Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[F:56][C:57]([F:61])([F:60])[CH2:58][OH:59]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:56][C:57]([F:61])([F:60])[CH2:58][O:59][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: OCC(F)(F)F
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(OCC(F)(F)F)cc2CN1Cc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 34.4 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 0.298 mmol), palladium(II) acetate (0.004 g, 0.02 mmol), rac-2-(di-t-butylphosphino)-1,1′-binaphthyl (0.009 g, 0.025 mmol), and cesium carbonate (0.163 g, 0.5 mmol) in toluene (5 mL) was treated with 2,2,2-trifluoro ethanol (0.061 mL, 0.6 mmol) and stirred at 110° C. for 12 h. After this time the solvent was evaporated and silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded the desired product (0.040 g, 34%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.39 (q, 2H), 4.73 (s, 2H), 6.86 (s, 1H), 6.98 (s, 1H), 7.23 (d, 2H), 7.34 (d, 2H). GC-MS: m/z 389 (M)+0.354, (M−35)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[O:9]1[CH2:14][CH2:13][C:12](=[CH:15][C:16](O)=[O:17])[CH2:11][CH2:10]1.OC1C=C(O)C=C2C=1C(=O)CC(C)(C)O2>>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:15][C:12]3([O:5]2)[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)C=C1CCOCC1
Agent: CC1(C)CC(=O)c2c(O)cc(O)cc2O1
Product: O=C1CC2(CCOCC2)Oc2cc(O)ccc21

Procedure:
The subject compound was synthesized from resorcinol and (tetrahydropyran-4-yliden)acetic acid according to the method described in Example 42, (1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[C:18]([F:25])[C:17]=1[O:26][CH3:27].[F-].[Cs+]>COCCOC.O.C(OCC)(=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>[CH3:1][O:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:26][CH3:27])[C:18]=2[F:25])[N:6]=1)=[O:4]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(Cl)nc(N)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1OC
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
6-Amino-2-chloro-5-methoxypyrimidine-4-carboxylic acid methyl ester (0.2 g, 0.9 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (0.29 g, 1.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (65 mg, 0.1 mmol), and cesium fluoride (0.28 g, 1.9 mmol) were combined in 1 mL of 1,2-dimethoxyethane and 1 mL of water. The reaction mixture was heated in a CEM microwave at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min and 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, washed with brine, dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (162 mg, 51.1% yield): mp 155-158° C.; 1H NMR (CDCl3): δ 7.58 (dd, 1H), 7.20 (dd, 1H), 5.56 (br s, 2H) 4.00 (s, 3H), 3.99 (d, 3H), 3.94 (s, 3H).
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[O:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[C:43]([O:42][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:44]=2)=[O:21])[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 16 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate from the previous step (0.186 g, 0.5 mmol) was reacted with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]urea as solid (0.037 g, 16%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.54 (s, 2H), 7.56 (m, 7H), 7.50 (d, 1H), 7.38 (s, 1H), 7.22 (m, 2H), 6.54 (s, 1H), 4.73 (m, 2H), 4.58 (m, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 1.33 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [N:1]1([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C([O-])(O)=O.[Na+].[Li+].[Cl-]>C(Cl)Cl>[Cl:31][CH2:12][CH2:11][CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCC(c1ccccc1)n1ccc2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCCC(c1ccccc1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 3-indol-1-yl-3-phenyl-propan-1-ol (0.166 g, 0.66 mmol) in CH2Cl2 (20 mL) and triethylamine (0.087 g, 0.85 mmol) at 0° C. was added methanesulfonyl chloride (0.083 g, 0.72 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into an aqueous saturated solution of NaHCO3 (50 mL) and extracted with CH2Cl2 (2×50 mL). The organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The residue was diluted in MeCN (50 mL) and treated with LiCl (0.084 g, 1.98 mmol), and the reaction mixture was heated to reflux temperature for 24 hours. The solvent was removed under vacuum and the crude product was chromatographed (SiO2, Hexanes/EtOAc, 9:1) to afford 0.145 g (81% yield) of 1-(3-chloro-1-phenyl-propyl)-1H-indole as an oil.
Reaction SMILES: C[C:2]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:9]#[N:10])[C:3]#[CH:4].[F-].[Cs+].Cl.[CH2:20](N(CC)C1C=CC=CC=1)C>>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]2[C:6]=1[O:5][C:2]([CH:3]([CH3:4])[CH3:20])=[CH:16]2
Reactant: C#CC(C)(C)Oc1cc(C#N)ccc1OC
Reactant: CCN(CC)c1ccccc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc(C#N)c2cc(C(C)C)oc12

Procedure:
5.3 g of 3-(1,1-dimethylprop-2-yn-1-yloxy)-4-methoxybenzonitrile and 5.3 g of cesium fluoride are refluxed for 12 h in 30 ml of N,N-diethylaniline with nitrogen aeration. After cooling, the mixture is stirred into 300 ml of 4 N hydrochloric acid, the resulting emulsion is extracted three times with 5.0 ml of ethyl acetate, and the organic extracts are combined, dried over calcined potassium carbonate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene. After evaporating the corresponding fractions, the title compound is obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=3[N:12]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc2nc(Nc3ccc(Br)cc3)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
1,2-Diamino-5-trifluoromethylbenzene (0.25 g, 1.42 mmol) was diluted in toluene (5 mL) and treated with 4-bromophenylisothiocyanate (0.30 g, 1.42 mmol). The dark solution was stirred at 100° C. for 15 minutes, then treated with 1,3-dicyclohexylcarbodiimide (0.44 g, 2.13 mmol). The reaction was maintained at 100° C. for 5 h. The reaction was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4), and concentrated under reduced pressure. The dark brown oil was purified by flash chromatography on silica gel, eluting with a gradient from 9:1 hexanes/ethyl acetate to 100% ethyl acetate. The title compound was obtained as a light pink solid (0.50 g, 30%). 1H NMR (300 MHz, DMSO-d6) δ 11.3 (broad d, 1 H), 9.87 (d, 1 H), 7.50 (d, 2 H), 7.61 (d, 1 H), 7.55–7.42 (m, 3 H), 7.35–7.30 (m, 1 H); LC/MS m/z 356.2 (MH+), retention time 2.33 minutes.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][NH:9]1.[OH-].[Na+]>CO>[CH3:3][O:4][C:5]1[CH:20]=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH:12]([OH:16])[CH2:11][CH2:10][NH:9]1
Reactant: COc1ccccc1CC1NCCC(=O)C1(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1CC1NCCC(O)C1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.31 g) is added to 2-(2-methoxy-benzyl)-3,3-dimethyl-piperidin-4-one (2.00 g, prepared according to J. Med. Chem. 2002, 45, 3755-3765 from racemic starting material) dissolved in methanol (20 mL). The solution is stirred at room temperature for 3 h and then 1 M sodium hydroxide solution (40 mL) is added. After stirring for another 10 min, the mixture is extracted with dichloromethane. The combined organic extracts are washed with water and dried (MgSO4). The solvent is evaporated to give the title product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:18]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[C:2]3[N:1]=[N:18][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2nsc(C(N)=O)c2N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nsc3c(=O)[nH]nnc23)cc1
Reaction time: 1 h
Yield: 78.5 %

Procedure:
1 g of 4-amino-3-(4-methoxyphenyl)-5-isothiazolecarboxamide in 10 ml of glacial acetic acid and 3 ml of concentrated hydrochloric acid was stirred at 0° C. during the addition of a solution of 416 mg of sodium nitrite in 5 ml of water. The cooling bath was removed, the mixture was stirred for 1 hour and the precipitated product was removed by filtration. Recrystallization from aqueous dimethylformamide gave 820 mg of 7-(4-methoxyphenyl)-isothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one as an off-white solid of melting point 213° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:12][CH:11]2[NH:13][CH:7]([CH2:8][O:9][CH2:10]2)[CH2:6]1)=[O:4].[CH3:14][O:15][C:16]([C:18]1[C@H:19]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[Cl:38])[N:20]=[C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[NH:22][C:23]=1[CH2:24]Br)=[O:17].CCN(C(C)C)C(C)C>C(Cl)CCl.CCOC(C)=O>[Cl:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[C@H:19]1[C:18]([C:16]([O:15][CH3:14])=[O:17])=[C:23]([CH2:24][N:13]2[CH:7]3[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:12][CH:11]2[CH2:10][O:9][CH2:8]3)[NH:22][C:21]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[N:20]1
Reactant: COC(=O)C1CC2COCC(C1)N2
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(CN2C3COCC2CC(C(=O)OC)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution 3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester (90 mg, 0.48 mmol) (PharmaBlock (Nanjing) R&D Co. Ltd, CAS: 1363382-76-6) and (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (104 mg, 0.24 mmol) in ClCH2CH2Cl (5 mL) was added DIPEA (0.15 mL, 0.48 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc (60 mL), washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4, concentrated under reduced pressure to give methyl 9-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylate as a crude product which was used directly in next step.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([O:18]CCCC)=[O:17])[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1>[OH-].[Na+]>[O:1]=[C:2]1[NH:7][N:6]=[CH:5][C:4]([C:8]([NH:10][C@@:11]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][O:13][CH2:12]2)=[O:9])=[CH:3]1
Reactant: CCCCOC(=O)[C@]1(NC(=O)c2cn[nH]c(=O)c2)CCOC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@]1(C(=O)O)CCOC1)c1cn[nH]c(=O)c1
Yield: 71 %

Procedure:
n-Butyl(S)-3-[(6-oxo-1,6-dihydro-pyridazine-4-carbonyl)-amino]-tetrahydrofuran-3-carboxylate (21.0 g, 67.9 mmol) was stirred vigorously in 200 mL of 1N sodium hydroxide solution for 1 hour. The mixture was then extracted twice with 100 mL of diethyl ether, the alkaline aqueous phase was then combined with 50 mL of 4N hydrochloric acid. The mixture was then evaporated to dryness and the residue was stirred with 150 mL ethanol. Undissolved ingredients were then filtered off and the filtrate was evaporated down. In this way the product was obtained in a yield of 71% of theory. The product thus obtained was further processed without purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1.O>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:31][CH2:30][CH2:29][O:28][CH2:27][C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCOCc1ccncc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 68.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (7.4 mL, 53 mmol) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (9.78 g, 44.2 mmol) in anhydrous DMF (200 mL). 2-(Pyridin-4-ylmethoxy)ethylamine (6.8 g, 45 mmol) was added, and the reaction was stirred at room temperature for 17.5 hours. The reaction solution was slowly added to water (1.8 L) and stirred for two hours to form a precipitate, which was isolated by filtration and washed with cold hexane (200 mL). The solid was dried under reduced pressure for one hour to provide 10.15 g of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine as a yellow solid. An analysis by HPLC indicated that starting material and an isomer were present as impurities.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[H][H]>C(OCC)(=O)C.[Pd]>[S:1]1[C:5]([C@H:6]([OH:25])[CH2:7][CH2:8][C@H:9]2[C@H:13]([OH:14])[CH2:12][C:11](=[O:15])[C@@H:10]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: [H][H]
Reactant: O=C(O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O)[C@@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCCCCC[C@H]1C(=O)C[C@@H](O)[C@@H]1CC[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,3R)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-hydroxy-5-oxocyclopentyl)hept-5-enoic acid (Example 7, 1 molar equivalent) is dissolved in ethyl acetate (0.05 M) under a nitrogen atmosphere. 10% Pd/C (10 mol %) is added and hydrogen gas is introduced. After stirring for several hours at room temperature the reaction mixture is filtered over Celite. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes (+0.4% acetic acid) to afford the title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][CH:23](OC)[CH:24]=[CH2:25].[OH-].[Na+]>O.C(OCC)C>[OH:2][C:1]1[CH:3]=[C:4]2[C:6]([CH2:25][CH2:24][CH:23]([O:22][CH3:21])[O:5]2)=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: C=CC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COC1CCc2ccc(O)cc2O1
Reaction time: 4 h
Yield: 43 %

Procedure:
A 500-milliliter flask fitted with a dropping funnel was charged with 11.0 g of resorcinol, 0.2 g of p-toluenesulfonic acid monohydrate and 100 ml of diethyl ether for dissolution, and the mixture was cooled with ice. To this solution was slowly added dropwise 13.0 ml of acrolein dimethyl acetal under room temperature. After the dropwise addition, the mixture was stirred for 4 hours while being cooled with ice. To this was added 30 ml of water, the solution was weakly alkalized with a 5% sodium hydroxide aqueous solution, and the organic layer was then washed. After the separation of layers in the solution, the aqueous layer was extracted three times with 50 ml of diethyl ether, and thus obtained ether layers were combined with the previous organic layer. The combined layer was washed with 50 ml of water, and diethyl ether was then removed by distillation in vacuo therefrom. The resulting residue was purified by distillation to obtain 7.7 g of a colorless liquid (yield 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1.C(O[Na])(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Brc1cncnc1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncnc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of 5-bromopyrimidine (325 mg, 2.04 mmol), 4-amino-1-Boc-piperidine (425 mg, 2.12 mmol), Pd2(dba)3 (41 mg, 0.045 mmol), (±)-BINAP (78 mg, 0.13 mmol) and t-BuONa (210 mg, 2.19 mmol) in freshly degassed toluene (7.0 mL) was stirred at 85° C. under argon for 2 hours. Basic work-up and purification gave 4-(pyrimidin-5-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a pale brown solid (415 mg, 73%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][CH2:21][C:22]([OH:30])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]2[NH:20][CH2:21][C:22]([O:30][S:32]([CH3:31])(=[O:34])=[O:33])=[C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:24]=2)[CH2:17][CH2:16][CH:15]([O:18][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1=C(O)CNC(C2(NC(=O)OCc3ccccc3)CCC(O)CC2)=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(OS(C)(=O)=O)CNC(C2(NC(=O)OCc3ccccc3)CCC(OS(C)(=O)=O)CC2)=N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 853.1 %

Procedure:
To a stirred solution of ethyl 2-(1-(benzyloxycarbonylamino)-4-hydroxycyclohexyl)-5-hydroxy-1,6-dihydropyrimidine-4-carboxylate (1.75 g, 4.05 mmol) in THF (25 mL) was added methanesulfonyl chloride (0.94 mmol, 12.17 mmol) and triethylamine (1.7 mL, 12.75 mmol) at 5° C. and the mixture stirred at room temperature for 18 h. The resulting white precipitate was filtered off and washed with THF. The filtrate and washings were concentrated to afford an amber oil. A solution of this oil in methanol (20 mL) was treated with K2CO3 (560 mg, 4.05 mmol) at room temperature for 3 h. The mixture was then concentrated and the residue dissolved in ethyl acetate (200 mL), washed with 1N HCl (100 mL) followed by brine (100 mL) and then dried (Na2SO4), filtered and concentrated to give 2.3 g of the title compound as an amber oil, which was used in the next step without further purification. LCMS (M+H)=588.41.
Reaction SMILES: [C:1]12([CH2:8][Mg]Br)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH:11]([CH:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:12]>C1COCC1>[C:1]12([CH2:8][CH2:12][CH:11]=[CH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2
Reactant: C=CC(Cl)c1ccccc1
Reactant: Br[Mg]CC12C=CC(CC1)C2
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CCC12C=CC(CC1)C2

Procedure:
Monomer norbornenylethylstyrene (N) was first synthesized as shown in FIG. 1. Norbornenylmethyl bromide (mainly the endo isomer) was treated with magnesium in THF to form the corresponding Grignard reagent. In the presence of a catalytic amount of Li2CuCl4, this norbornenylmethyl magnesium bromide (1.15 equiv) was coupled with vinylbenzyl chloride (1 equiv) at −78° C. in THF to produce the p-norbornenylethylstyrene (N) in a conversion of 85%. The 13C and 1H NMR spectra of purified N (silica column/hexanes) indicated a product of high purity and all resonances were consistent with the structure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([CH2:15][PH:16]([O:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:26]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CC(C[PH](=O)OCCc1ccc(N)cc1)C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC(C[PH](=O)OCCc1ccc(NC(=O)c2ccccc2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
2-[(4-Aminobenzyl)methoxyphosphinoylmethyl]4-methylpentanoic acid benzyl ester (230 mg, 0.57 mmole), benzoyl chloride (96 mg, 0.68 mmole), and triethylamine (69 mg, 0.68 mmole) were combined in cold (ice bath) chloroform (10 ml). After stirring for 1 hour at ice bath temperature the reaction mixture was diluted with chloroform (150 ml) and washed with water (20 ml), 1N hydrochloric acid (2×20 ml) and saturated sodium bicarbonate solution (2×20 ml) and dried with magnesium sulfate. After filtration and concentration the yellow residue was chromatographed (ethyl acetate) to give 190 mg (66%) of 2-[(4-Benzoylaminobenzyl)methoxy phosphinoylmethyl]4-methylpentanoic acid benzyl ester as a light yellow oil.