Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=O)=[CH:39][C:38]=1[C:46]([F:49])([F:48])[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(O)C.CN(C=O)C.[Pd]>[F:21][C:18]([F:19])([F:20])[C:17]([N:16]([CH2:15][C:11]1([OH:14])[CH2:10][CH2:9][N:8]([C:41](=[O:43])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH3:35])=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[CH2:13][CH2:12]1)[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)CCN(CC1(O)CCN(Cc2ccccc2)CC1)C(=O)C(F)(F)F
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Agent: [Pd]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCC(O)(CN(CCC(C)C)C(=O)C(F)(F)F)CC2)cc1C(F)(F)F
Reaction time: 16 h
Yield: 56.7 %

Procedure:
Palladium (50.8 mg, 0.48 mmol) 10% on activated carbon and N-[(1-benzyl-4-hydroxy-4-piperidyl)methyl]-2,2,2-trifluoro-N-isopentyl-acetamide (112 mg, 0.29 mmol) in propan-2-ol (3 mL) was stirred under an atmosphere of hydrogen for 18 hours. The catalyst was filtered through Celite® and washed with MeOH. The organics were concentrated in vacuo to provide a clear oil. To the oil was added DMF (2 mL) and triethylamine (40 μL, 0.29 mmol) and this solution was added dropwise to a solution 4-methoxy-3-(trifluoromethyl)benzoic acid (64 mg, 0.29 mmol) and HATU (110 mg, 0.29 mmol) in DMF (1 mL). The reaction mixture was stirred for 16 hours. The solution was partitioned between water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in MeOH and purified by reverse phase HPLC (Gilson 20-99% water/MeOH) to give 2,2,2-trifluoro-N-[[4-hydroxy-1-[4-methoxy-3-(trifluoromethyl)benzoyl]-4-piperidyl]methyl]-N-isopentyl-acetamide (82 mg, 56%). ESI-MS m/z calc. 498.5. found 499.5 (M+1)+; Retention time: 1.86 minutes (3 min run).
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: C1CCOC1
Solvent: CSC
Product: CCC1(CC(=O)OC)CCC(c2ccccc2)CC1=O
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one (X) prepared by the process of Example 1, Step (c) (61.1 mmol, 12.0 g), CuBr.Me2S (6.11 mmol, 1.256 g) and Me2S (12.3 ml) were stirred in 85 ml of dry THF at -40° C. under nitrogen and treated with 61.1 mmol (20.4 ml of 3M in THF), of PhMgBr added dropwise over 30 minutes. The reaction was then quenched with 250 ml of 1M HCl (aq.) and extracted with 4×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 11.87 g (43.3 mmol, 71%) of product. The two diastereomers were separated by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associates, Milford, Ma., affording 4.8 g of each isomer, designated "less polar isomer" and "more polar isomer."
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9]I)[C:4]#[N:5].CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CC(C)=O>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][CH2:9][N:31]1[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:37])[C:4]#[N:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O
Agent: [K]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#CC(CF)(CCCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-6-iodo-hexanenitrile (9.0 g, 22.5 mmol), dry DMF (30 ml), and potassium phthalimide (4.2 g, 1 equivalent) is stirred and heated at 80° C. for 4 hours. The DMF is removed under reduced pressure (0.1 mm Hg), and the residue is taken up in chloroform. The chloroform mixture is filtered, and the filtrate is washed with 2 N NaOH, 2 N HCl, and water. Evaporation of solvent gives a residue which, when dissolved in the minimum amount of acetone, crystallizes upon addition of ether. After standing at 5° C. overnight, the colourless crystals are collected (7.0 g), mp (Kofler) 136° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:14])[N:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][N:5]1[C:4](=[O:14])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[NH:7][C:6]1=[O:12]
Reactant: C#C[Si](C)(C)C
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)[nH]c2cccc(C#C[Si](C)(C)C)c2c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
To a degassed solution of 5-bromo-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline (1.0 g, 4.0 mmol) in 20 ml of DMF and 20 ml of triethylamine was added trimethylsilylacetylene (1.6 ml, 12 mmol), 50 mg of triphenylphosphine, 20 mg of palladium(II)acetate, and 1 mg of cuprous(I)iodide. The mixture was stirred under nitrogen, at 70° C. After 7 h additionally 0.4 ml of trimethylsilylacetylene was added and heating continued for 4 h. Then the mixture was evaporated in vacuo and the residue extracted with 100 ml of dichloromethane and 100 ml of water. The organic layer was washed twice with 100 ml of water, dried over anhydrous sodium sulfate, treated with charcoal, filtered through a pad of celite, and evaporated. The residue was triturated with ether/petroleum ether (1:1) and filtered off and dried giving 0.50 g (46%) of 1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-5-trimethylsilylethynyl-quinazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH2:16])[CH2:7][O:8]2.C(N(CC)CC)C.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][NH:16][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH2:7][O:8]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCN(CCN)C1COc2cccc(OC)c2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CCNS(=O)(=O)c1ccc(C)cc1)C1COc2cccc(OC)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
4 mmol of the compound prepared in Example 14 are dissolved in 30 ml of dichloromethane cooled in ice. 11.4 mmol of triethylamine are added dropwise, followed by 4 mmol of tosyl chloride dissolved in dichloromethane. The mixture is left stirring for 30 minutes at room temperature. The solvent is then evaporated off and the expected product is obtained after purification by chromatography on a silica column (elution solvent: dichloromethane).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C@@H:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([CH2:20][NH:21][CH3:22])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[CH3:34][O:35][C:36](=[O:40])[CH:37](Br)[CH3:38]>O>[CH3:34][O:35][C:36](=[O:40])[CH:37]([N:21]([CH3:22])[CH2:20][C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=2)[C@H:10]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:38]
Reactant: COC(=O)C(C)Br
Reactant: CNC[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)N(C)C[C@H]1CCc2cc(OC)ccc2[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of cis-6-methoxy-2-methylaminomethyl-1-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride (1.00 g; prepared according to the procedures in Process 1), cesium carbonate (5.13 g) and N,N-dimethylformamide (20 cm3) was added methyl-2-bromopropionate (0.35 cm3) and the resultant mixture was stirred at 75° C. for 5 h. The reaction was then allowed to cool to room temperature and water (100 cm3) was added. The resulting mixture was extracted with diethyl ether (2×100 cm3) and the combined organic extracts were washed with water (100 cm3), dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product (1.11 g) was purified by column chromatography [basic alumina, eluting with toluene-hexane (1:1)] to afford the title compound as a gum (284 mg); positive ion ESI (M+H)+ 368.4.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]([F:32])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1ncccc1Br
Reactant: CC1(C)OB(c2ccc(C(F)(F)c3ccccc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(C(F)(F)c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (19.4 mg) was added to a mixture of 1-bromo-4-(difluoro(phenyl)methyl)benzene (376 mg), potassium acetate (391 mg) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (506 mg) in DME (10 mL) and DMSO (0.5 ml). The mixture was stirred at 80° C. under nitrogen overnight. Activated-carbon powder was added and the mixture was stirred for 5 min. The insoluble material was removed by filtration. The filtrate was concentrated in vacuo to give a brown oil of 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (38.4 mg) was added to a suspension of 3-bromopyridin-2-amine (192 mg), the prepared 2-(4-(difluoro(phenyl)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and sodium carbonate decahydrate (634 mg) in DME (10 mL) and water (2 mL) and the mixture was stirred at 80° C. under nitrogen for 3 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (291 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[I:10]I.[OH-].[K+]>>[I:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: c1ccc2[nH]ncc2c1
Agent: [K+]
Agent: [OH-]
Product: Ic1n[nH]c2ccccc12

Procedure:
An additional approach to compounds such as x is outlined in Scheme 4. Treatment of an appropriate alcohol R5—OH and a base such as NaH and the like, followed by addition of xvii will provide the ether xviii. The bromide xviii can be converted into the methylated intermediate xix via palladium-mediated cross coupling with Me3B3O3 and the like. The nitro derivative xix can be treated with Pd/C in the presence of HCOONH4 to produce the amine xx. The amine xx can be acylated to provide xxi. The acylated amine xxi can be treated with iso-amyl nitrate in the presence of Ac2O/KOAc and the like to provide the N-acyl indazole xxii. Compounds such as xxii can be treated with ammonia and the like to produce indazoles xxi. The indazole xxi can be treated with iodine and KOH and the like to provide the iodo-indazole xxii. The indazole nitrogen can be protected with trityl chloride and base and the like to provide xxiii. The iodo-indazole xxiii can be converted into xxiv via cross coupling using the appropriate boronic acid and the like and an appropriate palladium catalyst. The chloro-pyridine xxiv can be converted into examples such as x using the appropriate amine (HN(R2)R3), palladium catalyst, and ligand followed by deprotection of the trityl group using standard conditions.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(Cl)(Cl)Cl.C(O)C>[OH:27][C@@H:13]1[C@@:12]2([CH3:28])[C@@H:11]([CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C@H:16]2[C@@H:15]([C@:20]3([CH3:26])[C@H:19]([CH2:18][CH2:17]2)[CH2:24][C:23](=[O:25])[CH2:22][CH2:21]3)[CH2:14]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 25.9 %

Procedure:
The above mixture of oxidation products of deoxycholic acid (310 mg) resulted from the eluate of chloroform-ethanol (97:3, v/v) was dissolved in a small amount of chloroform-ethanol (99:1, v/v) and the solution was absorbed on silica gel (20 g) column. The column was eluted with chloroform-ethanol (98:2, v/v) and then with chloroform-ethanol (97:3, v/v). Each 10 ml portions of the eluate was collected in a fraction tube. Fractions which showed a corresponding single spot by thin layer chromatography were combined and the solvent was distilled off by a rotary evaporator. As the results, 12α-hydroxy-3-keto-5β-cholanic acid (80 mg) was obtained from the first half of the fractions eluted with chloroform-ethanol (98:2, v/v) and 12α-hydroxy-3-keto-4-cholenic acid (10 mg) was obtained from the latter half thereof. 12α-Hydroxy-3-keto-5β-pregnan-20α-carboxylic acid (5 mg) was obtained from the first half of the fractions eluted with chloroform-ethanol (97:3, v/v) and 12α-hydroxy-3-keto-chola-1,4 -dienic acid (10 mg) was obtained from the latter half thereof.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N1C=CC=CC=1.N[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C.[Cu](F)F>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccccc1
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 84 %

Procedure:
The process of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride in a mixture of 100 mL of acetonitrile/20 mL of pyridine and 4.65 g (50 mmol) of aniline in 10 mL of acetonitrile at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 4.9 g of the title compound as a colorless oil in 84.5% yield.
Reaction SMILES: C1([C:7](=[N:14]CCCO)C2C=CC=CC=2)C=CC=CC=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.[Cl:52][C:53]1[CH:54]=[C:55]([N:60]2[C:64](=[O:65])[O:63][N:62]=[C:61]2[C:66]2[C:67]([NH:71][C:72](=O)[C:73](F)(F)F)=[N:68][O:69][N:70]=2)[CH:56]=[CH:57][C:58]=1[F:59].[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81]>O1CCCC1>[F:78][C:79]([F:84])([F:83])[C:80]([OH:82])=[O:81].[NH2:14][CH2:7][CH2:73][CH2:72][NH:71][C:67]1[C:66]([C:61]2[N:60]([C:55]3[CH:56]=[CH:57][C:58]([F:59])=[C:53]([Cl:52])[CH:54]=3)[C:64](=[O:65])[O:63][N:62]=2)=[N:70][O:69][N:68]=1
Reactant: OCCCN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NCCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
A solution of 3-[(diphenylmethylene)amino]propan-1-ol (80 mg, 0.33 mmol) and triphenylphosphine (93 mg, 0.36 mmol) in tetrahydrofuran (1 mL) at 0° C. was treated with diisopropyl azodicarboxylate (75 μL, 0.38 mmol) dropwise. The reaction mixture was stirred at 0° C. for 15 min, treated with a solution of N-{4-[4-(3-chloro-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-2,2,2-trifluoroacetamide (100 mg, 0.25 mmol) in tetrahydrofuran (0.5 mL), and stirred at 25° C. for 16 h. The reaction mixture was treated with trifluoroacetic acid (1 mL), stirred at 25° C. for 3 h, and concentrated to a crude residue. This material was purified by preparative LCMS to give the desired product (18 mg, 15%). LCMS for C13H13ClFN6O3 (M+H)+: m/z=355.1
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([F:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(C1C=CC(C(N)=S)=CC=1)(C)C.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[C:9]([F:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)c(F)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH:12]([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>C1(C)C=CC=CC=1>[CH:12]([C:3]1[CH:4]=[C:5]([Br:11])[CH:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=1[CH:23]=[O:24])([CH3:14])[CH3:13]
Reactant: CC(C)c1cc(Br)cc(C(C)C)c1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)c1cc(Br)cc(C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 150 mL of dry toluene solution of 1-iodo-2,6-diisopropyl-4-bromobenzene (17.6 g, 0.048 mol) was treated with n-BuLi (1.6 M in hexane, 75 mL) at −78° C. in 30 minutes. After stirring for 15 minutes, dry DMF (20 mL) in 50 mL of toluene was added dropwise. The resulting mixture was slowly warmed up to room temperature. After regular work up, the crude product was distilled at 140° C. under vacuum to afford 2,6-diisopropyl-4-bromobenzaldehyde (11.5 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Cl:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][CH2:24][CH2:23][CH2:22][Cl:21])(=[O:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1OCCCCl
Temperature: 25 °C
Yield: 78.8 %

Procedure:
A stirred mixture of 1-[3-acetylamino-4-hydroxyphenyl]ethanone (7.7 g, 40 mmol), K2CO3 (5.7 g), 3-chloro-1-bromopropane (8.9 g, 56 mmol) and acetone (100 ml) was refluxed for 16 hours. The reaction was allowed to cool to ambient temperature and filtered. Concentration of the filtrate yielded 8.5 g of a white solid. The solid was recrystallized from toluene and then from ethanol to afford 6.5 g of an off-white solid. A 3.3 g sample of this material was flash chromatographed on silica gel with ethyl acetate as eluent. Concentration of the appropriate fractions afforded 2.8 g of a solid. The solid was recrystallized from toluene and then from ethanol-water to yield 2.2 g (51%) of a solid, m.p.=124°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:38])[NH:18][C:19]2[S:20][C:21]3[CH2:27][C@@H:26]([N:28]([CH2:35][CH2:36][CH3:37])C(=O)C(F)(F)F)[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:12]=1)[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:38])[NH:18][C:19]2[S:20][C:21]3[CH2:27][C@@H:26]([NH:28][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:24][C:22]=3[N:23]=2)[CH:12]=1)[CH3:10])=[O:7]
Reactant: CCCN(C(=O)C(F)(F)F)[C@H]1CCc2nc(NC(=O)c3cccc([C@@H](C)NC(=O)c4ccc(OC)c(OC)c4)c3)sc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCN[C@H]1CCc2nc(NC(=O)c3cccc([C@@H](C)NC(=O)c4ccc(OC)c(OC)c4)c3)sc2C1
Yield: 66.5 %

Procedure:
Dissolve 3,4-dimethoxy-N—[(R)-1-(3-{(S)-6-[propyl-(2,2,2-trifluoro-acetyl)-amino]-4,5,6,7-tetrahydro-benzothiazol-2-ylcarbamoyl}-phenyl)-ethyl]-benzamide (109 mg, 0.18 mmol) into 10 mL of MeOH and add 5 mL of H2O. To this add K2CO3 (200 mg, 1.50 mmol) and heat the mixture overnight at 55° C. LC-MS analysis indicates the desired material. Add trifluoroacetic acid, dissolve into MeOH and purify via the Gilson Prep HPLC system (5%-70% CH3CN/H2O) to give 62.6 mg of the title compound. MS, electrospray 523.67 (M+H), rt 1.14 min.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=2)[CH:20]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[Br:18][C:19]1[CH:20]=[C:21]2[C:26]([CH:25]=[CH:24][C:23]([C:12]3[C:11]4[C:6]([C:5]5[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=5[CH:13]=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[CH:22]2)=[CH:27][CH:28]=1
Reactant: Brc1ccc2ccc(Br)cc2c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccc2ccc(-c3cc4ccccc4c4ccccc34)cc2c1
Temperature: 85 °C
Reaction time: 7 h
Yield: 38.7 %

Procedure:
In argon atmosphere, a mixture of 18.64 g (83.9 mmol) of 9-phenanthreneboronic acid, 30.00 g (104.9 mmol) of 2,7-dibromonaphthalene, 4.85 g (4.2 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of dimethoxyethane, 200 ml of toluene, and 106 ml of a 2 M sodium carbonate was stirred at a bath temperature of 85° C. for 7 h. The reaction mixture was added with water and extracted with toluene. After washing with water, the organic phase was dried over magnesium sulfate. Then, the toluene was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography to obtain 12.46 g (yield: 31.0%) of 7-bromo-2-(9-phenanthrenyl)naphthalene.