Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=2)[O:14][CH:15]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:38])[CH3:37].O>ClCCl>[C:36]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:28])[CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH:25]([CH3:26])[CH3:27])[CH:17]=2)[O:14][CH:15]=1)(=[O:38])[CH3:37]
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3O)co2)cc1OC(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2nc(CCC(=O)c3ccccc3OC(C)=O)co2)cc1OC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 0.2 g quantity of the compound obtained in Example 223 and 0.1 ml of triethylamine were dissolved in 5 ml of dichloromethane, 0.1 ml of acetyl chloride was added to the obtained solution, and the mixture was stirred for 6 hours at room temperature. At the completion of the reaction, water was added to the reaction mixture, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed twice with water, and the solvent was distilled off. The residue was purified using a silica gel column (n-hexane:ethyl acetate=2:1), and the obtained crude crystals were recrystallized with ethanol, thereby yielding 15 mg of white powdery 2-{3-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-yl]propionyl}phenyl acetate.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:15]C)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.C1(=O)[O:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:15])[CH:9]=1
Reactant: O=C1CCCCO1
Reactant: COC(=O)c1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCO)c1cccnc1
Reaction time: 2 h
Yield: 54.8 %

Procedure:
A stirred solution of potassium tert-butoxide (83.55 g) in tetrahydrofuran (500 ml) under nitrogen at room temperature is treated with a solution of methyl nicotinate (68.5 g) and delta-valerolactone (75.0 g) in tetrahydrofuran (125 ml), continuously during 1 hour, maintaining the temperature between 22° C. and 32° C. The mixture is stirred for 2 hours and is then treated with water (750 ml). The resulting mixture is washed with xylene (125 ml) and the aqueous layer is then treated with concentrated hydrochloric acid (400 ml) during a period of 15 minutes, maintaining the temperature between 23° C. and 44° C. The solution is stirred for 90 minutes and then the solution is washed with dichloromethane (250 ml). The aqueous layer is basified to pH8-pH9 by treatment with aqueous sodium hydroxide solution (specific gravity 1.3; 480 ml) and then it is washed with xylene* (125 ml) and extracted with dichloromethane (3×250 ml). The combined dichloromethane extracts are dried over magnesium sulphate and the solvent is removed by evaporation under reduced pressure, to give 4-hydroxybutyl 3-pyridyl ketone (49.1 g), in the form of a yellow oil which crystallises to form a pale brown solid, m.p. 36°-38° C. [NMR (CDCl3): 1.7(m,2H), 1.9(m,2H), 3.1(t,2H); 3.7(t,2H), 7.4(m,1H), 8.2(dt,1H), 8.8(m,1H), 9.2(m,1H)].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)c2ccc(Br)cc2O1
Reactant: CC(C)(C)[Mg]Cl
Product: CC1(C)C=C(C(C)(C)C)c2ccc(Br)cc2O1

Procedure:
7-bromo-2,2-dimethyl-chroman-4-one (Compound 65, 1.8 g, 7 mmol) was treated by the procedure described immediately above (using t-butylmagnesium chloride) to produce the title compound as a clear oil: (500 mg, 25%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH2:21]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Yield: 95.5 %

Procedure:
6 ml of dimethylformamide was added to 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate and 3.17 g (19.1 mM) of ethyl p-hydroxybenzoate, followed by sufficient stirring. Into the resultant solution was added 0.77 g (19.3 mM) of sodium hydride (60%), followed by heat-refluxing for 7 hours. After the reaction, dimethylformamide was distilled off, followed by addition of water and extraction with ether. To the ether extract liquid was added anhydrous sodium sulfate for drying, followed by distilling-off of the ether and separation-purification by column chromatography (developer solvent: methylene chloride) to obtain 5.80 g (18.2 mM) of ethyl p-(10-undecenyl)oxybenzoate. Yield: 91.2%.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])=[O:8])[CH3:2].O.O.[OH-].[Li+].Cl>O1CCOCC1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])=[O:8])[CH3:34]
Reactant: CCN(CC)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of Example 299A (244 mg, 0.505 mmol) in dioxane (8 mL) and distilled water (4 mL) was treated with lithium hydroxide monohydrate (212 mg, 5.05 mmol), stirred at 60° C. overnight, cooled to room temperature, treated with 1N HCl, and extracted with ethyl acetate two times. The combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 470 (M+H)+; (ESI(−)) m/e 468 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.73 (br s, 1H), 9.10 (br s, 1H), 9.01 (t, 1H), 7.99 (t, 2H), 7.92 (dd, 1H), 7.84 (dd, 1H), 7.76 (dt, 1H), 7.70-7.45 (m, 5H), 3.65 (m, 4H), 3.25 (m, 4H), 1.24 (t, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](=[O:19])([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:9]([C:8]1[CH:11]=[C:16]([CH:13]=[CH:14][CH:7]=1)[O:19][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Yield: 188.6 %

Procedure:
m-Hydroxybenzaldehyde (12.2 g), N-(3-bromopropyl)phthalimide (26.8 g), anhydrous potassium carbonate (13.8 g) and potassium iodide (1.7 g) were suspended in acetonitrile (600 ml), and the suspension was heated under reflux for 18 hours. After cooling, the precipitate was removed, and the solvent was evaporated under reduced pressure. The residue was distributed between benzene and water. The organic layer was washed successively with a 1N aqueous NaOH solution, water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 29.16 g (yield 94%) of N-[3-(3-formylphenoxy)propyl]phthalimide as crystals.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:8](=[O:19])[N:7]([CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[C:23]#[N:24])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=2[N:3]=1.[NH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]([NH2:38])[CH2:32]1.C(N(CC)CC)C.O>CS(C)=O.ClCCl>[NH2:38][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][N:31]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:9]3[C:8](=[O:19])[N:7]([CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])[C:6](=[O:29])[N:5]([CH3:30])[C:4]=3[N:3]=2)[CH2:32]1
Reactant: Cn1c(=O)n(Cc2ccccc2C#N)c(=O)c2c1nc(Br)n2Cc1ccccc1Cl
Reactant: NC1CCCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(=O)n(Cc2ccccc2C#N)c(=O)c2c1nc(N1CCCCC(N)C1)n2Cc1ccccc1Cl
Reaction time: 5 h

Procedure:
2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile (75B) (250 mg, 0.5 mmol) and azepan-3-ylamine (294 mg, 2.5 mmol), and triethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO and the mixture was subjected to microwaves (method F, 100° C., 300 W) for five hours. To the reaction mixture was added 100 ml of water and 100 ml of dichloromethane, and the organic layer was separated and dried over sodium sulfate. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=8.77 min.). Evaporation of the solvent afforded the title compound as an yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:7][C:6]=3[S:5][C:4]=2[N:3]=1.Cl[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:28][O:27][C:25]([N:8]1[CH2:7][C:6]2[S:5][C:4]3[N:3]=[C:2]([CH3:1])[C:14]([C:15](=[O:17])[CH3:16])=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[C:11]=2[CH2:10][CH2:9]1)=[O:26]
Reactant: CC(=O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCNC3
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N1CCc2c(sc3nc(C)c(C(C)=O)c(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 394.3 %

Procedure:
To a stirred solution of 50 mg (0.15 mmol) 1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl)-ethanone (the preparation of which is described in example 23) in 5 ml dichloromethane was added 0.02 ml (0.022 mmol) methyl chloroformate and 32 mg (0.022 mmol) potassium carbonate. The mixture was stirred at RT for 1 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 1:1) afforded 33 mg (56%) 3-Acetyl-2-methyl-4-phenyl-5,8-dihydro-6H-9-thia-1,7-diaza-fluorene-7-carboxylic acid-methyl ester as a light yellow solid. ES-MS m/e (%): 381 (M+H+, 100);
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][C:12]=1[CH3:13])(=O)=O.O[C:21]1[CH:36]=[CH:35][C:24]([CH:25]=[C:26]([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:13][C:12]1[O:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:9][C:8]=1[CH2:7][CH2:6][O:5][C:21]1[CH:36]=[CH:35][C:24]([CH:25]=[C:26]([C:31]([O:33][CH3:34])=[O:32])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
2-(5-Methyl-2-phenyl-4-oxazolyl)ethyl methanesulfonate obtained in Example 4 (compound [7]; 24.4 g) and dimethyl 2-(4-hydroxybenzylidene)malonate obtained in Preparation Example 1 (compound [8]; 20.5 g) were mixed with tetrabutylammonium bromide (1.4 g) and toluene (210 mL). The mixture was heated to 90° C. and dissolved. Then potassium carbonate (13.2 g) was added and the mixture was stirred at 110° C. for 6 hr. The reaction mixed was ice-cooled and water (210 mL) was added, which was followed by stirring. After standing still, the aqueous layer was removed and 10% aqueous sodium chloride solution (210 mL) was added to the organic layer with stirring. The reaction mixture was allowed to stand and the aqueous layer was removed. The organic layer was concentrated and the concentrated residue was dissolved in methanol (150 mL) under heating. The reaction mixture was cooled to 10° C. or less and the reaction mixture was stirred for 1 hr. The obtained crystals were collected by filtration and washed with methanol (65 mL) to give the title compound (compound [9]; 31.1 g, yield 85.0%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1>CS(C)=O.[Cu]I>[Br:1][C:2]1[N:6]=[CH:5][N:4]([C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: Brc1nc[nH]n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Temperature: 100 °C
Yield: 56.2 %

Procedure:
To a 100 mL round bottomed flask, equipped with a stir bar, was added copper(I) iodide (0.397 g, 2.08 mmol), 3-bromo-1H-1,2,4-triazole (4.62 g, 31.2 mmol), and cesium carbonate (6.79 g, 20.83 mmol), as solids. These solids were diluted with anhydrous dimethyl sulfoxide (34.7 mL). Then 1-iodo-4-(trifluoromethoxy)benzene (1.65 mL, 10.4 mmol) was added as a liquid. The flask was placed under nitrogen atmosphere, and the suspension was heated to an internal temperature of 100° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®, washing with excess ethyl acetate (200 mL). The filtrate was poured into a brine solution (200 mL), and the layers were partitioned. The aqueous phase was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash column chromatography using 10-50% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (1.80 g, 54%): 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −57.06; ESIMS m/z 308, 310 ([M+H]+).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]([CH3:42])([CH3:41])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([OH:38])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[Si:51](OS(C(F)(F)F)(=O)=O)([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52]>C(Cl)Cl>[Si:1]([O:8][C@H:9]([C:27]([CH3:41])([CH3:42])[C:28](=[O:40])[C@H:29]([CH3:39])[C@@H:30]([O:38][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C@@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][CH:35]=[CH2:36])[CH2:10][C:11]([O:13][C@@H:14]([CH2:24][CH:25]=[CH2:26])/[C:15](/[CH3:23])=[CH:16]/[C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)=[O:12])([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCCC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)O[C@@H](CC=C)/C(C)=C/c1csc(C)n1)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of (3S,6R,7S,8S)-(S,E)-2-methyl-1-(2-methylthiazol-4-yl)hexa-1,5-dien-3-yl 3-((tert-butyldimethylsilyl)oxy)-7-hydroxy-4,4,6,8-tetramethyl-5-oxotridec-12-enoate (Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960-7973) in DCM at −50° C. was treated with 2,6-lutidine (1.82 mL, 15.7 mmol) followed by TBSOTf (3.60 mL, 15.7 mmol). The reaction mixture was stirred at the same temperature for 0.5 h, quenched by NH4Cl (sat.) and extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by chromatography on SiO2 (hexanes:ethyl ether=100:2 to 10:1) followed by the second chromatography (hexanes: diethyl ether=100:4 to 100:6 to 10:1) afforded 0.281 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13]>CC(O)=O>[Br:1][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([CH3:3])[C:5]=1[OH:13]
Reactant: BrBr
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(Br)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Br2 (122.2 g, 0.765 mol) was added into a solution of 2-methyl-4-nitrophenol (90.0 g, 0.588 mol) in HOAc (1.17 L) at room temperature. The resulting solution was stirred at room temperature for 4 h. TLC showed the reaction was complete. The solution was added into ice-water (3 L) slowly and filtered. The filter cake was dissolved into EA (2.5 L) and washed with saturated NaHSO3 (3×500 mL). The EtOAc layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2-bromo-6-methyl-4-nitrophenol (110 g, 80%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.30 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 6.22 (s, broad, 1H), 2.41 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[OH:12].CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Cl:11])[C:3]=1[O:12][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCc1cc(Cl)c(O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Temperature: 100 °C
Yield: 43.2 %

Procedure:
A mixture of 2,6-dichloro-4-(2-hydroxy-ethyl)-phenol (16) (12.5 g, 60.2 mmol) in N,N-dimethyl acetamide (28 mL) was treated with potassium tert-butoxide (6.5 g, 57.8 mmol) under nitrogen at room temperature. The suspension was heated to 100° C. and stirred until a solution formed. The reaction was then treated with 3,6-dichloro-4-isopropyl pyridazine (7) (9.2 g, 48 mmol) followed by a rinse with N,N-dimethyl acetamide (3 mL). The reaction mixture was stirred at 135° C. for 24 h. The reaction was cooled to room temperature, diluted with water (30 mL) and extracted with tert-butyl methyl ether (1×60 mL) followed by isopropyl acetate (1×60 mL). The organic layers were combined and were washed with a 1N aqueous sodium hydroxide solution (1×25 mL) and water (2×25 mL). The organic layer was separated and distilled to a volume of approximately 30 mL. This solution was treated with heptane (30 mL). The mixture was stirred under reflux for 30 min and then cooled to room temperature. The resulting solid was filtered, washed with ether and dried overnight to afford 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (17) (7.5 g, 44%) as a white solid; LRMS for C15H15Cl3N2O2 (M+H) m/z=363. Molecular Weight=361.6580; Exact Mass=360.0199
Reaction SMILES: O[C:2]1[CH:7]=CN=C[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:41][O:42][CH:43]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]CCC)[CH2:44][OH:45]>C1COCC1.N1C=CC=CC=1>[CH3:41][O:42][CH:43]([CH:46]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:3][CH2:2][CH3:7])[CH2:44][OH:45]
Reactant: Oc1ccncc1
Reactant: CCCCCCCCCCCCCCCCC(CO)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCC)C(CO)OC
Reaction time: 8 h
Yield: 199.7 %

Procedure:
Preparation of pyridine terminated 4-hexadecylethylene glycol monomethylether (Ligand 2). 4-hydroxypyridine (2.0 g, 22 mmol), triphenylphosphine (6.3 g, 24 mmol), and diisopropyl azodicarboxylate (4.8 g, 24 mmol) in THF (250 mL) were stirred at room temperature under nitrogen for 30 min.; hexadecylethylene glycol monomethylether (14.3 g, 20 mmol) was added, and the mixture was stirred overnight. THF was removed under vacuum, and the residue was purified by column chromatography eluting with chloroform:acetone:methanol mixtures to yield 2 (12.0 g, 78%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, aromatic), 6.82 (d, aromatic), 4.15 (t, pyr-O—CH2—CH2), 3.86 (t, pyr-O—CH2—CH2), 3.66 (br, CH2, 3.37 (s, CH3) ppm; 13C NMR (75 MHz, CDCl3) δ 164.7, 150.9, 110.2, 72.6, 71.8, 70.8, 70.4, 70.1, 67.1, 69.2, 58.9 ppm; HRMS calcd. 769.4441; Found M−H 768.4385.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4](OCC)=O.BrC[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:20][CH:19]=1.Cl>C(O)C.C(O)(=O)C>[C:2]([CH2:3][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH2:15][CH2:4][CH2:3][C:2]([OH:10])=[O:9])=[CH:23][CH:22]=1)([OH:10])=[O:9]
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)CCCCCc1ccc(CCCCCC(=O)O)cc1
Temperature: 0 °C
Yield: 68.9 %

Procedure:
First, 483 mg of metallic sodium was dissolved in 21 ml of absolute ethanol, and after adding dropwise 6.72 g of diethyl malonate under ice-cooling, the mixture was refluxed for 5 minutes. After cooling, a mixture of 3.48 g of 1,4-bis(4-bromobutyl)benzene and 1.12 g of diethyl malonate was added dropwise at a room temperature, and the mixture was refluxed for 50 minutes. To the resulting white suspension, after cooling, 21 ml of ice water was added. The mixture was adjusted to pH 7.0 with 1N hydrochloric acid, and evaporated under a reduced pressure to remove the ethanol. The aqueous layer was twice extracted with 50 ml of benzene, and the extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to remove the solvent, and then the remaining diethyl malonate at 140° C. To the colorless oil thus obtained were added 30 ml of acetic acid and 30 ml of concentrated hydrochloric acid, and the mixture was refluxed for 20 hours, and then cooled. The resulting crystal was filtered, washed with water and dried to obtain 2.11 g of the title compound as a colorless crystal.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C@H:17]([CH3:32])[CH2:16][CH2:15]3)[CH2:7]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C@H:17]([CH3:32])[CH2:16][CH2:15]3)[CH2:7]1)(=[S:42])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC[C@@H](C)N3C(=O)OCc2ccccc2)C(=O)O1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=S)NC[C@H]1CN(c2ccc3c(c2)CC[C@@H](C)N3C(=O)OCc2ccccc2)C(=O)O1

Procedure:
The product of EXAMPLE 14, Step 2 (1.0 g, 2.3 mmol) and Lawesson's Reagent (0.50 g, 1.3 mmol) are stirred in Toluene (20 mL) at reflux for 2 hours. Solvent is removed by evaporation and the residue is chromatographed on silica gel using 0-4% MeOH/CH2Cl2 eluant. The title compound is isolated as a white solid 1.0 g (97%); HRMS (FAB) calcd for C24H27N3O4S+H1 454.1800, found 454.1813.