:38][C@H:39]([NH2:43])[C:40]([OH:42])=[O:41])=[O:36])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(OC)=O.B(OC[C@@H](C(O)=O)N)(O)O>P([O-])([O-])([O-])=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]([S:24][CH2:25][C@@H:26]([NH:34][C:35]([CH2:37][CH2:38][C@H:39]([NH2:43])[C:40]([OH:42])=[O:41])=[O:36])[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[C@@H:16]([OH:23])[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SC[C@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)[C@@H](O)CCCC(=O)O
Agent: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)OC
Agent: N[C@@H](COB(O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Product: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H](SC[C@@H](NC(=O)CC[C@H](N)C(=O)O)C(=O)NCC(=O)O)[C@@H](O)CCCC(=O)O

Procedure:
LTC4 synthase prepared as a crude fraction from guinea pig lung was used. The test compounds7were tested in duplicate at a concentration of 300 μg/ml. The test compound and/or vehicle was incubated with 12 μg enzyme, 0.3 μg LTA4 methyl ester, 0.2% (w/w) albumin (to stabilize the product) and 4.5 mM serine borate (to prevent conversion of LTC4 to LTD4) in phosphate buffer pH 7.8 for 30 minutes at 37° C. The reaction was terminated by addition of ice-cold methanol. Formation of LTC4 was quantitated by RIA (radioimmunoassay).