Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:28]=[C:27]([CH2:29][NH2:30])[O:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:19][CH2:20][CH2:21]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:30][CH2:29][C:27]2[O:26][N:25]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:28]=2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-cyclobutoxy-nicotinic acid (example CA) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 92.8%, 451.1 (M−H)−.
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].[O:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.ClCC(OC(=O)CCl)=O>C1(C)C=CC=CC=1>[C:8]([C:1]1[O:6][CH:4]=[CH:3][CH:2]=1)(=[O:7])/[CH:9]=[CH:10]/[CH3:11]
Reactant: c1ccoc1
Reactant: C/C=C/C(=O)O
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: C/C=C/C(=O)c1ccco1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 41.1 %

Procedure:
In 50 ml of toluene were dissolved 4.31 g (0.05 mole) of crotonic acid, 4.43 g (0.065 mole) of furan and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution was added 0.71 g of boron trifluoridediethyl ether complex and the resulting mixture was then stirred at 50° C. for 6.5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 2.8 g of 2-crotonylfuran.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]=[O:34])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:29]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:30]([CH:33]([OH:34])[CH:19]([CH2:18][C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:31][N:32]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COC(=O)CCc1cccs1
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCc1ncc(C(O)C(Cc2cccs2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a solution of diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 mL) held at -78° C. under argon was added n-butyl lithium (7.3 mL, 0.0183 mol of 2.5M in toluene), and the mixture was stirred for 10 minutes. Then, methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 mL) was added, and the mixture was stirred for 30 minutes at -78° C. A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (3 g, 0.0111 mol) in tetrahydrofuran (4 mL) was added, and the resulting mixture was stirred at -78° C. for 30 minutes. The reaction was partitioned between saturated ammonium chloride solution and ether, the organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to 6.67 g of crude product. This was flash chromatographed over 70 g of silica gel with 4:1 ethyl acetate/hexanes to provide 4.03 g (81%) of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-[(2-thienyl)methyl]propanoate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[S:23][C:24]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[S:23][C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1sc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(-c3ccccc3)c(CCC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionate (360 mg), lithium hydroxide hydrate (83.5 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (2.1 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-thiazolyl]propionic acid (338 mg, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 121–122° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1.[CH:10]([CH:12]=[CH2:13])=[O:11]>O1CCCC1>[CH:12]([CH:10]([OH:11])[CH2:3][CH2:4][CH:5]1[O:9][CH2:8][CH2:7][O:6]1)=[CH2:13]
Reactant: C=CC=O
Reactant: BrCCC1OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(O)CCC1OCCO1
Temperature: -78 °C
Yield: 46 %

Procedure:
A dry, 3-necked flask equipped with argon inlet, stirring bar, and dropping funnel was charged sequentially with magnesium turnings (1.047 g, 43.05 g-atom) and a solution of 2-(2-bromoethyl)-1,3-dioxolane (6 g, 33.14 mmole) in tetrahydrofuran (70 ml). The reaction vessel was placed in an ultrasonic cleaning bath and subjected to sonication for 2.5 hours with occasional swirling while maintaining the bath temperature at 25°-30° C. The brown mixture was then cooled to -78° C. and treated dropwise with freshly distilled acrolein (2.21 ml, 33.14 mmole) in tetrahydrofuran (15 ml). The resulting thick mixture was stirred at -78° C. for an additional 30 minutes, the cooling bath was replaced with an ice bath and the reaction was quenched with a saturated sodium sulfate solution (ca. 30 ml), followed by solid sodium sulfate. The clear supernate was decanted from the precipitated solids which were washed with ethyl acetate (3×100 ml). The combined washings were dried (sodium sulfate), filtered, and concentrated in vacuo of 4.28 g of oil. The crude product was chromatographed on 140 g of silica gel (230-400 mesh) with 40% ethyl acetate:hexane to afford 2.41 g of the title compound as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])([F:21])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:21][C:18]1([CH2:22][N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester (23 g) in dichloromethane (250 ml), and the mixture was stirred at room temperature for 5 hours. The obtained solution was concentrated, and the residue was recrystallized from ether to obtain a trifluoroacetic acid salt of 2-(4-fluoro-piperidin-4-ylmethyl)-isoindole-1,3-dione.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH:4]([CH2:35][C:36]1[N:37]=[CH:38][S:39][CH:40]=1)[NH:5][C:6](=[O:34])[C@@H:7]([CH2:15][S:16]([C:19]([CH3:33])([C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20])(=[O:18])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:33][C:19]([S:16]([CH2:15][C@@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:6]([NH:5][CH:4]([C:3]([OH:41])=[O:2])[CH2:35][C:36]1[N:37]=[CH:38][S:39][CH:40]=1)=[O:34])(=[O:18])=[O:17])([C:21](=[O:32])[N:22]([CH3:31])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20]
Reactant: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N(C)CCc1ccccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(CCc1ccccn1)C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)NC(Cc1cscn1)C(=O)O
Reaction time: 3 h
Yield: 124.6 %

Procedure:
A solution of 300 mg of N-[(S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D,L-alanine methyl ester in 2.5 ml of dioxan was treated with a solution of 24.3 mg of lithium hydroxide hydrate in 1 ml of water and stirred at 50 for 3 hours. Subsequently, the solution was partitioned between ethyl acetate and water and the organic phase was extracted three times with water. The aqueous extracts were adjusted to pH 2 with ethyl acetate and with 2N hydrochloric acid and evaporated under reduced pressure. There were obtained 365 mg of N-[(S)-α-[[[1 -methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D ,L-alanine as a colourless foam which was used directly in the next step.
Reaction SMILES: Br[CH:2]([CH2:8][CH:9]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:16])(=[S:15])[CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH2:12]([C:11]1[S:15][C:8]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9][N:16]=1)[CH2:13][CH3:14]
Reactant: CCCC(N)=S
Reactant: CCOC(=O)C(Br)CC=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCc1ncc(CC(=O)OCC)s1
Yield: 73.3 %

Procedure:
A mixture of 20.6 g of ethyl 2-bromo-4-oxo-butyrate, 10.9 g of thiobutyramide and 400 ml of dichloroethane was refluxed under a nitrogen atmosphere which recycling the dehydrated condensate. The mixture was cooled and then mixed with 45 ml of a saturated sodium bicarbonate aqueous solution. The mixture was decanted and the organic phase was dried and evaporated to dryness. The liquid residue was chromatographed over silica gel and elution with a 8-2 cyclohexane-benzene mixture yielded 15.4 g of ethyl 2-propyl-5-thiazole-acetate. The IR spectrum in CHCl3 showed an ester carbonyl at 1737cm-1 and C=C at 1536cm-1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([O:20][CH3:21])=[CH2:19].[NH2-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[CH2:19][C:18]([O:20][CH3:21])([O:17][CH3:16])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: C=C(OC)OC
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(OC)Cc2ccc(OCc3ccccc3)cc21
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a 6 mL THF solution of 1-(benzyloxy)-4-bromobenzene (500 mg, 1900 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and ketene dimethyl acetal (359 μL, 3800 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added neat sodium amide (107 μL, 3800 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting mixture was heated to 80° C. and stirred for 48 hours. After the reaction was complete, it was quenched by slow addition of water. The resulting mixture was then extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Solvent was removed in the presence of silica gel, and the residue was purified by column chromatography with 20% EtOAc/hexane to afford desired product H7.1 (274 mg, yield, 60%). MS ESI (pos.) m/e: 271.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:15]=[C:16]([O:39][CH3:40])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=3)=[CH:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:18]=2[N:19]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[C:41](O)(=O)[CH3:42]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14]1[N:15]=[C:16]([O:39][CH3:40])[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][C:26]4[NH:29][C:41]([CH3:42])=[N:30][C:25]=4[CH:24]=3)=[CH:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:18]=2[N:19]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc(N)c(N)c1)cn2COCC[Si](C)(C)C
Reactant: CC(=O)O
Product: COc1nc(Nc2ccc(C(=O)N(C)C)cc2Cl)nc2c1c(-c1ccc3[nH]c(C)nc3c1)cn2COCC[Si](C)(C)C
Temperature: 115 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
3-Chloro-4-(5-(3,4-diaminophenyl)-4-methoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-N,N-dimethylbenzamide (1 equiv) was dissolved in acetic acid (40 equiv) and stirred at 115° C. for 3 h. After the reaction was complete, the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to afford the title compound (73% yield). MS (ESI) m/z 606.2[M+1]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][OH:6].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>O>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(CCO)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Yield: 87.8 %

Procedure:
In a round-bottomed flask, 3.3 g of (-)-3-trifluoromethyl-1-heptanol and 5.7 g of pyridine were placed and stirred, and 3.4 g of p-toluenesulfonyl chloride was added, followed by 4 hours of reaction at 15°-20° C. The reaction mixture was poured into water, acidified with hydrochloric acid and extracted with diethyl ether, followed further by drying with sodium sulfate, and distilling-off of the solvent to obtain 5.3 g of (+)-3-trifluoromethylheptyl p-toluenesulfonate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[N+:10]([O-])([OH:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[N+:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCO2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
2,3-dihydrobenzofuran (5 g, 41.6 mmol) was dissolved in 35 mL of acetic acid, and ¼ HNO3 (0.9 mL, 45.4 mmol) was added dropwise. At the beginning of reaction, it was heated to 70° C., then the residual HNO3 was added. After 0.5 hour, the reaction was cooled, added into ice-water, and then neutralized with Na2CO3. The water layer was extracted with ethyl acetate. The organic layers were combined and dried, concentrated under vacuum, purified by column chromatography to obtain a product (1 g, 14.6%).
Reaction SMILES: C(OC(=O)C1C=CC=C(C#C[C:13]2[CH:25]=[CH:24][C:16]3[O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][O:21][C:15]=3[CH:14]=2)C=1)C.[C:27]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:31][CH:30]=1)#[CH:28].IC1C=CC2OCC(C)(C)COC=2C=1>>[CH3:22][C:19]1([CH3:23])[CH2:18][O:17][C:16]2[CH:24]=[CH:25][C:13]([C:28]#[C:27][C:29]3[CH:39]=[CH:38][C:32]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:14][C:15]=2[O:21][CH2:20]1
Reactant: C#Cc1ccc(C(=O)N(C)C)cc1
Reactant: CCOC(=O)c1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1
Agent: CC1(C)COc2ccc(I)cc2OC1
Product: CN(C)C(=O)c1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound is prepared in analogy to 3-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester (10) from 4-ethynyl-N,N-dimethyl-benzamide and 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5) as a light brown solid, MS (ESI) 699.4 (100, [2M+H]+), 350.4 (15, [M+H]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][C:21]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(COCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reaction time: 15 h
Yield: 63.7 %

Procedure:
Under a nitrogen atmosphere, 113 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry DMF. A solution of 0.60 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 0.65 g of 4-fluoro-3-phenoxybenzyl bromide in 5 ml of dry DMF was then added at room temperature, and the reaction solution was stirred at that temperature for 15 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (25:1) mixture] to obtain 0.64 g of the desired compound.
Reaction SMILES: C([S:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=O)C.O.C(OCC)(=O)C>N>[SH:4][CH2:5][CH2:6][N:7]([CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:8](=[O:21])[NH:9][C@@H:10]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(=O)SCCN(CCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N(CCS)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
(2S)-2-[3-[2-(Acetylthio)ethyl]-3-phenethylureido]-3-phenylpropionic acid (Compound No. 7-30, 646 mg) is dissolved in 28% aqueous ammonia (15 ml) under a nitrogen atmosphere, and the solution is stirred at room temperature for one hour. To the reaction mixture are added water and ethyl acetate, and the aqueous layer is separated from the organic layer. To the aqueous layer is added 6 N hydrochloric acid under ice cooling to acidify it, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give 415 mg (81%) of the titled compound (Compound No. 11-1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[CH:23][S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:24]([CH3:25])=[CH:23][S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1csc2nc(-c3ccno3)nc(Cl)c12
Reactant: NCc1ccc(F)cc1
Product: Cc1csc2nc(-c3ccno3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:19]([O:26][C:27](=[O:46])[CH:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:29][C:30](O)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:3]1([NH:2][C:30](=[O:31])[CH2:29][CH:28]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:38][CH:39]=2)[C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:46])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1(CC(=O)OCc2ccccc2)CCCC1
Reactant: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1)NC1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of benzyl 2-(1-aminocyclopentyl)acetate hydrochloride (66 mg, 0.245 mmol), 4-(benzyloxy)-3-(biphenyl-4-ylmethyl)-4-oxobutanoic acid (78 mg, 0.209 mmol), WSC.HCl (60.1 mg, 0.314 mmol) and 1-hydroxy-7-azabenzotriazole (42.7 mg, 0.314 mmol) in DMF (2 ml) was added DIPEA (0.055 ml, 0.314 mmol) at room temperature. After stirred for 4 hours, the reaction was quenched with H2O. The product was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give benzyl 4-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentylamino)-2-(biphenyl-4-ylmethyl)-4-oxobutanoate (93 mg); Retention time=1.85 minutes (condition B); MS (m+1)=590.3; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ ppm 1.61-1.72 (m, 6H) 1.96-2.06 (m, 2H) 2.17-2.46 (m, 2H) 2.81-3.00 (m, 4H) 3.22-3.29 (m, 1H) 5.02-5.12 (m, 4H) 5.62 (br s, 1H) 7.15-7.57 (m, 19H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:36])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[O:23][C:24]5[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([C:34]#[N:35])=[CH:27][C:25]=5[N:26]=4)=[CH:18][CH:17]=3)[O:10][C:9]2=[O:37])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:44][C:45]([F:57])([F:56])[O:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1B(O)O>O1CCCC1.O.C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.[CH-]1C=CC=C1.[Fe+2].[Pd]>[C:34]([C:28]1[CH:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH2:13][C@H:11]4[O:10][C:9](=[O:37])[N:8]([C:5]5[CH:4]=[CH:3][C:2]([C:48]6[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=6[O:46][C:45]([F:44])([F:57])[F:56])=[CH:7][N:6]=5)[CH2:12]4)=[O:36])=[CH:17][CH:18]=3)=[N:26][C:25]=2[CH:27]=1)#[N:35]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CN(c5ccc(Cl)cn5)C(=O)O4)cc3)oc12
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NC[C@@H]4CN(c5ccc(-c6ccccc6OC(F)(F)F)cn5)C(=O)O4)cc3)oc12
Temperature: 150 °C
Yield: 60.3 %

Procedure:
To a mixture of N-{[(5R)-3-(5-chloropyridin-2-yl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (52 mg, EXAMPLE 27) and potassium carbonate (55 mg) in 1 ml of tetrahydrofuran and 1 ml of water was added 2-trifluoromethoxyphenylboronic acid (82 mg) and palladium di-tert-butylphosphinoferrocene (13 mg). The mixture was heated via microwave for 25 min at 150° C. The sample was cooled to room temperature, and was purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 3 column volumes to provide the title compound as an off-white solid (39 mg, 61%). Mass spectrum (ESI) 642.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.43 (s, 8.35 (d, J=7.8 Hz, 2H), 8.28 (d, J=8.7 Hz, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.94 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.52 (s, 1H), 7.40 (m, 4H), 6.76 (bs, 1H), 4.98 (m, 1H), 4.48 (dd, J=9.1 Hz, 10.7 Hz, 1H), 4.13 (m, 2H), 3.72 (m, 1H), 3.49 (sept, J=6.9 Hz, 1H), 1.46 (d, J=7.1 Hz, 6H).