Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:16])[CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:44]1([C:50]2[N:55]=[CH:54][C:53]([NH2:56])=[CH:52][CH:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:16])[CH2:12][C:13]([NH:56][C:53]2[CH:54]=[N:55][C:50]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:51][CH:52]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: Nc1ccc(-c2ccccc2)nc1
Reactant: O=C(O)CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCC(Oc2cc(F)ccc2Cl)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 17.4 %

Procedure:
To a stirred solution of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-propionic acid (0.1 g, 0.00032 mole) in DMF (5 mL) was added DMAP (0.059 g, 0.00048 mole), HOBt (0.051 g, 0.00038 mole) and EDCI.HCl (0.073 g, 0.00038 mole). After 2 minutes 6-phenyl-pyridin-3-ylamine (0.06 g, 0.00035 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (50% ethyl acetate in hexane) to afford 0.026 g (19%) of 3-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 468 (M+1)+, 93.7%, 1H NMR (CDCl3): δ 10.5 (s, 1H), 8.8 (s, 1H), 8.3 (d, 1H), 8.0 (d, 2H), 7.7 (d, 1H), 7.4 (m, 4H), 6.7 (m, 2H), 4.7 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.7 (m, 2H), 3.55 (s, 2H), 2.0 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:35]=[C:36]([CH:38]4[CH2:41][N:40]([C:42]5[CH:51]=[CH:50][C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[N:43]=5)[CH2:39]4)[N:37]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OCC5C=CC=CC=5)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1>CO.C(Cl)Cl.[Pd]>[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:35]=[C:36]([CH:38]5[CH2:39][N:40]([C:42]6[CH:51]=[CH:50][C:49]7[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=7)[N:43]=6)[CH2:41]5)[N:37]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C5CN(c6ccc7ccccc7n6)C5)cn34)cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: c1ccc2nc(N3CC(c4cn5c(-c6ccc(N7CCNCC7)nc6)cnc(N6CCOCC6)c5n4)C3)ccc2c1

Procedure:
Compound 29d (100 mg, 0.147 mmol) in MeOH (15 mL) and DCM (5 mL) was hydrogenated over 10% Pd/C (20 mg) overnight under balloon pressure. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated and dried under reduced pressure to obtain the title compound 99. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J=2.3 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.84-7.92 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.49-7.60 (m, 2H), 7.33-7.37 (m, 1H), 7.19-7.25 (m, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 5.77 (s, 1H), 4.44-4.52 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 4.10-4.20 (m, 4H), 3.68-3.78 (m, 8H), 3.36 (br. s., 2H), 2.97-3.10 (m, 2H), 2.56 (br. s., 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H33N9O: 548.3 (M+H). Found 548.3.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][C:49](O)=[O:50])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[O:50]=[C:49]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:48][CH2:47][NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.9 g, 15.4 mmol), pyrrolidine (3.2 g, 16.8 mmol) and diisopropylethylamine (5.4 mL, 42.2 mmol) was added to a suspension of 3-((tert-butoxycarbonyl)amino)propanoic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (3.0 g, 88% yield). MS m/z: 243.26 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.F[C:16]1[CH:21]=[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])[C:19]([F:35])=[CH:18][C:17]=1[N+:36]([O-:38])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:35][C:19]1[C:20]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:21][C:16]([O:1][C:2]2[C:3]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:4][C:5]([CH3:8])=[N:6][CH:7]=2)=[C:17]([N+:36]([O-:38])=[O:37])[CH:18]=1
Reactant: COC(=O)COc1nc(C)ncc1O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To a mixture of 0.15 g of 5-hydroxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 0.16 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene and 2 ml of N,N-dimethylformamide was added 74 mg of potassium carbonate, and the mixture was stirred for 1 hour at 70° C. The reaction solution was cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:33]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:32])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:31])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]2)[N:6]=1.[F:41][C:42]1[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:43]=1B(O)O>>[NH2:33][C:4]1[S:3][C:2]([C:43]2[C:44]([F:49])=[CH:45][CH:46]=[C:47]([F:48])[C:42]=2[F:41])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:31])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]([O:29][CH3:30])[CH2:16][O:15]1)=[O:32]
Reactant: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC[C@H]1NC(=O)OC(C)(C)C
Reactant: OB(O)c1c(F)ccc(F)c1F
Product: CO[C@H]1CO[C@H](c2c(NC(=O)c3nc(-c4c(F)ccc(F)c4F)sc3N)cnn2C)CC[C@H]1N

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6R)-5-(tert-butoxycarbonylamino)-6-methoxy-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 98), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 262. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.91 (s, 1H), 7.66-7.53 (m, 3H), 7.37-7.26 (m, 1H), 5.08 (t, J=5.6 Hz, 1H), 3.92-3.71 (m, 2H), 3.69 (s, 3H), 3.46-3.33 (m, 1H), 3.33-3.21 (m, 1H), 3.02 (s, 3H), 2.47-2.35 (m, 1H), 1.76-1.63 (m, 1H), 1.62-1.50 (m, 2H). LCMS (ES+) m/z 497 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C([O:19][CH:20](OCC)[CH:21]=[CH2:22])C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[K+].Cl>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2](/[CH:22]=[CH:21]/[CH:20]=[O:19])=[CH:3][CH:4]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CC(OCC)OCC
Reactant: Brc1ccc(CCCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C/C=C/c1ccc(CCCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.8 %

Procedure:
To a solution of 1-bromo-4-(3-phenylpropyl)-benzene (684 mg, 2.48 mmol) in DMF (10 mL) were added acrolein diethyl acetal (1.7 mL, 11.1 mmol), tetrabutylammonium acetate (1.87 g, 6.2 mmol), potassium carbonate (514 mg, 3.72 mmol), potassium chloride (185 mg, 2.48 mmol), and palladium(II) acetate (50 mg, 0.22 mmol). After stirring at 90° C. for 4 h, the reaction mixture was cooled to RT and HCl (2M, 15 mL) was added. After stirring for 10 min at RT, the mixture was extracted with MTBE and washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Purification by MPLC (20% ethyl acetate in hexanes) gave 390 mg (2E)-3-[4-(3-phenylpropyl)phenyl]acrylaldehyde as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:13])([F:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[BH4-].[Na+].Cl>C(O)C>[F:12][C:5]([F:13])([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of difluoro-phenyl-acetic acid ethyl ester (5.0 g, 25.0 mmol) in ethanol (150 mL) was added sodium borohydride (1.37 g, 36 mmol) at rt. The mixture was stirred for 2.5 h at room temperature. HCl aqueous (1N) was added and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the product 2,2-difluoro-2-phenyl-ethanol (3.4 g, 86.1%), which was used to the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[F:19])C(OC)=O)#[N:2].[Na+].[Cl-]>CS(C)=O.O>[F:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: COC(=O)C(CCC#N)c1ccc([N+](=O)[O-])cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCc1ccc([N+](=O)[O-])cc1F
Temperature: 160 °C
Reaction time: 24 h
Yield: 170.8 %

Procedure:
A mixture of compound 66 (1.2 g, 4.5 mmol), NaCl (0.8 g, 13.5 mmol) and water (1.4 mL) in DMSO (30 mL) was stirred at 160° C. for 24 h under N2. After cooling, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified with silica gel column chromatography (PE:EtOAc=5:1) to give the compound 67 (1.6 g, 43%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.99-8.04 (m, 1H), 7.91-7.96 (m, 1H), 7.38-7.44 (m, 1H), 2.93 (t, 2H, J=7.5 Hz), 2.41 (t, 2H, J=7.0 Hz), 1.98-2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:37]([O:44][C:45](=[O:48])[CH2:46]Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:46][C:45]([O:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:48])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N(CC(=O)OCc2ccccc2)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 115.5 %

Procedure:
To a solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (1 g) in DMF (20 ml) was added potassium carbonate (0.92 g) and benzyl-2-bromoacetate (0.33 g), and the mixture was stirred under nitrogen at room temperature for 72 h. The reaction mixture was filtered, concentrated under reduced pressure, and the residue partitioned between water and DCM. The organic layer was isolated, dried (over magnesium sulphate and purified by SPE (silica, cyclohexane:ethyl acetate 2:1) to give the title compound (1.0 g) as a white solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10]([Cl:22])[CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[C:1]([NH:8][CH2:9][CH:10]([Cl:22])[CH2:11][S:12]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:31])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC(Cl)CSc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cl)CS(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step B, 2.II, 207 mg, in 9 ml of CH2Cl2 is treated dropwise at 0° C. over 70 minutes with 121 mg of m-chloroperbenzoic acid (MCPBA) (85%) in 9 ml of CH2Cl2 under N2. The solution is stirred 1 hour at 25° C., washed with aqueous NaHCO3, dried with MgSO4, filtered, evaporated (209 mg) and purified by preparative thin layer chromatography on silica gel with 4:1 (v/v) CHCl3 -ethylacetate, affording 97 mg of pure product, Rf 0.25.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:15]3[CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[NH:18][C:14]=3[CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H-].[Na+].[Br:25][CH2:26][CH2:27]Br>CN(C=O)C.O>[Br:25][CH2:26][CH2:27][N:18]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:15]=2[CH:16]=[C:17]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOc1cccc(-c2nccc3[nH]c(C(=O)OC)cc23)c1
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCBr)c1
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(3-ethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (230 mg, 0.776 mmole) in DMF (7 mL) was added NaH (60% dispersion in mineral oil, 40 mg, 1.000 mmole) at RT. After gas evolution had ceased 1,2-dibromoethane (1 mL, 11.60 mmole) was added rapidly. After stirring overnight the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine then dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-25 g SiO2, 0-50% EtOAc/hexanes) gave the title compound (135 mg, 43%) as a clear gum. 1H NMR (400 MHz, CDCl3): δ8.51 (d, J=6.0 Hz, 1 H); 7.60 (d, J=1.0 Hz, 1 H); 7.49-7.45 (m, 2 H); 7.40 (m, J=7.9 Hz, 1 H); 7.31 (dd, J=6.0, 1.0 Hz, 1 H); 6.99 (ddd, J=8.2, 2.6, 1.1 Hz, 1 H); 4.92 (t, J=6.83 Hz, 2 H); 4.12 (q, J=7.0 Hz, 2 H); 3.91 (s, 3 H); 3.71 (t, J=7.12 Hz, 2 H); 1.43 (t, J=7.12 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[CH2:27]([O:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:8](=[O:12])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (5.00 g) in dimethyl formamide (150 ml) under nitrogen at room temperature, was added sodium hydrogen carbonate (15.47 g). The reaction mixture was stirred at room temperature for 30 mins then allyl bromide (2.39 ml) was added, and stirring continued for a further 36 h at room temperature. The mixture was poured into water (200 ml) and the emerging precipitate was filtered and triturated with boiling methanol to give the desired compound as a beige solid in 50% yield. 1H NMR (360 MHz, DMSO-d6) 5 4.04 (2H, dd, J=6.45 Hz, J=1.84 Hz, OCH2CHCH2), 5.08 (2H, m, OCH2CHCH2), 5.88 (1H, m, OCH2CHCH2), 7.23 (1H, dd, J=12.45 Hz, J=3.00 Hz, 6-H), 7.36 (6H, m, Ph+8-H), 7.81 (1H, d, J=12.45 Hz, 5-H), 11.94 (1H, bs, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[C:13]([O:15]C)[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:15][C:13]1[CH:12]=[C:11]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:10]=[C:9]([O:8][CH3:1])[CH:14]=1
Reactant: CCOC(=O)C=Cc1cc(OC)cc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cc(O)cc(OC)c1
Reaction time: 15 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 3-(3-(benzyloxy)-5-methoxyphenyl)acrylate (6.00 g) in methanol (100 mL) was added 10% palladium-activated carbon (500 mg) was added, and the mixture was stirred for 15 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.00 g) as a colorless oil.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13]1[O:18][CH2:17][N:16]([C:19]([CH3:29])([CH3:28])[CH:20]([CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[CH2:27])[OH:21])[C:15](=[O:30])[C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCOCC>ClCCl>[CH3:12][C:13]1[O:18][CH2:17][N:16]([C:19]([CH3:28])([CH3:29])[C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[CH2:27])=[O:21])[C:15](=[O:30])[C:14]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1CCCC1C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Reaction time: 3 h
Yield: 50.3 %

Procedure:
Powdered molecular sieve (4 A, 17 g) and pyridinium chlorochromate (4.3 g) were added to a stirred solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.1 g) in dichloromethane at 20° C. After 3 hours, ether was added and the mixture filtered, evaporated and the residue purified by silica gel column chromatography eluting with n-hexane/ethyl acetate (3:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-one (Compound 1072, 1.55 g), NMR: 1.49(s,3H), 1.55(s,3H), 1.93(s,3H), 1.85-2.00(3H) 2.25-2.52(2H), 3.89(1H), 4.87(s,1H), 5.28(2H), 7.2-7.4(5H).
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:26]5[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=5)=[C:18]4[O:21][CH2:22]OCC)=[CH:13][C:12]=3[O:35]C)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH:45]1[C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[C:12]([O:35][CH2:17][CH2:18][O:21][CH3:22])[CH:13]=3)[C:18]=2[O:21][CH3:22])=[CH:34][CH:33]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOCOc1c(-c2ccc(C(=O)Cl)cc2)ccc2cc(OC)c(C34CC5CC(CC(C5)C3)C4)cc12
Reactant: c1ccc(CN2CCNCC2)cc1
Product: COCCOc1cc2ccc(-c3ccc(C(=O)C4CNCCN4Cc4ccccc4)cc3)c(OC)c2cc1C12CC3CC(CC(C3)C1)C2
Yield: 64.6 %

Procedure:
Following the procedure of Example 27(b), but reacting 7.3 g (14.4 mmol) of 4-[7-(1-adamantyl)-6-methoxy-ethoxymethoxy-2-naphthyl]benzoic acid chloride with 2.5 ml (14.4 mmol) of 4-benzylpiperazine, 3 g (33%) of the expected compound were obtained, which compound had a melting point of 176°-7° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:24]2[C:16](=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=2)[C@@H:15]([N:25]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:26]2[N:27]=[N:28][N:29]([CH3:31])[N:30]=2)[CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[F:46][C:43]([F:44])([F:45])[C:35]1[CH:34]=[C:33]([CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=1)[CH2:32][N:25]([C:26]1[N:27]=[N:28][N:29]([CH3:31])[N:30]=1)[C@@H:15]1[C:16]2=[CH:17][C:18]3[CH2:19][O:20][CH2:21][C:22]=3[CH:23]=[C:24]2[N:11]([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13][CH2:14]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CCOCc3ccccc3)c3cc4c(cc32)COC4)n1
Agent: [Pd]
Solvent: CO
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(CCO)c3cc4c(cc32)COC4)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Purge a solution of (S)-[5-(2-Benzyloxy-ethyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.14 mmol) in methanol (20 mL) with nitrogen and add a catalytic amount of Pd/C. Purge the resulting mixture with hydrogen and stir at room temperature for 5 h. Purge the reaction with nitrogen, filter through Celite®, and wash with methanol (50 mL). Remove solvent under vacuum. Chromatograph the crude product over silica gel, eluting with ethyl acetate/hexane (5-100%) to provide the title compound as a colorless foam. MS (ES+): 557 (M+H).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:36]4[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: OCCN1CCNCC1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinamide was prepared starting from intermediate E and N-(2-hydroxyethyl)piperazine. MS calcd. for C28H28ClN5O3 [(M+H)+] 518.2, obsd. 518.0.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)([C:18]#[N:19])[CH:10]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[Cl:33][C:29]1[CH:28]=[C:27]([CH:10]2[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]2([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:18]#[N:19])[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)CC1C(C(=O)OC(C)(C)C)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1C(C(=O)O)NC(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 76 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 32c (1.2 g, 2.5 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-5-(3-Chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-3-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a yellow solid (1.0 g, 76%).