Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Cc1ccc(O)cc1N
Product: Cc1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-hydroxy-2-methylaniline (36 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (19 mg, 28%). 1H NMR (Acetone-d6): 8.91 (s, 1H), 8.75 (dd, J=1.2, 4.8 Hz, 2H), 8.55 (s, 1H), 8.22 (dd, J=1.8, 4.8 Hz, 2H), 7.23 (s, 1H), 7.18 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.76 (dd, J=3.0, 8.7 Hz, 1H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13](O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2.P(Br)(Br)(Br)(Br)[Br:21]>>[Br:21][CH:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(O)c1ccc2cc(OC)ccc2c1
Reactant: BrP(Br)(Br)(Br)Br
Product: CCOC(=O)C(Br)c1ccc2cc(OC)ccc2c1

Procedure:
To 0.0476 moles of ethyl 6-methoxy- 2-naphthylglycolate there is added slowly with stirring at 40°-50°C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture is stirred at room temperature for 16 hours, then diluted with 70 ml. of petroleum ether, and poured into 125 ml. of ice-cold water. The organic phase is separated, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to obtain ethyl α-bromo-6-methoxy-2-naphthylacetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:20][C:21]1[C:22]([F:31])=[C:23]([C:27]([O:29][CH3:30])=[O:28])[S:24][C:25]=1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:18]#[N:19])[CH:11]=1
Reactant: COC(=O)c1sc(Br)c(Br)c1F
Reactant: N#Cc1cc(B(O)O)ccc1OCc1ccccc1
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: Cc1ccccc1
Product: COC(=O)c1sc(-c2ccc(OCc3ccccc3)c(C#N)c2)c(Br)c1F

Procedure:
(4-Benzyloxy-3-cyanophenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate were dissolved in a mixed solution of toluene and a 1M aqueous sodium carbonate solution and the whole was heated at 110° C. for 2.5 days in the presence of tetrakis(triphenylphosphine)palladium to obtain methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate. Methyl 4-bromo-5-(4-benzyloxy-3-cyanophenyl)-3-fluorothiophene-2-carboxylate and triethylamine were stirred at room temperature in 1,4-dioxane under a hydrogen atmosphere at normal pressure in the presence of palladium-carbon to obtain methyl 5-(3-cyano-4-hydroxyphenyl)-3-fluorothiophene-2-carboxylate. FN: 276.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23]OS(C)(=O)=O)[CH:7]=1)[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:30]=[N+:31]=[N-:32])[CH:7]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2COS(C)(=O)=O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN=[N+]=[N-])c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
[3-(2-Methanesulfonyloxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (1.0 mmol) and sodium azide (0.195 g, 3.0 mmol) were combined in DMF (10 mL) and stirred at 80° C. for 1 hour. Once no starting material was seen by analytical LCMS, the mixture was cooled to room temperature and partitioned between EtOAc and H2O. The aqueous layer was separated and extracted twice with EtOAc, and the combined organic layers were washed three times with H2O, and then dried and concentrated. The residue was purified by silica gel chromatography (0-10% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([N+]([O-])=O)[C:3]=1[CH:12]=[CH:13][N:14](C)C>CC(O)=O.O.O.[Zn]>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: Cc1ccc([N+](=O)[O-])c(C=CN(C)C)c1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2[nH]ccc2c1Br
Temperature: 0 °C
Yield: 19 %

Procedure:
[2-(2-Bromo-3-methyl-6-nitro-phenyl)vinyl]-dimethyl-amine (10 g) was dissolved in AcOH/H2O (100 mL:25 mL), cooled to 0° C. and treated with Zn (30 g) added slowly in portions. After complete addition, the reaction mixture was heated at 110° C. overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography to afford the title compound (1.4 g, 20%)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[O:29])[NH:19][C:18]2=[O:43])[CH2:12]1)=O)C1C=CC=CC=1>[Pd].CO>[O:43]=[C:18]1[NH:19][C:20]([C:28]([N:30]2[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]2)=[O:29])=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]1[CH:13]1[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n(C3CCCN(C(=O)OCc4ccccc4)C3)c2-c2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2[nH]c(=O)n(C3CCCNC3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 mL of methanol was added to a flask containing 16F (0.50 g, 0.85 mmol) prepared in the previous step and 10% Pd/C (0.05 g). The reaction flask was evacuated and purged with hydrogen, then stirred under a balloon of hydrogen overnight at RT. The mixture was filtered over a pad of Celite and the filtrate was concentrated in vacuo. The residue was reconstituted in ethyl acetate, washed with brine, dried over MgSO4, and concentrated to give tert-butyl 4-(2-oxo-5-phenyl-1-(piperidin-3-yl)-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate (16H), as a glassy oil in quantitative yield. ESI-MS: m/z 456.4 (M+H)+.
Reaction SMILES: [C:1]1([CH:6]=[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:10][C:9]=3[C:8]2=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([OH:19])=[O:18])=[CH:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: Cc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)CCC(=CC1=CCCC1)C2=O
Agent: Cl
Product: Cc1cc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2=CCCC2)ccc1C#N

Procedure:
The title compound was injustices prepared from methyl 6-(cyclopent-1-en-1-ylmethylene)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate; Preparation 24 and 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 according to Method B and Method C. The title compound was largely present as (±)-(3RS,3aRS)-2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.85 (m, 4H), 1.88-2.12 (m, 2H), 2.18 (s, 2H), 2.38 (s, 3H), 2.99 (d, J=4.0 Hz, 2H), 3.55-3.75 (m, 1H), 5.39 (d, J=10.7 Hz, 1H), 5.62 (s, 1H), 6.86 (br. s., 1H), 7.13 (br. s., 1H), 7.52 (d, J=8.6 Hz, 1H), 7.69-7.89 (m, 2H), 8.03 (d, J=7.8 Hz, 1H), 12.99 (s, 1H); ES-MS m/z 398 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:24])=[C:11]([NH:13][C:14]([C:16]3[S:20][C:19](B(O)O)=[CH:18][CH:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH3:34]>>[C:32]([C:30]1[CH:29]=[CH:28][C:27]([CH3:34])=[C:26]([C:19]2[S:20][C:16]([C:14]([NH:13][C:11]3[CH:12]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:8]=[CH:9][C:10]=3[CH3:24])=[O:15])=[CH:17][CH:18]=2)[CH:31]=1)#[N:33]
Reactant: Cc1ccc(C#N)cc1Br
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(-c2cc(C#N)ccc2C)s1

Procedure:
The title compound was prepared by coupling 5-(5-(cyclopropylcarbamoyl)-2-methylphenylcarbamoyl)thiophen-2-ylboronic acid (Example 210, Step A) with commercially available 2-bromo-4-cyanotoluene using the method described in Step B of Example 136 to afford a white solid after purification by reverse phase preparative HPLC (Example 213). HPLC Ret time=3.36 min. LCMS [M+H]+ 416.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]([CH2:18][CH2:19]Cl)[CH3:17])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH3:17])[CH2:18][CH2:19][N:23]3[CH2:22][CH2:21][NH:24][C:7]3([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: NCCN
Reactant: CN(CCCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN2CCNC2(c2ccccc2)c2cc(Cl)ccc21

Procedure:
A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2-chloroethylmethylamino)benzophenone, 3.0 g. (50 mmole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The solvents were removed by evaporation and the residue containing starting material and the product was washed with water, chromatographed over Florisil, and recrystallized from petroleum ether to give the above-titled product as yellow prisms, m.p. 100° -102°.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[C:42]([Cl:44])[C:16]([C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=3[CH3:37])=[CH:27][CH:26]=2)[C:21]([OH:23])=[O:22])=[O:18])=[C:15]([Cl:45])[CH:14]=1.O=C1CCC(=O)N1[O:53][C:54](=O)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]1[C:77](=[O:78])[CH:76]=[CH:75][C:74]1=[O:79].CCN(C(C)C)C(C)C>>[Cl:45][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:54](=[O:53])[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]2[C:77](=[O:78])[CH:76]=[CH:75][C:74]2=[O:79])[CH:43]=[C:42]([Cl:44])[C:16]=1[C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=2[CH3:37])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:18]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCN)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid trifluoroacetate salt (203 mg, 0.3 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (154 mg, 0.3 mmol), and DIPEA (194 mg, 261 uL, 1.5 mmol), and after HPLC purification, resulted in an amorphous white solid (175 mg, 61%). ES(+)-HRMS m/e calcd. for C44H54Cl2N6O14 (M+H)+ 961.3148, obsd. 961.3156.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].[F:13][C:14]([F:33])([F:32])[C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][NH:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][N:24]=[C:23](Br)[CH:22]=1.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:32][C:14]([F:13])([F:33])[C:15]1[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=1)[CH2:18][NH:19][C:20](=[O:28])[C:21]1[CH:22]=[CH:23][N:24]=[C:25]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:26]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
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: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2ccccc2[N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
Into a 250-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-nitrophenylboronic acid (500 mg, 2.99 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (30 mL), N-(3-(trifluoromethyl)benzyl)-2-bromoisonicotinamide 21a (1.08 g, 3.01 mmol, 1.00 equiv), Pd(PPh3)4 (334.7 mg, 0.30 mmol, 0.10 equiv), and a solution of sodium carbonate (1.6 g, 15.09 mmol, 5.00 equiv) in water (4 mL). The resulting solution was stirred for 1.5 h at 80° C. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined and dried over magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/EtOAc (20:1-5:1). The product was obtained as 1.0 g (83%) of a light yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:30][CH:29]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([O:6]CC1C=CC=CC=1)=[O:5].[H][H]>C(O)C.[Pd]>[OH:1][CH:2]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:32][CH:33]=1)[CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccn2)cc1
Reaction time: 2 h

Procedure:
To a solution of benzyl (2RS,3RS)-3-hydroxy-3-[4-(pyridin-2-yloxy)phenyl]-2-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]propanoate (4.99 g, 8.95 mmol) in ethanol (500 ml) was added 10% palladium/carbon (containing water by 50%, 500 mg), and the mixture was stirred under a 1 atm hydrogen stream for 2 hrs. The reaction solution was filtered with celite and the filtrate was concentrated to give the objective substance (4.50 g, 100%, crude). The present compound was used for the next reaction as a crude compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.[O-:30][Mn](=O)(=O)=O.[K+]>CC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:30])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a solution of N-(6′-bromo-1′-(1-ethoxyvinyl)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-yl)-2-methylpropane-2-sulfinamide (5) (200 mg, 0.48 mmol) in acetone (15 mL) at room temperature (23° C.) was added a KMnO4 solution (5.8 mL, prepared by dissolving 9.5 g of KMnO4 in 100 mL of H2O). The mixture was stirred room temperature for 16 h. Another portion of KMnO4 solution (2.2 mL) was added and stirred another 12 h. The reaction was quenched with 5% NaHSO3, stirring until colorless clear solution achieved before combined. The combined organic phases were extracted with EA 2 times, washed with brine, dried over Na2SO4, evaporated after filtration. The residue was purified by flash chromatography on silica gel eluted with EA in hexane (0-60%) to afford the desired amino ester (6) (62.8 mg, 31%). MS ESI+ve m/z 486 (M+H)+.
Reaction SMILES: [C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([F:48])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:42][C@@H:43]([OH:47])[C:44]([OH:46])=[O:45])[NH:27][C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:31]=3)=[O:29])=[CH:21][CH:20]=2)[CH:18]=1.CCN(CC)CC>CC(C)=O>[CH:6]([O:5][C:1]([O:2][CH2:3][O:46][C:44](=[O:45])[C@H:43]([OH:47])[CH2:42][N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[F:48])=[CH:20][CH:21]=1)[NH:27][C:28]([C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:31]=1)=[O:29])=[O:9])([CH3:8])[CH3:7]
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)C[C@@H](O)C(=O)O)c1cc(-c2ccccc2F)no1
Reactant: CC(C)OC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(-c2ccccc2F)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 7.4 %

Procedure:
Chloromethyl isopropyl carbonate (17.3 mg, 114 μmol) and NaI 17.0 mg, 114 μmol) were combined in acetone (1.0 mL, 14 mmol) and heated at 60° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (20.0 mg, 38 μmol) dissolved in acetone (1.0 mL) and treated with Et3N (10.6 μL, 76 μmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The product was freeze dried and purified by reverse phase preparative HPLC to yield the title compound (1.8 mg, purity 100%). MS m/z [M+H]+ calc'd for C31H28ClF2N3O8, 644.15. found 644.1.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:16]([C:19]1[CH:30]=[CH:29][C:22]([CH2:23][CH:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][CH:20]=1)([OH:18])=[O:17]>>[C:26]([CH:24]([NH:25][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:23][C:22]1[CH:29]=[CH:30][C:19]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)([OH:28])=[O:27]
Reactant: NC(Cc1ccc(C(=O)O)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1ccc(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)cc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 4-carboxy-DL-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in good yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.O.O.O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14]>>[NH2:7][C:4]1[S:5][C:6]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])=[C:2]([CH3:1])[N:3]=1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1csc(N)n1
Solvent: O
Product: Cc1nc(N)sc1C(O)(C(F)(F)F)C(F)(F)F

Procedure:
The title compound was prepared from commercially available of 4-methylthiazol-2-amine (Aldrich) and hexafluoroacetone trihydrate (Aldrich) according to the procedure described in European Journal of Organic Chemistry, (21), 4286-4291; 2003. MS (ESI+) m/z 281 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11](=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=O>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[N:10]1[C:14](=[O:16])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:21]
Reactant: O=C(O)c1ccccc1C(=O)NC1Cc2ccccc2C1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1Cc2ccccc2C1
Temperature: 120 °C
Yield: 615.9 %

Procedure:
To a solution of compound 747-B (1.8 g, 0.74 mmol) in DMF (20 mL) was added DMAP (0.782 g; 0.74 mmol) and the reaction mixture was heated at 120° C. for 18 h. The reaction mixture was cooled, diluted with H2O, and the precipitate filtered and dried under vacuo to afford 1.2 g of compound 747-C as a light brown solid. 1H-NMR (CDCl3) δ 3.18 (dd, 2H), 3.63 (dd, 2H), 5.16 (q, 1H), 7.14-7.24 (m, 4H), 7.68-7.77 (m, 2H), 7.79-7.90 (m, 2H); MS: m/z 264.1 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3].Br[C:36]1[C:37]([CH3:45])=[N:38][N:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=12>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([C:36]2[C:37]([CH3:45])=[N:38][N:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=23)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reactant: Cc1nn2ccccc2c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCn1ccnc1-c1sc(-c2c(C)nn3ccccc23)cc1-c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (180 mg, 0.29 mmol) in DMF (4.0 mL) was added [3-bromo-2-methylpyrazolo[1,5-a]pyridine (50 mg, 0.2 mmol) (azeotroped from toluene) and Bis(triphenylphosphine)palladium(II) chloride (8.5 mg, 0.012 mmol). The resulting mixture was degassed and stirred for 1 h at 100° C. under an atmosphere of argon. The reaction mixture was allowed to cool, concentrated and the residue was partially purified by silica gel column chromatography (40 g, eluting with 30% EtOAc in hexanes to EtOAc to give 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine, 82 mg. To a solution of [A] 3-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-2-methylpyrazolo[1,5-a]pyridine (70 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol) and acetic acid (0.4 mL, 7 mmol) in DCM (1.5 mL) was added slowly phenylsilane (0.1 mL, 0.8 mmol) and the reaction mixture stirred at 40° C. for 2 h. The reaction mixture was concentrated and the product was purified by column chromatography on silica gel eluting with 1-3% MeOH in DCM. The product was further purified by preparative hplc, formic acid gradient. The title compound was isolated as a colorless lyophilized solid, 25 mg. LC/MS (FA) ES+ 425.0, 427.6, 428.4, 429.3. 1H NMR (400 MHz, d4-MeOH) δ: 8.48 (d, J=8.3 Hz, 1H), 7.85-7.87 (m, 1H), 7.50-7.60 (m, 1H), 7.31-7.39 (m, 3H), 7.18 (s, 1H), 7.04 (s, 2H), 6.90-6.95 (m, 1H), 2.62 (s, 3H).