Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH:3]=[CH2:4].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])(=O)C.[K+].O>CO.Cl[Pd]Cl>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:4]=[CH:3][C:2]([F:6])([F:5])[F:1])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C=CC(F)(F)F
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: FC(F)(F)C=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
At 130° C., 96 g of 3,3,3-trifluoropropene, 155 g of 1-benzyloxy-4-iodobenzene, 68.5 g of potassium acetate and 0.85 g of PdCl2 in 750 ml of methanol were reacted in an autoclave for 20 hours. After cooling to room temperature, the reaction mixture was mixed with water and extracted with ether. The combined organic phases were washed with water, dried and concentrated to give the title product as a colourless crystalline powder, which was reacted further without any purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>O1CCCC1>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH3:23])[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C[C@@H](N(Cc2ccccc2)Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
0.500 g (S)-5-dibenzylaminopiperidin-2-one are suspended in 15 ml of tetrahydrofuran. While cooling with the ice bath 0.175 g potassium-tert-butoxide are added. The reaction mixture is then stirred for 30 minutes at ambient temperature. While cooling with the ice bath 0.095 ml methyl iodide are added. The reaction mixture is then stirred for 48 hours at ambient temperature and then mixed with a saturated NaCl solution. The product is extracted with ethyl acetate. 0.450g of the product are obtained as an oil.
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OCC3C=CC=CC=3)=O)[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)OC2CCC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(OC1CCC1)N1CCNCC1
Reaction time: 12 h

Procedure:
A suspension of 5.90 g Piperazine-1,4-dicarboxylic acid benzyl ester cyclobutyl ester and 0.25 g Pd/C (10%) in 50 ml ethyl acetate was stirred under an atmosphere of hydrogen (3 bar) for 12 h. The mixture was filtrated over a plug of Celite, washed with ethyl acetate and the combined wash solutions concentrated to give the title compound as colourless oil. Yield: 3.3 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:28]([CH2:30][NH2:31])[OH:29]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:31][CH2:30][CH2:28][OH:29])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (1900 mg; 4.57 mmol; 1 eq), is dissolved in anhydrous DCM (180 ml). The reaction is put under nitrogen. Triethylamine (3.2 ml; 22.9 mmol; 5 eq) and ethanolamine (1.1 ml; 18.3 mmol; 4 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (1760 mg; 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH2:23][CH2:24]O)[O:19][C:18]2=[O:33])[CH3:16])=[CH:11][CH:10]=1.N1C=CC=CC=1.P(Br)(Br)[Br:41]>C(Cl)Cl>[Br:41][CH2:24][CH2:23][C@@:20]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:19][C:18](=[O:33])[N:17]([C@H:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)[CH3:16])[CH2:22][CH2:21]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCBr)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (250 mg, 0.55 mmol) in methylene chloride (10 mL) was added pyridine (0.5 mL) and PBr3 (75 mg). The formed mixture was stirred for 2 h. The mixture was washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(2-bromoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (60 mg, 23%). 1H NMR: (400 MHz, CDCl3): δ=1.45 (d, 3H), 2.12-2.38 (d, 4H), 2.43 (m, 1H), 2.94 (m, 2H), 3.49 (m, 1H), 5.22 (m, 1H), 6.83 (m, 2H), 6.95 (m, 4H), 7.19 (m, 1H), 7.22 (m, 2H).
Reaction SMILES: CS[C:3]([C:13]1[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH2:12])[CH3:4].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:12][C:6]1[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([C:13]1[N:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[N:18]=1)[CH3:4]
Reactant: COc1cc(OC)nc(C(C)(SC)c2cccc(Cl)c2N)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(C(C)c2cccc(Cl)c2N)n1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-{1-methylthio-1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 3 g (8.8 mmol) in 100 ml methanol, nickel (II) chloride hexahydrate 4.2 g (17.7 mmol) was added at 0° C. and the mixture was stirred for 30 minutes. Then, at the same temperature, sodium borohydride 1.35 g (35 mmol) was added little by little thereto. The solution was stirred at room temperature for 1 hour and then the solvent was distilled off. 2N-hydrochloric acid was added to the residue and then 28% aqueous ammonia was added and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous solution of sodium hydroxide and the solvent was distilled off. After washing with hexane, the deposited crystals were filtered to obtain 2-{1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 2.12 g (82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:10][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>C(O)C>[CH2:30]([N:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=2)[C:12](=[O:13])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:31]
Reactant: CCI
Reactant: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccc(F)cc1

Procedure:
A 6 gram portion of 1-(4-fluorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one (prepared according to the teaching outlined above) was mixed with 4 grams potassium carbonate and 15 ml. ethyl iodide in 100 ml. ethanol and refluxed overnight. The desired product was isolated in the usual way, yield 1.8 grams, m.p. approximately 92° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12](Cl)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1.[SH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:24][CH:23]=1.C(OCC)(=O)C>C(O)(C)(C)C>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[N:13]=[C:12]([S:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])=[CH:26][CH:27]=3)[N:11]=[C:10]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=2)[CH:3]=1
Reactant: CCC(=O)Nc1ccc(S)cc1
Reactant: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cc1cc(Nc2cc(C)[nH]n2)nc(Sc2ccc(NC(=O)CC)cc2)n1
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A suspension of Ethyl 2-(6-(5-methyl-1H-pyrazol-3-ylamino)-2-chloropyrimidin-4-yl)acetate (0.676 g, 2.29 mmol) and N-(4-mercaptophenyl)propionamide (0.415 g, 2.29 mmol) in t-butanol (10 ml) was heated under reflux overnight. Reaction mixture was then cooled to room temperature, ethyl acetate (20 ml) added causing precipitation of product. Solid was collected by filtration, washed with sat. sodium hydrogen carbonate solution, water, diethyl ether then dried by suction to leave title compound as a yellow solid (0.425 g, 43%). 1H NMR (DMSO) 1.12 (3H, t), 1.20 (3H, t), 2.00 (3H, s), 2.40 (2H, q), 3.66 (2H, s), 4.11 (2H, q), 5.05 (1H, br s), 5.30 (1H, br s), 7.53 (2H, d), 7.79 (2H, d), 10.20 (1H, s); ES+ 441.
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[CH2:21]([Mg]Cl)[CH3:22]>C1COCC1>[CH2:21]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:22]
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 355 mg (1.17 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml THF were added at <10° C. drop-wise over 20 min 2.35 ml (4.7 mmol) 2M ethylmagnesium chloride solution in THF. The resulting brown solution was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NH4Cl solution (cooling with ice bath) and extracted three times with tert-butyl methyl ether. The combined organic phases were washed three times with brine, dried over Na2SO4, filtered and evaporated. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as yellow oil: MS (ISP): 286.1 ((M+H)+.).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[CH:13]3)=[O:8])=[CH:5][CH:4]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](N)=[CH:28][CH:29]=2)C=N1.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.CN(C)C1C=CC(C(O)=O)=CC=1.C(Cl)CCl>CN(C=O)C.O>[NH2:22][C:30]1[CH:25]=[CH:26][C:27]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:20][CH:19]=4)=[CH:18][CH:17]=3)[CH:13]=[N:14]2)=[CH:28][CH:29]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc3[nH]ncc3c2)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CN(C)c1ccc(C(=O)O)cc1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(C(=O)Nc2ccc3c(cnn3-c3ccc(N)cc3)c2)cc1

Procedure:
Compound 371 was prepared according to the general procedure described in Scheme IV. Preparation of 4-(dimethylamino)-N-(1H-indazol-5-yl)benzamide: 1H-Indazol-5-amine (200 mg, 1.50 mmol), hydroxybenzotriazole (20 mg, 0.15 mmol), triethylamine (0.23 mL, 1.65 mmol), and 4-(dimethylamino)benzoic acid (273 mg, 1.65 mmol) were taken up in DMF (7.5 mL) and stirred. EDC (317 mg, 1.65 mmol) was added to the solution last. After the addition, the solution was stirred at room temperature for 4 h. Water was then added to the solution and stirred for 10 min. The formed precipitate was filtered and washed well with water, followed by hexanes. The solid was dried under vacuum to give 410 mg (97%) of the product as a brown solid.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[CH3:12][C:13](=[C:21]([CH3:23])[CH3:22])[CH2:14][CH2:15][C:16]([O:18]CC)=O.[Cl-].[NH4+]>C(OCC)C>[CH3:12][C:13](=[C:21]([CH3:22])[CH3:23])[CH2:14][CH2:15][C:16]1([OH:18])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)CCC(C)=C(C)C
Reactant: BrCCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: BrCCBr
Product: CC(C)=C(C)CCC1(O)CCCC1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
Magnesium turnings (9.53 g, 0.39 mol) were covered with dry diethyl ether (50 ml) at room temperature under nitrogen. 1,2-Dibromoethane (0.5 ml) was added in one portion. As soon as a visible reaction had started (bubbling), magnetic stirring was switched on and a solution of 1,4-dibromobutane (50 g, 0.225 mol) in dry diethyl ether (360 ml) was added at a rate such as to maintain a constant reflux (1 hour). The reaction was further refluxed for 1 hour before cooling in an ice-water bath. Ethyl 4,5-dimethyl-4-hexenoate (26.5 g, 0.156 mol) in dry diethyl ether (30 ml) was added dropwise. Then the reaction was warmed up to room temperature and the reaction was refluxed for 1 hour. It was recooled in an ice-water bath before adding a saturated aqueous ammonium chloride solution (250 ml, slowly). After warming up to room temperature and shaking vigorously, the phases were separated. The organic phase was washed with aqueous saturated bicarbonate (250 ml) and water (500 ml). Each aqueous phase was re-extracted with diethyl ether (250 ml). Combined extracts were dried over anhydrous sodium sulfate. The product was purified by column chromatography on silica gel (eluting with heptanes/ethyl acetate 11:1 to 3:1) followed by bulb-to-bulb distillation (110° C./1 mbar). 22.62 g of the title compound (99.6% pure, 0.122 mol, 78%) were obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43](OC)=[O:44])=[N:8]1.O.[OH-].[Li+].[C:53]([NH2:62])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)([CH3:55])[CH3:54].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.O1CCCC1.O>[CH3:54][C:53]([NH:62][C:43]([C:42]1[CH:47]=[CH:48][CH:49]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:44])([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[CH3:55]
Reactant: CC(C)(N)c1ccccc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.1 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), cumylamine (0.270 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 40–100% ethyl acetate/hexanes gave the title compound (0.376 g, 81% yield). ES-MS (m/z) 507 [M+1(−Tr)]+
Reaction SMILES: C([O:8][C:9]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.O1CCCC1>[Pd].CO>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:32]=[CH:31][C:30]([C:27]2[O:26][C:25]([C:22]3[CH:21]=[C:10]([C:11]([OH:13])=[O:12])[C:9]([OH:8])=[CH:24][CH:23]=3)=[CH:29][CH:28]=2)=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccccc1)c1cc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccc(-c3ccc(C(F)(F)F)cc3)o2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A mixture of benzyl 2-benzyloxy-5-[5-(4-trifluromethylphenyl)-2-furyl]benzoate (2.64 g), 5% palladium on carbon (2.6 g), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred under a hydrogen atmosphere at normal pressure and room temperature for 30 min. Palladium on carbon was removed by filtration, and the filtrate was concentrated. The residue was recrystallized from ethanol to give 5-[5-(4-trifluoromethylphenyl)-2-furyl]salicylic acid (1.07 g, yield 62%) as a colorless crystalline powder. melting point: 272–273° C.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C(OC)C=CN=1>>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][N:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=1
Reactant: COc1ccnc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COc1ccnc(Cl)c1
Product: COc1ccnc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 61 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-methoxypyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (144 mg, 0.302 mmol) and 2-chloro-4-methoxypyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (88 mg, 61%): 1H NMR (CDCl3, 400 MHz) δ 8.43 (d, 1H, J=5.6 Hz), 7.63 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 6.75 (dd, 1H, J=5.8, 2.6 Hz), 4.85 (dd, 1H, J=7.3, 5.8 Hz), 3.9 (s, 3H), 2.59 (t, 2H, J=7.6 Hz), 1.93 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.90 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.3, 165.5, 151.1, 150.6, 148.9, 142.7, 128.3, 128.2, 125.5, 125.3, 109.0, 105.1, 68.7, 55.3, 36.4, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 18.2, −5.0, −5.1.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC#N>[CH2:19]([O:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccccc1OCc1ccccc1
Yield: 94.71 %

Procedure:
To a solution of 68 (5.8 g, 34.9 mmol) in CH3CN (150 ml) was added K2CO3 (10.6 g, 76.8 mmol). The mixture was added benzyl bromide (6.57 g, 38.39 mmol) and refluxed for 8 h under N2 atmosphere. The reaction mixture was cooled to 25° and poured into H2O (500 ml), and then extracted with CH2Cl2. The organic layer was washed with H2O, dried over MgSO4 and evaporated. The crude products were purified by distillation to give 73 as colorless liquid. (8.5 g, 33.2 mmol). Yield: 94.71%; MS (EI, 70 eV): m/z 256.3 (M+); 1H-NMR (CDCl3, 200 MHz): δ 1.33=(t, J=7.2 Hz, 3H), 4.35 (q, =7.2, 7.0 Hz, 2H), 5.15 (s, 2H), 7.00 (d, =8.0 Hz, 2H), 7.32-7.45 (m, 5H), 7.49 (d, J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.8 Hz, 1H); 13C-NMR (CDCl3, 50 MHz) δ: 166.60, 158.01, 136.77, 133.25, 131.69, 128.49, 127.80, 126.99, 121.20, 120.56, 113.75, 70.57, 60.93, 14.29; Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[CH:20]1([C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(O)[CH3:24])[CH2:22][CH2:21]1>ClCCl>[CH:20]1([C:23]([C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: Cc1ccc(C(C)(O)C2CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(C)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 ml (3.00 mmol) of trifluoroacetic acid was added to 885 mg (4.99 mmol) of the compound from Example 8A and 440 mg (2.50 mmol) of the compound from Example 137A in 44 ml of dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 87.4 mg (10% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[OH:7])=[CH:4][CH:3]=1.[N:18]1([C:27]2[O:28][C:29]([CH2:39][CH2:40][C:41](O)=[O:42])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:31]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O>[N:18]1([C:27]2[O:28][C:29]([CH2:39][CH2:40][C:41]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([CH:6]([P:8]([O:9][CH2:10][CH3:11])([O:12][CH2:13][CH3:14])=[O:15])[OH:7])=[CH:16][CH:17]=3)=[O:42])=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[N:31]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1
Reactant: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(Cl)cc1
Reactant: CCOP(=O)(OCC)C(O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(O)c1ccc(NC(=O)CCc2oc(-n3cnc4ccccc43)nc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of diethyl 4-amino-α-hydroxybenzylphosphonate (50 mg), 3-{3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (54 mg), 1-hydroxy-7-aza-1H-1,2,3-benzotriazole (38 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (43 mg) and N,N-dimethylformamide (0.5 ml) was stirred overnight at room temperature. To the reaction mixture was added 0.1N aqueous hydrochloric acid solution (2 ml) and the reaction mixture was extracted with ethyl acetate (2 ml). The organic layer was concentrated, introduced into preparative HPLC and purified to give 3-[2-(1H-benzoimidazol-1-yl)-4-(4-chlorophenyl)-5-oxazolyl]-N-(4-[(diethylphosphono)(hydroxy)methyl]phenyl}propionamide (52 mg, 58%). Recrystallization from ethyl acetate-isopropyl ether gave yellow prism crystals. melting point: 171–172° C. MS (ESI+): 609 (M+H)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:24])[C:15]2[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:24][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([O:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCOc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOc1cccnc1N(C)C1CCNCC1
Reaction time: 0.75 h

Procedure:
A mixture of 1-benzyl-4-[N-methyl-N-(3-ethoxy-2-pyridinyl)amino]piperidine (EXAMPLE 70, 1.40 g), palladium-on-carbon (10%, 1.4 g) and ammonium formate (813 mg) in methanol (25 ml) is degassed, stirred at 65° for 45 min, cooled to 20°-25°, and filtered to remove catalyst. The filtrate is concentrated under reduced pressure to give the title compound, NMR (CDCl3) 7.83, 6.97, 6.71, 4.02, 3.88, 3.15, 2.88, 2.63, 1.75 and 1.46δ.