Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH:35]([F:37])[F:36]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:35]([F:37])[F:36])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.080 g), N,N-dimethylformamide (2.0 mL) and potassium carbonate (0.080 g) at −80° C. was added chlorodifluoromethane (0.4 mL). The flask was sealed and the resulting mixture warmed to room temperature and then stirred at this temperature for 17 hours. The excess chlorodifluoromethane was allowed to evaporate and the residue diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a light brown solid, 0.10 g.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:12])[CH2:10][CH3:11])[S:6][CH:7]=1.[C:13]1([CH:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:9]([NH:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][N:24]2[CH2:25][CH2:26][CH:21]([O:20][CH:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:22][CH2:23]2)[N:4]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Nc1nc(CCl)cs1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 0 °C
Yield: 26.9 %

Procedure:
A stirred mixture of 4-chloromethyl-2-propionylaminothiazole (0.64 g), 4-(diphenylmethoxy)piperidine (0.8 g) and sodium bicarbonate (0.3 g) in N,N-dimethylformamide (8 ml) was heated at 80° to 90° C. for 2 hours. The reaction mixture was poured into ice water. The resulting precipitate was collected, washed with water and dried in vacuo. The precipitate was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give white crystals. The crystals were recrystallized from a mixture of toluene and diisopropyl ether and dried under reduced pressure to give 2-propionylamino-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.35 g).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2>>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: Brc1cnc2ccccc2c1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cnc3ccccc3c1)O2

Procedure:
This compound was obtained by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 2.3 g (10 mmol), with 3.12 g (15 mmol) of 3-bromoquinoline as described in Example 15. The product was crystallized from methylene chloride/ethanol and was recrystallized from ethyl acetate to yield tan crystals with m.p. 199°-203°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:14]=2)[C:5]([CH3:25])=[C:4]([CH3:26])[N:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[CH:14]=[C:13]([CH2:12][NH:11][C:6]3[C:5]([CH3:25])=[C:4]([CH3:26])[N:3]=[C:2]([N:41]([CH2:40][C:39]4[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:52][CH:51]=4)[CH2:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=4)[C:7]=3[N+:8]([O-:10])=[O:9])[O:17][N:16]=2)=[CH:19][CH:20]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCc2cc(-c3ccc(F)cc3)no2)c1C
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)c(C)c(NCc3cc(-c4ccc(F)cc4)no3)c2[N+](=O)[O-])cc1
Yield: 94 %

Procedure:
Under a nitrogen atmosphere, 2-chloro-N-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-5,6-dimethyl-3-nitropyridin-4-amine (25.00 g, 66.35 mmol), toluene (250 mL), triethylamine (11.1 mL, 79.6 mmol), and N,N-bis(4-methoxybenzyl)amine (18.8 g, 73.0 mmol) were combined and heated at reflux for three days. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate and saturated aqueous potassium carbonate. The ethyl acetate layer was separated and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with water and brine. The combined aqueous fractions were extracted with ethyl acetate. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 37.29 g of N4-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-N2,N2-bis(4-methoxybenzyl)-5,6-dimethyl-3-nitropyridin-2,4-diamine as an orange solid.
Reaction SMILES: COC1C=CC([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([NH:23][C:24](=[O:37])[C@H:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[O:28])[C:17]3=[O:38])[CH:14]=2)=CC=1.[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([NH:23][C:24](=[O:37])[C@H:25]([CH2:33][CH:34]([CH3:35])[CH3:36])[C@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[O:28])[C:17]3=[O:38])[CH:14]=2)=[CH:43][CH:42]=1
Reactant: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1CCCCN(Cc2cncc(-c3ccc(OC)cc3)c2)C1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1CCCCN(Cc2cncc(-c3ccc(C(F)(F)F)cc3)c2)C1=O

Procedure:
The general procedure reported for the compound of Example 30 was followed using 4-trifluoromethylphenyl boronic acid. Purification by HPLC afforded 6.0 mg of the desired product from as its trifluoroacetic acid salt. MS (M+Na)+=583.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[NH:12]C(=O)C)([O:3][CH3:4])=[O:2]>CO>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[C:6]=1[NH2:12]
Reactant: COC(=O)c1cccc(Cl)c1NC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(Cl)c1N
Yield: 18.3 %

Procedure:
A stirred solution of 0.1 g (2.3 mmole) of N-(2-carbomethoxy-6-chlorophenyl)acetamide in 10 mL of methanol containing 0.2 mL of conc. H2S04 was heated at reflux for ca. 18 hr. The methanol was removed in vacuo and the residue treated with 5 mL of EtOAc and 5 mL of H2O respectively. The phases were mixed and separated. The aqueous layer was extracted with 2×5 mL of EtOAc and the combined EtOAc solution dried (Na2SO4), filtered, and the solvent removed from the filtrate in vacuo. The product was purified by preparative thin layer chromatography (TLC) using 9:1 (v/v) CH2Cl2EtOAc. The band containing product was extracted with EtOAc and filtered. The solvent was removed from the filtrate in vacuo to afford 78 mg (91% yield) of methyl 3-chloroanthranilate as a light yellow solid: 1H NMR (CDCl3, TMS) δ7.80 (d, 8 Hz, H6), 7.39 (d, 8 Hz, H4), 6.55 (t, 8 Hz, H5), 6.25 (broad s, NH2), 3.90 (s, OCH3).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[CH:26]=[C:25]3[C:21]([C:22]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28]4)=[N:23][NH:24]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:45]Cl>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13](/[CH:16]=[CH:17]/[C:18]2[CH:26]=[C:25]3[C:21]([C:22]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:32]4)=[N:23][N:24]3[CH2:45][C:44]3[CH:47]=[CH:48][C:49]([Cl:50])=[C:42]([Cl:41])[CH:43]=3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)c(Cl)c3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.42 h
Yield: 102.3 %

Procedure:
Sodium hydride (12.2 mg; 0.304 mmol) was added to a stirred solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl} piperidine-1-carboxylic acid tert-butyl ester (145 mg; 0.276 mmol) in dry DMF (5 ml) and the mixture was stirred at 23° under nitrogen for 25 min. 3,4-Dichlorobenzyl chloride (0.043 ml, 0.304 mmol; Aldrich) was added, and the mixture was stirred at 23° for 18 h. The solvent was evaporated in vacuo and the residue partitioned between water (25 ml) and ethyl acetate (3×20 ml). The organic layers were washed with 50:50 brine: water (30 ml) and brine, dried (MgSO4) and evaporated in vacuo to give a yellow oil (193 mg). Purification by flash chromatography on silica gel (Merck 9385), eluting with ether: cyclohexane 70:30 gave the title compound as a colourless oil (117 mg; 62%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:30]([N:27]([CH2:28][CH3:29])[C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:33][CH:32]=1)[CH3:31]
Reactant: CCN(CC)C(=O)c1ccc(C2(c3cccc(O)c3)CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(O)c3)CCNCC2)cc1
Reaction time: 20 h
Yield: 84.3 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-N,N-diethylbenzamide (1.11 g, 2.49 mmol) in acetic acid (8 mL) in a Parr pressure bottle was added Pd(OH)2 (10% on carbon, 0.4 g). The reaction mixture was shaken under 50 psi of H2 for 20 hours. The reaction mixture was then filterd through celite. The celite cake was washed with EtOAc (250 mL) and the organic layer was concentrated to remove the acetic acid. The residue was partitioned between CH2Cl2 (10 mL) and 30% aqueous NH40H (10 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 0.74 g of N,N-Diethyl-4-[4-(3-hydroxy-phenyl)-piperidin-4-yl]-benzamide (83% yield) which was used with no further purification. 1HNMR (400 MHz, CD3CO2D) δ 7.24-7.06 (comp, 5H), 6.75 (s, 1H), 6.70 (d, 1H), 6.58 (d, 1H), 3.49-3.40 (comp, 2H), 3.21-3.15 (comp, 2H), 2.90-2.85 (comp, 4H), 2.39-2.33 (comp, 4H), 1.20-1.15 (comp, 3H), 1.08-1.02 (comp, 3H); MS (M+1) 353.2.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].[F:25][C:26](I)([F:31])[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.C(OCC)(=O)C.O>[F:25][C:26]([F:31])([C:21]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([C:15]([F:23])([F:24])[F:14])[CH:22]=1)[C:27]([F:30])([F:29])[F:28]
Reactant: Nc1ccccc1C(F)(F)F
Reactant: FC(F)(F)C(F)(F)I
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(C(F)(F)C(F)(F)F)cc1C(F)(F)F
Temperature: -30 °C
Reaction time: 9 h
Yield: 20.7 %

Procedure:
To 40 ml of an aqueous solution of 7.04 g (40.4 mmol) of 85% sodium hydrosulfite and 3.40 g (40.4 mmol) of sodium hydrogen carbonate were added 13.6 g (33.7 mmol) of 2-(trifluoromethyl)aniline and 40 ml of DMF. To this reaction liquid was added 50 ml of a solution of 11.2 g (45.5 mmol) of 1,1,2,2,2-pentafluoroethyliodide in DMF (DMF was cooled to −30° C., and 1,1,2,2,2-pentafluoroethyl iodide was dissolved therein), and placed in an autoclave, followed by stirring at 110° C. for 9 hours. After being left to stand at room temperature overnight, water and ethyl acetate were added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1→5:1) to prepare 1.95 g (yield 21%) of a target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH2:9])[S:5][CH:6]=1.Cl[C:11]1[N:12]=[C:13]([NH2:29])[C:14]2[N:15]=[CH:16][N:17]([C:27]=2[N:28]=1)[C@@H:18]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]1[OH:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[S:5][CH:6]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCCc1cc(Br)cs1
Product: Nc1nc(NCCc2cc(Br)cs2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Condensation of 2-(4-bromo-2-thienyl)-ethylamine with 2-chloroadenosine essentially according to the procedure in the previous examples yields 2-[2-(4-bromo-2-thienyl)-ethylamino]-adenosine, melting at 136°-144°.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]([CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:12][CH:11]=1>C(O)(=O)C>[Br:1][C:12]1[CH:11]=[C:10]([F:9])[C:18]2[O:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)NCCCc1ccc(F)c2c1CCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CC(=O)NCCCc1c(Br)cc(F)c2c1CCO2
Reaction time: 48 h

Procedure:
N-Bromosuccinimide (569 mg) was added to a solution of N-[3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (690 mg) in glacial acetic acid (15 ml) at room temperature under nitrogen and the mixture stirred for 48 h. The solution was evaporated and the residue partitioned between sodium carbonate (2N; 20 ml) and ethyl acetate (20 ml). The combined organic extracts were washed with brine (25 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography. Eluting with dichloromethane/methanol 50:1 gave the title compound as a colourlss solid (644 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C@@H:24]4[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]4)=[O:23])=[CH:17][CH:16]=3)=[CH:11][NH:10][N:9]=2)[CH:7]=1.[NH:31]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:32]([C:39](O)=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C>C1COCC1>[C:45]([O:44][C:42](=[O:43])[NH:31][C@H:32]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]([N:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[C:22](=[O:23])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[OH:30])=[N:9][NH:10][CH:11]=2)=[CH:20][CH:19]=1)=[O:40])([CH3:48])([CH3:46])[CH3:47]
Reactant: O=C(Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)[C@@H]1CCCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCCC[C@H]1C(=O)Nc1ccc(C#Cc2c[nH]nc2-c2cc(Cl)ccc2O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a mixture of compound 26A (468 mg, 1.11 mmol) and BOC-D-Phg-OH (11A, 280 mg, 1.11 mmol) was added anhydrous THF (10 mL) and the resultant mixture was stirred at rt for 5 min. DIPC (0.258 mL, 1.67 mmol) was added slowly at rt. The reaction mixture was stirred at rt overnight. Solvent was removed. The residua were dissolved in a small amount of ethyl acetate. Solid was removed by filtration. The filtrate was purified by silica column chromatography eluting with hexanes-ethyl acetate (v/v 3/1, 2/1, 1/1) to provide the title compound (27A, 275 mg) as an off-color foam-like powder in 37.8% yield. 1H NMR (CDCl3, 500 MHz) δ 10.74 (br s, 2H), 8.75 (s, 1H), 8.52 (s, 1H), 7.82 (d, 2H, J=8.0 Hz), 7.79 (s, 1H), 7.58 (d, 2H, J=8.5 Hz), 7.43 (m, 5H), 7.21 (dd, 1H, J=8.0, 2.0 Hz), 6.98 (d, 1H, J=9.0 Hz), 5.61 (d, 1H, J=6.5 Hz), 5.56 (s, 2H), 3.90 (d, 1H, J=12.5 Hz), 3.20 (t, 1H, J=12.0 Hz), 2.51 (m, 1H), 1.62 (m, 2H), 1.55-1.30 (m, 11H), 0.91 (m, 1H). LCMS (ESI) m/z 720.27 (MNa+), 676.17 (MNa+), 654.22 (MH+), 554.11, 345.17, 289.12 (100). HPLC: tR=5.55 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)=[CH:5][CH:4]=[CH:3]1.[H-].[Li+].Br[CH2:30][CH2:31][CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43]>CN(C=O)C>[O:43]=[C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41](=[O:42])[N:33]1[CH2:32][CH2:31][CH2:30][O:1][C:2]1[N:7]=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(=O)[nH]3)nc12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cccc(OCCCN4C(=O)c5ccccc5C4=O)n3)nc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.091 g, 0.26 mmol) in DMF (2 mL) was added LiH (3.2 mg, 0.39 mmol) at 0° C. After stirring for 20 minutes, a solution of 2-(3-bromopropyl)isoindoline-1,3-dione (0.14 g, 0.52 mmol) in DMF (1 mL) was added, and the reaction was warmed up to ambient temperature and stirred for 17 hours. After cooling to 0° C., the reaction was quenched with ice-water (30 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica column chromatography, eluting with 1.5% MeOH/DCM to yield the desired product (0.117 g, 84% yield). MS (apci) m/z=541.1 (M+H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:17][CH3:18])([CH2:15][CH3:16])[O:4][C@@H:5]1[C@H:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[NH:7][C:6]1=[O:14])[CH3:2].C(N(C(C)C)CC)(C)C.[CH:28]([O:31][C:32](Cl)=[O:33])([CH3:30])[CH3:29]>ClCCl.CN(C1C=CN=CC=1)C>[CH2:17]([Si:3]([CH2:15][CH3:16])([CH2:1][CH3:2])[O:4][CH:5]1[CH:8]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:7]([C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[O:33])[C:6]1=[O:14])[CH3:18]
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccco1
Reactant: CC(C)OC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC1C(=O)N(C(=O)OC(C)C)C1c1ccco1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
(3R, 4R)-3-Triethylsilyloxy-4-(2-furyl)azetidin-2-one (0.51 g, 1.91 mmol) in 25 mL of dichloromethane was stirred with diisopropylethyl amine (0.78 mL, 4.4 mmol) and i-propylchloroformate (4.0 mL, 1.0M in toluene, 4.0 mmol) in addition to a catalytic amount of DMAP. The solution was stirred for 1 h and diluted with dichloromethane and washed with brine, dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (eluted with 5:1 hexane/ethyl acetate) to give 649 mg of the title product (Y: 96%); IR(KBr) 1822, 1812, 1716, 1374, 1314, 1186, 1018, 1004, 746 cm-1 ; 1H NMR (CDCl3,300MHz) δ7.39 (m, 1H), 6.35 (m, 2H), 5.08 (ABq, J=15.6, 5.6 Hz, 2H), 4.96 (d, J=10.0 Hz, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.17 (d, J= 6.3 Hz, 3H)), 0.83 (t, J=7.8, 9H), 0.50 (m, 6H); 13C NMR (CDCl3,75.5 Hz) δ165.5, 148.6, 147.8, 142.9, 110.5, 109.9, 77.6, 71.1, 55.9, 21.7, 21.6, 6.3, 4.4; DCIMS M+H calcd for C17H28NO5Si: 354, Found: 354.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]([CH3:24])([CH3:23])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1)([OH:3])=O.OC1C2N=NNC=2C=CC=1.[CH3:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[C:46]([CH3:51])=[CH:45][C:43]=1[NH2:44].Cl.CN(C)CCCN=C=NCC>ClCCl.C(N(CC)CC)C>[CH3:41][C:42]1[CH:48]=[C:47]([O:49][CH3:50])[C:46]([CH3:51])=[CH:45][C:43]=1[NH:44][C:1](=[O:3])[CH2:4][N:5]([CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]([CH3:23])([CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:10][CH:9]=1
Reactant: COc1cc(C)c(N)cc1C
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN(CC(=O)O)Cc2ccco2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(NC(=O)CN(CCc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
98 mg of 1,1-dimethylethyl 2-[[4-[2-[(carboxymethyl)(2-furanylmethyl)amino]-ethyl]phenyl]thio]-2-methyl-propanoate, 33 mg of hydroxybenzotriazole, 0.09 ml of triethylamine, 34 mg of 2,5-dimethyl-4-methoxyaniline and 49 mg of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are dissolved in 5 ml of dichloromethane. The mixture is stirred at room temperature for 20 h and extracted with 1 N NaOH, 1 N HCl, water and sat. NaCl solution. The combined organic phases are dried (MgSO4) and purified chromatographically (dichloromethane/ethyl acetate 5+1). This gives 48 mg of a viscous oil.