Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([O:4][NH:5][C:6](=[C:9]1[C:14](=[O:15])[CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](C)(C)[CH2:11][C:10]1=[O:23])[CH2:7][CH3:8])[CH3:3].[C:24](Cl)(=[O:26])[CH3:25]>CC(C)=O>[C:24]([O:23][C:10]1[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14](=[O:15])[C:9]=1[C:6](=[N:5][O:4][CH2:2][CH3:3])[CH2:7][CH3:8])(=[O:26])[CH3:25]
Reactant: CCONC(CC)=C1C(=O)CC(C)(C)C(C(=O)OCC)C1=O
Reactant: CC(=O)Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(C)=O)CCC(C(=O)OCC)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium salt of 2-(1-ethoxyaminopropylidene)-4-ethoxycarbonyl-5,5-dimethylcyclohexane-1,3-dione (3.1 g) was suspended in 50 ml of acetone and acetylchloride (0.8 g) was added to it at room temperature. After stirring for 3 hours, the reaction mixture was poured into ice-water and extracted with chloroform. The extract was washed with one normal sodium hydroxide and dried over magnesium sulfate. The solvent was removed is vacuo and the desired product was obtained as an oily substance.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>>[OH:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][OH:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28]
Reactant: OCCNCCO
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN(CCO)CCO

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and diethanolamine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h then 60° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.83 (s, 1H), 8.76 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 4.30 (br, 2H), 3.95 (t, 2H), 3.90 (s, 3H), 3.39 (m, 4H), 2.56-2.36 (m, 6H), 1.74 (m, 2H), 1.38 (m, 4H), 1.28 (m, 2H); MS (ESI): 539.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([NH2:13])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([CH:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[C:18](OC)=[O:19])(=O)[CH3:15]>CC1C=CC=CC=1C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]3[N:13]=[C:14]([CH3:15])[C:17]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:18]([OH:19])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(-c2cccc(Cl)c2)n[nH]1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1O
Yield: 98.8 %

Procedure:
To a solution of 3-(3-chlorophenyl)-1H-pyrazol-5-amine (23 g, 119 mmol), dimethyl 2-acetylsuccinate (22.35 g, 119 mmol) in o-Xylene (200 mL) was added p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 2 h. The solid was filtered and washed with hexanes to afford (39 g, 99%) of the title compound. 1H NMR (500 MHz, METHANOL-d4) δ 8.14-7.95 (m, 1H), 7.93-7.79 (m, 1H), 7.51-7.27 (m, 2H), 6.62-6.35 (m, 1H), 3.72 (s, 3H), 3.67 (s, 2H), 2.39 (s, 3H).
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)(=O)=O)CC#C.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)C=C[CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:16]([N:22]1[CH2:27][CH2:26][N:25]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:24][CH2:23]1)[CH2:17][C:18]#[CH:19]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCN1CCN(c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
A mixture of but-3-ynyl-p-toluenesulfonate (8.97 g), 1-phenylpiperazine (6.49 g) and sodium bicarbonate (3.7 g) in dimethylformamide (100 mL) is stirred at 80° C. for 14 hours. The solvent is evaporated and the residue dissolved in dichloromethane, washed with water and dried over MgSO4. The solution is filtered through silica gel and the product eluted with 10% ethyl acetate/hexanes to give 6.76 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.[OH-].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH:12]([O:15][CH3:16])[O:11][CH3:10])=[C:4]([CH3:9])[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Cc1cc(Br)ccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(COc1ccc(Br)cc1C)OC

Procedure:
A mixture of 4-bromo-2-methylphenol (5 g), bromoacetaldehyde dimethyl acetal (3.8 ml) and potassium hydroxide (3.0 g) in dimethylsulphoxide (15 ml) was heated to reflux for 21/2 h. Water (50 ml) was added to the cooled mixture which was then extracted with ether (4×50 ml). The extracts were washed with 5N sodium hydroxide (50 ml) and brine (50 ml), dried (MgSO4), then evaporated in vacuo to give the title compound as a brown oil (6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH2:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1.[N:42]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:41])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([CH:24]4[CH2:29][O:28][CH2:27][CH2:26][N:25]4[C:30](=[O:39])[CH:31]([NH:38][C:48]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:49])[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][N:10]([CH3:40])[N:9]=2)[CH:7]=1
Reactant: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(N)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(C#Cc2ccc(NC(=O)C3COCCN3C(=O)C(NC(=O)N3CCOCC3)c3ccccc3)cc2)c(-c2cc(Cl)ccc2O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of compound 9D in anhydrous CH2Cl2 were slowly added 4-morpholinecarbonyl chloride (14D, 1.2 eq) and triethylamine (1.5 eq), successively. The reaction mixture was stirred at rt overnight. It was concentrated to small volume and purified with silica column chromatography eluting with dichloromethane/EtOAc to give the title compound (15D) which was recrystallized from hexanes/acetone to provide compound 15D as white powder in ˜60% yield. 1H NMR (CDCl3, 500 MHz) δ 10.67 (s, 1H), 8.93 (s, 1H), 8.70 (s, 1H), 7.93 (d, 2H, J=7.5 Hz), 7.63 (s, 1H), 7.55 (d, 2H, J=7.5 Hz), 7.45 (s, 5H), 7.19 (d, 1H, J=8.0 Hz), 6.97 (d, 1H, J=8.0 Hz), 5.60 (d, 1H, J=6.5 Hz), 5.28 (s, 1H), 5.18 (d, 1H, J=6.5 Hz), 4.86 (d, 1H, J=12.0 Hz), 3.97 (s, 3H), 3.83 (m, 4H), 3.70 (br s, 4H), 3.45 (m, 2H), 3.37 (m, 2H), 3.17 (m, 1H). LCMS (ESI) m/z 705.43 (MNa+), 683.39 (MH+). HPLC: tR=4.95 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:32](O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:22][C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:23])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(OCc1ccccc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and benzyl alcohol. Colorless crystals (278 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].Cl.Cl[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:15][C:16]1[CH:21]=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: COc1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C=O)ccc1OCc1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (2.75 g, 16.55 mmol) in acetonitrile (75 mL) was added 5-(chloromethyl)-2-methoxypyridine hydrochloride (3.37 g, 17.38 mmol) and potassium carbonate (9.15 g, 66.20 mmol). The mixture was heated to reflux. After 3 h, the yellow mixture was allowed to cool to room temperature and was diluted with water (400 mL), resulting in the formation of a precipitate. The solids were isolated by filtration and washed with water (50 mL). The filtrate was extracted with chloroform (2×100 mL). The organic phases were combined with the previously isolated solids. The resulting solution was dried over magnesium sulfate, filtered, and concentrated to provide 3.40 g (72%) of 3-ethoxy-4-((6-methoxypyridin-3-yl)methoxy)benzaldehyde as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][C:5]2([CH3:13])[CH3:12].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]2[CH2:25][CH2:24][C@H:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22]2)[CH:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:15]1[CH:16]=[N:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]3)[CH:20]=1)[C:5]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(c2cncc(Br)c2)C1
Reactant: CC1(C)NC(=O)c2ccc(Cl)cc21
Product: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(N2CC[C@H](O)C2)c1

Procedure:
In analogy to the procedure described for the preparation of example 137, 5-chloro-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12), 3-bromo-5-[(S)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridine was used (step C) to yield the title compound as a white solid. MS: 358.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](=[S:17])[NH2:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](=O)[CH2:28]Br)=[CH:25][CH:24]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]3[S:17][CH:28]=[C:27]([C:26]4[CH:31]=[CH:32][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[N:16]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: NC(=S)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CO
Product: COc1ccc(-c2csc(-c3cc4c(Nc5cccc(Cl)c5)ncnc4[nH]3)n2)cc1
Reaction time: 17 h

Procedure:
57.5 mg (0.19 mmol) of 4-(3-chloroanilino)-6-(thiocarbamoyl)-7H-pyrrolo[2,3-d]pyrimidine (see Example 10) in 3 ml of methanol and 57.3 mg (0.25 mmol) of 4-methoxyphenacyl bromide are heated to boiling for 17 h. Cooling of the pale yellow suspension, filtering and washing with isopropanol/diethyl ether yields 4-(3-chloroanilino)-6-[4-(4-methoxyphenyl)thiazol-2-yl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=15.4; TLC-Rf=0.33 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=434.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>>[O:29]1[CH2:28][CH:27]1[CH2:25][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nc(-c2ccc(O)cc2)n1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C(F)(F)F)nc(-c2ccc(OCC3CO3)cc2)n1
Reaction time: 1.5 h

Procedure:
The mixture of 17.0 g of 2-(4-hydroxyphenyl)-4-methyl-6-(trifluoromethyl)-pyrimidine, 23.1 g of potassium carbonate and 135 ml of epichlorohydrin is stirred at a temperature of 130° for 1.5 hours, then filtered with suction while hot; the filter residue is subsequently washed with methylene chloride and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallised from isopropanol and yields 2-[4-(2,3-epoxypropoxy)-phenyl]-4-methyl-6-(trifluoromethyl)pyrimidine having a melting point of 97°-99°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:1][C:2]1[C:3]([NH:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[S:27]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of methyl 3-amino-2-[(3-hydroxypropyl)amino]benzoate (1.00 g, 4.46 mmol) in tetrahydrofuran (12 mL) was added 2,4-dichlorophenyl isothiocyanate (910 mg, 4.46 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated and the residue was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a brown solid (1.87 g, 4.37 mmol, 98%).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:26]=[CH:27][C:28]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[CH2:16]([C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]#[N:39])=[CH:32][C:31]=2[CH2:40][CH:41]([CH3:43])[CH3:42])[CH:26]=[CH:27][C:28]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2ccccc2)c1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
0.10 ml (0.59 mmol, 1.8 eqv) triflic anhydride was added to a solution of 116.8 mg (0.32 mmol) 3-(3′-Benzyl-4′-hydroxy-2-Isobutyl-1,1′-biphenyl-4-yl)propanenitrile (25) in 5 ml pyridine at 0° C. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 18 h. After that, water was added and the mixture was extracted with Et2O. The comb. org. fractions were washed with brine, dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (1+1)) yielded 136.9 mg (0.27 mmol, 85%) 26 as a pale violet solid: Rf (Hexanes/EtOAc (1+1)) 0.59, 1H NMR (500 MHz, CDCl3) δ 0.64 (d, 6H, J=6.62 Hz), 1.51 (m, 1H), 2.31 (d, 2H, J=7.25 Hz), 2.61 (t, 2H, J=7.41 Hz), 2.93 (t, 2H, J=7.41 Hz), 4.07 (s, 2H), 7.03-7.08 (m, 4H), 7.13-7.21 (m, 4H), 7.24-7.31 (m, 3H); LRMS (EI) m/z 503 (10), 502 (36), 501 (100), 369 (17), 368 (45), 326 (14), 91 (43); HRMS (EI) Calcd. for C27H26F3NO3S: 501.158551. Found: 501.158983.
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:19]C.O>C(Cl)Cl>[OH:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:6]=1[OH:5])[C:10]([OH:12])=[O:11]
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 69.7 %

Procedure:
Boron tribromide (392 μL, 4.15 mmol) was added to a suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 1.66 mmol) in DCM (10 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 70 h. The reaction mixture was cautiously added to stirring iced water (50 mL) and stirred for 10 min. The product was extracted with DCM (2×20 mL), and then the combined organic extracts were washed with brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica chromatography (12 g, 0-10% MeOH in DCM) to afford 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5) (257 mg, 68%) as a white solid: m/z 221 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.83 (1H, br s), 10.45 (2H, br d), 7.56 (2H, dd).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[CH2:21](O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: OCCc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride dispersion in mineral oil (0. 175 g) and stirred for 15 minutes. The mesylate of phenethyl alcohol (1.28 g) was added and the mixture was stirred and heated under argon at 60° C. overnight. The cooled mixture was treated with glacial acetic acid (3 drops) and the volatiles were removed under vacuum. The residue was mixed with water, the product was extracted with diethyl ether (3×50 mL) and the organic layers were washed in turn with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloromethane-hexane; 3: 1) to provide 0.4 g of 4-[(2-phenylethyl)oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][OH:33])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.2 g) was dissolved in 25 ml of ethyl acetate, to which 0.29 ml of methanesulfonyl chloride and 0.53 ml of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (15 ml×2) and 15 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1). The desired fraction was concentrated and the residue was recrystallized from a mixture of 5 ml of diisopropyl ether and 10 ml of hexane to give 1.26 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[C:24]([O:28][C:29](=[O:64])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([OH:63])/[CH:38]=[CH:39]/[C@H:40]([O:55][Si](C(C)(C)C)(C)C)[C@@H:41]([O:47][Si](C(C)(C)C)(C)C)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([CH3:27])([CH3:26])[CH3:25]>O>[C:24]([O:28][C:29](=[O:64])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]([OH:63])/[CH:38]=[CH:39]/[C@H:40]([OH:55])[C@@H:41]([OH:47])[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])([CH3:25])([CH3:26])[CH3:27]
Reactant: CCCCC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC[C@H](O)[C@@H](O)/C=C/[C@@H](O)CCCCCCCC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.42 h

Procedure:
Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 420 μL, 0.416 mmol) was added to a tetrahydrofuran solution (500 μL) of (9S,12S,13S)-(E)-12,13-di-tert-butyldimethylsiloxy-9-hydroxy-10-octadecaenoic acid t-butyl ester (12) (11.6 mg, 0.189 mmol) at room temperature, and the mixture was stirred for 3 hours and 25 minutes. The temperature of the reaction solution was raised to 70° C., and the solution was stirred for 1 hour and 30 minutes. The temperature of the reaction solution was returned to room temperature, water (1 mL) was added, the mixture was extracted with chloroform (5 mL) three times, and the organic layer was washed with saturated brine (5 mL) dried over sodium sulfate, and concentrated. The resulting colorless oily crude product (20 mg) was separated and purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to obtain (9S,12S,13S)-(E)-9,12,13-trihydroxy-10-octadecaenoic acid t-butyl ester (13) as a colorless oily substance (6.5 mg, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41](Cl)=[O:42].C(=O)(O)[O-].[Na+]>ClCCl>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[C:41]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]=2)=[CH:22][CH:23]=1)=[O:42]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Yield: 89.9 %

Procedure:
630 mg (2.04 mmol) ethyl 2-[3-(4-aminobenzyl)-1H-indazol-1-yl]acetate was dissolved in 20 mL dichloromethane. 0.85 mL (6.11 mmol) triethylamine was added, and in an ice bath a dichloromethane solution dissolving 428 mg (2.25 mmol) 2-naphthoyl chloride was added slowly, and reacted in an ice bath for 3 h. An aqueous solution of sodium bicarbonate was added to quench, extracted with ethyl acetate, rotate evaporated to dryness, chromatographed on a column to obtain a white solid 850 mg, at a yield of 89.7%.