Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:14]C(=O)OC(C)(C)C)=[O:13])[N:10]=[C:4]2[C:3]=1I.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].[F:71][C:72]1[C:73]([C:79]2[CH:84]=[C:83]([NH2:85])[C:82]([CH3:86])=[CH:81][N:80]=2)=[N:74][C:75]([CH3:78])=[CH:76][CH:77]=1>O1CCOCC1.O.CS(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH2:14])=[O:13])[N:10]=[C:4]2[C:3]=1[NH:85][C:83]1[C:82]([CH3:86])=[CH:81][N:80]=[C:79]([C:73]2[C:72]([F:71])=[CH:77][CH:76]=[C:75]([CH3:78])[N:74]=2)[CH:84]=1
Reactant: Cc1ccc(F)c(-c2cc(N)c(C)cn2)n1
Reactant: CC(C)(C)OC(=O)NC(=O)Cn1cc2ncc(F)c(I)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(F)c(-c2cc(Nc3c(F)cnc4cn(CC(N)=O)nc34)c(C)cn2)n1
Temperature: 110 °C

Procedure:
To a solution of tert-butyl 2-(6-fluoro-7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)acetylcarbamate (62 mg, 0.148 mmol) in dioxane (4 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.34 mg, 0.037 mmol), Pd2(dba)3 (33.8 mg, 0.037 mmol), sodium tert-butoxide (42.5 mg, 0.443 mmol), and 3′-fluoro-5,6′-dimethyl-2,2′-bipyridin-4-amine (35.3 mg, 0.162 mmol) and the mixture was heated at 110° C. for 3 hours. The solution was then cooled, diluted with water and extracted with EtOAc (3×75 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give a residue which was suspended in DMSO and purified by preparative HPLC using a gradient of 20-65% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to give the title compound. The title compound was combined with 1N HCl (4 mL) and lyophilized to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H), 2.60 (s, 3H) 3.43-3.58 (m, 1H) 3.61-3.79 (m, 1H) 7.29 (d, J=2.53 Hz, 1H) 7.35 (br. s., 1H) 7.53-7.65 (m, 1H) 7.71 (br. s., 1H) 7.82 (dd, J=11.12, 8.59 Hz, 1H) 8.52 (s, 1H) 8.76 (d, J=3.03 Hz, 1H) 8.87 (s, 1H) 10.14 (br. s., 1H). MS [M+H] found 410.4.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:7]([C:9](=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCOC(=O)CC#N
Reactant: CCC(=O)CC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(CC)CC
Reaction time: 48 h
Yield: 50.8 %

Procedure:
A mixture of 473 g (5.5 mol) of 3-pentanone, 565 g (5 mol) of ethyl cyanoacetate, 60 g (1 mol) of acetic acid, 38.5 g (0.5 mol) of ammonium acetate and 500 ml of toluene was stirred and heated under a Dean-Stark trap for 7 hr. and then allowed to stand for 2 days at room temperature. The reaction mixture was washed three times with 1 l of water and concentrated on the rotary evaporator at a low temperature. The residue was distilled in vacuum to give 460 g of ethyl 2-cyano-3,3-diethylacrylate, bp 118°-120°/8 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6](/[CH:7]=[N:8]/[C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[O:28][CH3:29]>CO>[OH:15][C@H:10]1[C@H:9](/[N:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH2:14][CH2:13][N:12]([C:27]([O:28][CH3:29])=[O:30])[CH2:11]1
Reactant: COC(=O)Cl
Reactant: COc1ccc(/C=N/[C@@H]2CCNC[C@H]2O)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC[C@@H](/N=C/c2ccc(OC)cc2)[C@H](O)C1
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of (3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (400 mg, 1.707 mmol) and DIPEA (0.447 mL, 2.56 mmol) in MeOH (50 mL) at 0° C. (ice bath) was treated with Methyl Chlorocarbonate (1 mL, 12.94 mmol). The reaction was stirred for 12 hour, and then the mixture was concentrated. The crude material was diluted with MeOH and applied on a SCX column (Phenomenex, Strata XC). The column was eluted with 2N ammonia in methanol and solvent removed to afford (3R,4R)-methyl 3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate (499 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[C:18](=[O:19])[CH:17]2[CH:12]([CH:13]3[O:20][CH:16]2[CH:15]=[CH:14]3)[C:11]1=[O:21].[F:22][C:23]([F:36])([F:35])[C:24]1[CH:29]=[C:28](Cl)[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[N:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])=O.[K+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu](I)I>[F:35][C:23]([F:22])([F:36])[C:24]1[CH:29]=[C:28]([CH:15]2[CH2:14][CH:13]3[O:20][CH:16]2[CH:17]2[CH:12]3[C:11](=[O:21])[CH:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[C:18]2=[O:19])[CH:27]=[C:26]([C:31]([F:32])([F:33])[F:34])[N:25]=1
Reactant: Cc1cc(C)c(C2C(=O)C3C4C=CC(O4)C3C2=O)c(C)c1
Reactant: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)n1
Agent: I[Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C2C(=O)C3C4CC(c5cc(C(F)(F)F)nc(C(F)(F)F)c5)C(O4)C3C2=O)c(C)c1
Temperature: 150 °C

Procedure:
A mixture of (1RS,2SR,6RS,7SR)-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-en-3,5-dione (400 mg, 1.4 mmol), 2,6-bis(trifluoromethyl)-4-chloropyridine (531 mg, 1.4 mmol), palladium acetate (16 mg, 0.07 mmol), 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl (67 mg, 0.14 mmol), potassium formate (353 mg, 4.2 mmol), tetrabutylammonium chloride (389 mg, 1.4 mmol) and copper iodide (53 mg, 0.28 mmol) in dry N,N-dimethylformamide (6 ml) are heated, at 150° C. for 30 minutes under microwave irradiation. Purification by preparative reverse-phase HPLC gives (1RS,2SR,6RS,7SR,8RS)-8-[2,6-bis(trifluoromethyl)pyridin-4-yl]-4-(2,4,6-trimethylphenyl)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH:7]=1)C.[OH:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[OH:22][CH2:23][C:24]1[CH:29]=[C:28]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:21])[CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1cccc(COc2ccc(I)cc2)c1
Reactant: OCc1cccc(B(O)O)c1
Product: O=C(O)Cc1cccc(COc2ccc(-c3cccc(CO)c3)cc2)c1

Procedure:
[3-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-phenyl]-acetic acid was prepared using general procedure 5 from [3-(4-iodo-phenoxymethyl)-phenyl]-acetic acid ethyl ester (of intermediate 4) and 3-(hydroxymethyl)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=349.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH2:11].[CH3:12][N:13]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18](=O)[C:17]=2[CH:16]=[CH:15][C:14]1=[O:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH:18]1[CH2:19][CH2:20][CH2:21][C:22]2[N:13]([CH3:12])[C:14](=[O:24])[CH:15]=[CH:16][C:17]1=2
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc(Cl)cc1Cl)CCC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 42 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)ethylamine (3.8 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (50 ml), with azeotropic removal of water, for 40 hrs. An additional 2.0 g of the amine was added and the mixture was refluxed for 36 hrs. The solution was cooled and concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in 50 ml of ethyl alcohol, and the mixture was stirred at room temperature for 1 hrs. The mixture was concentrated in vacuo, the residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate/hexanes provided 2.5 g (42%) of product, mp 102°-103° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:30]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([Br:30])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)-phenylacetate (490 mg, 1.2 mmol) obtained in Example 134, Step 2 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (220 mg, 1.2 mmol) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/1) to obtain methyl 3,5-bis(methoxymethoxy)-2-bromo-6-(4-methoxybenzoyl)phenylacetate (520 mg, 89%).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([C:10]2[C:11]([CH3:27])=[C:12]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>C(O)C.[Pt]=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:27])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: Cc1c(C=CCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(CCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 87.4 %

Procedure:
Hydrogen was passed through a solution of 6.3 g of the acid of Step A in 100 ml of ethanol in the presence of 120 mg of platinum oxide and after the absorption of 3.86 ml of hydrogen, the mixture was filtered. The filtrate was evaporated to dryness and the 6.3 g of raw product were dissolved in 10 ml of hot isopropyl ether to which 10 ml of petroleum ether were then added. The mixture stood at room temperature, was iced and vacuum filtered. The precipitate was washed with a 1:1 isopropyl ether-petroleum ether mixture and was dried under reduced pressure to obtain 5.535 g of 9-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-nonanoic acid melting at 64° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][CH:19]1[O:23][C:22](=[O:24])[CH:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[CH3:18][CH:19]1[O:23][CH:22]([OH:24])[CH:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1
Reactant: CC1CC(Oc2ccccc2)C(=O)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1CC(Oc2ccccc2)C(O)O1
Reaction time: 0.25 h
Yield: 101.6 %

Procedure:
13.5 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 3.8 g of 5-methyl-3-phenoxyoxolane-2-one in 40 mL of toluene at −78° C., and the obtained mixture was then stirred for 15 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and thereafter, 50 mL of a 20% potassium sodium tartrate aqueous solution was added to the mixture at room temperature. The thus obtained mixture was stirred for 1 hour, and the water layer was then removed. The water layer was extracted with 100 mL of ethyl acetate, and the combined organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure, so as to obtain 3.9 g of 5-methyl-3-phenoxyoxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: [CH2:1]([C:3]1([CH3:17])[CH2:8][CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[C:4]1=[O:16])[CH3:2].N>C1COCC1>[CH2:1]([C:3]1([CH3:17])[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCC1(C)CCCN(Cc2ccccc2)C1=O
Agent: N
Solvent: C1CCOC1
Product: CCC1(C)CCCNC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 221.1 %

Procedure:
Li metal (0.63 g, 90 mmol) was added to a well stirred solution of 3-ethyl-3-methyl-1-phenylmethyl-2-piperidinone (2.08 g, 9 mmol) in dry THF (27 mL) and then liquid NH3 (180 mL) was added slowly over a period of 5 min at -78° C. The cooling bath was removed and the reaction mixture stirred for 1 h in refluxing NH3. Then the reaction mixture was heated for 5-10 min at 60° C. to evaporate NH3 leaving a white residue which was treated carefully with water (50 mL) at 0° C., and the aqueous mixture extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo to give 2.81 g of a colorless viscous residue. Flash chromatography over silica gel (1% MeOH in CHCl3 -EtOAc, 1:1) afforded the lactam (1.10 g, 87% ) as a colorless solid: mp 67-69° C. (CH2Cl1-hexane).
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[OH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[C:18]([CH:17]1[CH2:4][CH:16]1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([OH:9])[CH:11]=1)(=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C(C=Cc1cccc(O)c1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C1CC1c1cccc(O)c1
Temperature: 15 °C
Yield: 99 %

Procedure:
To a 250 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 0.71 g (0.0178 moles) of 60% sodium hydroxide (oil suspension) and 50 mls of anhydrous DMSO. With stirring, under a nitrogen atmosphere, the trimethysulfoxonium iodide (3.9 g, 0.0178 moles) was added in one portion, and the reaction was stirred at ambient temperature for 30 minutes. The mixture was then cooled to 15° C., and a solution of 3-hydroxychalcone (2.0 g, 0.0089 moles) was added dropwide in 10 mls of DMSO. The reaction was stirred for 1 hour at 15° C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 100 mls of 0.1 N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 2.1 g of the title compound, 2-benzoyl-1-(3-hydroxyphenyl)cyclopropane, as a thick yellow oil. 100% crude yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH3:28])=[C:19]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:20]=2)=[CH:12][CH:11]=1>>[CH3:28][C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)=[N:20][C:19]=1[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Reactant: OB(O)c1cccs1
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 45 starting from 2-Thiophene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 339.1 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]([O:26]O)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][O:26][C:24](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1ccccc1
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
3 g (13 mmol) of 2-(tert-butoxycarbonyloxy)benzoic acid and 1.8 g (13 mmol) of benzenecarboperoxoic acid (prepared as described in Example 1-3) are dissolved in a diethyl ether/dichloromethane 6/4 mixture. The solution is cooled to 0° C. and then 2.6 g (13 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 50 ml of diethyl ether are added dropwise. After stirring at 0° C. for 3 hours, the reaction medium is filtered and then concentrated to dryness. The residue is purified by chromatography on silica gel eluted with a pentane/dichloromethane 4/6 mixture. 2.2 g of (2-(tert-butoxycarbonyloxy)benzoyl)benzoyl peroxide are obtained in the form of a white solid with a yield of 49%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([Br:12])=[C:7]([CH:11]=1)[CH2:8][OH:9]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CO)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Methoxy-2-bromobenzoic acid (85 g, 0.37 mol) is dissolved in anhydrous THF (100 mL) and cooled in an ice-salt bath until the temperature reaches −5° C. Borane-THF complex is added dropwise as a 1.0 M solution in THF (736 mL, 0.74 mol) at −5° C. After addition is complete, the reaction mixture is slowly warmed to room temperature and stirred for 12 hours. Water (40 mL) is slowly added dropwise and the reaction mixture stirred for 30 minutes. Additional water (350 mL) is added and the mixture is concentrated by rotary evaporator to remove most of the THF. The remaining material is extracted with EtOAc (800 mL). The organic layer is washed with saturated NaHCO3 (500 mL), brine (250 mL) and then dried (Na2SO4). Upon removal of the solvent by rotary evaporator, 5-methoxy-2-bromobenzyl alcohol is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])(=[O:25])=[O:24])=[C:18]([CH3:36])[CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1.[C:40](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH3:40])[S:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])(=[O:24])=[O:25])=[C:18]([CH3:36])[CH:17]=2)=[C:12]([CH:37]([CH3:39])[CH3:38])[O:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(S(=O)(=O)Nc2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc(S(=O)(=O)N(C)c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)c1

Procedure:
A solution of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)amino]sulfonyl}benzoate (32 mg, 56 μmol) in dimethylformamide (560 μL) was stirred with cesium carbonate (91 mg, 280 μmol) and methyl iodide (17.3 μL, 280 μmol) at 80° C. in a sealed vial. Water (2 mL) was added and the product was extracted with 50% ethyl acetate/hexanes. Yield=31 mg 94%) of methyl 3-{[(4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenyl)(methyl)amino]sulfonyl}benzoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][CH2:48][C:49](O)=[O:50].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([NH:16][C:49](=[O:50])[CH2:48][O:47][CH3:46])=[N:13][C:12]=2[CH3:17])=[CH:7][C:6]=1[C:18]([F:21])([F:20])[F:19])(=[O:3])=[O:4]
Reactant: COCC(=O)O
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(C(F)(F)F)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: COCC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Methanesulfonyl-3-trifluoromethyl-phenyl)-4-methyl-thiazol-2-ylamine (158a) (0.1 g, 0.3 mmol) is added to a solution of HATU (0.226 g, 0.6 mmol), methoxyacetic acid (0.046 ml, 0.6 mmol) and DIPEA (0.1 ml, 0.6 mmol) in DMF (7.5 ml). The reaction mixture was left to stir for 3 days at room temperature. The reaction mixture is filtered through basic alumina. The solvent is removed in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate-hexane (3:1) to give the titled compound.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(O[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)C=C.[OH-].[K+]>>[C:18]1([CH:19]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)=[O:10])[CH:21]=[CH:22][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCOc1ccc(C=O)cc1
Reactant: CC(=O)c1ccccc1O
Agent: [K+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General procedure for the synthesis of chalcone 32a-l: To a round-bottom flask was charged with 2′-hydroxyacetophenone 31 (1.0 equiv.), 4-allyloxybenzaldehyde (1.0 equiv.) and excess potassium hydroxide solution (3M solution in 96% EtOH). The mixture was stirred at room temperature for 16 h. When TLC indicated complete consumption of 2′-hydroxyacetophenone, the reaction mixture was acidified to pH 5 with 1 M HCl solution at ice-bath temperature. The mixture was continuously extracted with CH2Cl2 (30 mL×3). The combined organic layers were dried over MgSO4, filtered and evaporated under reduced pressure to give a crude mixture, which was washed with 5% ethyl acetate in hexane to furnish desired chalcone.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:30][C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[CH:30][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2cc(CNC(=O)C(F)(F)F)ccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)cc1OC
Yield: 29 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (1.20 g, 1.99 mmol), TFA (2 mL) and DCM (20 mL) to afford 0.280 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.78 (s, 3H), 3.85 (s, 3H), 4.46 (d, J=6.0 Hz, 2H), 7.51 (t, J=8.1 Hz, 1H), 7.65-7.68 (m, 3H), 7.78-7.84 (m, 2H), 10.09 (m, 1H), 12.70 (br s, 1H); MS (m/z): (M)+. 484.95.