Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC[N:17]([CH:21]([CH3:23])[CH3:22])C(C)C.Cl[C:25]1C(S(NC)(=O)=O)=CC=C(Cl)C=1C(O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:17][C:21]([CH3:23])([CH3:25])[CH3:22])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1Cl
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1

Procedure:
Prepared from a mixture of 2-chloro-5-(chlorosulfonyl)benzoic acid (200 mg, 0.78 mmol, 1 equiv) tert-butyl amine (98 μL, 0.94 mmol, 1.2 equiv) and DIEA (248 μL, 1.38 mmol, 2 equiv) following the general procedure for 2,6-dichloro-3-[(methylamino)sulfonyl]benzoic acid 881-1b. The crude reaction mixture was carried on without further purification.
Reaction SMILES: [F:1][C@:2]1([CH3:20])[C:6]([OH:8])([CH3:7])[C@@H:5]([CH2:9][OH:10])[O:4][CH:3]1[N:11]1[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]1=[O:19].C(=NC1CCCCC1)=NC1CCCCC1.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:20])[CH:3]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]2=[O:19])[O:4]1)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cn(C2O[C@H](CO)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(C2O[C@H](COC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a stirred solution of 1-((3R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (about 0.05 g, 0.17 mmol) in tetrahydrofuran (about 5 ml) was added N,N-dimethyl amino pyridine (about 0.06 g, 0.52 mmol), N,N′-methanediylidenedicyclohexanamine (about 0.071 g, 0.34 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (about 0.09 g, 0.52 mmol) at about 0° C. and stirred at room temperature for about 1 hour. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 1.5% methanol in dichloromethane as eluent furnished title compound (0.03 g) as a colorless solid. Yield: 46.8%; 1H NMR (300 MHz, CDCl3): δ 8.08 (bs, 1H), 7.23-7.22 (m, 1H), 6.37 (d, 1H, J=23.4 Hz), 4.95 (bs, 1H), 4.45-4.25 (m, 3H), 3.40-3.34 (m, 1H), 1.95 (s, 3H), 1.45 (d, 3H, J=22.8 Hz), 1.44 (s, 9H), 1.41 (m, 3H), 1.27 (s, 3H), ES Mass: [M+Na] 482 (100%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([N:1]2[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CC[C@H](O)C2)C1
Yield: 53.6 %

Procedure:
A mixture of (S)-pyrrolidin-3-ol (261 mg, 3.0 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (513 mg, 3.0 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was stirred at room temperature for 6 h before the addition of sodium triacetoxyborohydride (1.27 g, 6.0 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, Acetone:DCM, 0-40%) affording 3-((S)-3-Hydroxypyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a brown oil (390 mg, 54%). LCMS (Method A): RT 0.28 min [M+H]+ 243.0
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:58]([CH2:59]O)=[CH:57][N:56]=[C:55]2[S:61][CH2:62][C:63]2[C:68]([F:69])=[CH:67][CH:66]=[C:65]([F:70])[C:64]=2[F:71])=[CH:50][CH:49]=1>C1COCC1.C(OCC)(=O)C.O>[F:47][C:48]1[CH:53]=[CH:52][C:51]([N:54]2[C:58]([CH2:59][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:57][N:56]=[C:55]2[S:61][CH2:62][C:63]2[C:68]([F:69])=[CH:67][CH:66]=[C:65]([F:70])[C:64]=2[F:71])=[CH:50][CH:49]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phthalimide (783 mg, 5.32 mmol), di-tert-butylazodicarboxylate (1.23 g, 5.32 mmol) and triphenyl phosphine (1.4 g, 5.32 mmol) were added to a solution of (1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazol-5-yl)methanol (28) (980 mg, 2.66 mmol) in THF (30 mL) and the reaction was stirred overnight at room temperature. An additional equivalent of phthalimide, di-tert-butylazodicarboxylate and triphenyl phosphine was added and stirred overnight. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford 2-((1-(4-fluorophenyl)-2-((2,3,6-trifluoro benzyl)thio)-1H-imidazol-5-yl)methyl)isoindoline-1,3-dione (29) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C[Al](C)C.C[O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O.Cl>O1CCOCC1.C1(C)C=CC=CC=1>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]([NH:12][C:10]2[N:11]=[C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]3[N:9]=2)=[O:24])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3ccc(Br)cc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a solution of 24 mg (0.1 mmol) 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amine in 1 ml dioxane was added 0.4 ml (0.4 mmol) of a 1 M solution of AlMe3 in toluene and allowed to stir for 1 h at room temperature. 86 mg (0.4 mmol) 4-bromo-phenyl carboxylic acid methyl ester in I ml dioxane was added and the mixture was stirred for 48 h at 90° C. 0.5 ml 1N HCl aq. was added and the mixture was evaporated to dryness. The residue was taken up in 1.5 ml formic acid and 0.5 ml methanol and subjected to reversed phase HPLC chromatography eluting with a water/acetonitrile gradient. Evaporation of the eluents yielded 6 mg (15%) of the title compound. MS m/e (%): 423.3 (M+H+, 100).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[C:26]([OH:33])[C:25]=2[CH:34]([CH3:36])[CH3:35])=[O:22])[CH2:16][CH2:15]1.[CH:37](N(CC)C(C)C)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC>CO.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[C:26]([O:33][CH3:37])[C:25]=2[CH:34]([CH3:36])[CH3:35])=[O:22])[CH2:16][CH2:15]1
Reactant: CC(C)c1ccc(O)c(C(C)C)c1NC(=O)CN1CCN(CCCSc2nc3ccccc3o2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Solvent: CCCCCC
Product: COc1ccc(C(C)C)c(NC(=O)CN2CCN(CCCSc3nc4ccccc4o3)CC2)c1C(C)C
Reaction time: 14 h
Yield: 20.4 %

Procedure:
2-[4-[3-(Benzoxazol-2-ylthio)propyl]piperazin-1-yl]-N-(2,6-diisopropyl-3-hydroxyphenyl)acetamide (150 mg, 0.29 mmol) was dissolved in methanol (2 ml) and acetonitrile (3 ml), then N,N-diisopropylethylamine (227 mg, 1.76 mmol) and a solution of trimethylsilyl diazomethane in hexane (2.0M, 0.88 ml, 1.76 mmol) were added thereto and the mixture was stirred for 14 hours. The reaction solution was concentrated, made alkaline with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (developing solvent, hexane:acetone=7:3) and the resulting crude crystals were recrystallized from ethyl acetate and hexane to provide 31 mg (yield 20%) of the desired compound as colorless powdery crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)[C:48](=[O:52])N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.COC1C=C(N=C=O)C=CC=1>>[CH3:48][O:52][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: COc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 250 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-methoxy phenyl isocyanate. The compound of example 250 was used directly without isolation for the preparation of compound of example 251.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.[Cl:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>>[ClH:27].[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])=[CH:31][CH:32]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: Fc1ccc(CCCl)cc1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCc3ccc(F)cc3)cc12

Procedure:
6-[2-(4-fluoro-phenyl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, hydrochloride was prepared in 9% overall yield using the method described in example 85, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 81A) and 1-(2-Chloroethyl)-4-fluoro-benzene.
Reaction SMILES: C(OC1C=CC=CC=1[N+]([O-])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C1CN([P+](ON2N=N[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([O:58][C:59]([NH:61][CH:62]1[CH2:65][C:64]([OH:69])([C:66]([OH:68])=[O:67])C1)=[O:60])(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:69][C@@H:64]([CH2:65][CH2:62][NH:61][C:59]([O:58][CH2:54][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:60])[C:66]([OH:68])=[O:67])(=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(OCc1ccccc1)Oc1ccccc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CC(O)(C(=O)O)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC[C@H](OC(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cold solution of 200 mg of 3′,4′,3′″,4′″-tetra-dehydro-3,2′,6′,2′″,6′″-Cbz-neomycin (1 (3 from Example 4), 0.16 mmol) in 4.0 mL DMF was added 103 mg PyBOP (0.1972 mmol) and 3-(tert-butoxycarbonylamino)-1-hydroxycyclobutanecarboxylic acid (0.1972 mmol). The flask was then cooled to 0° C. and 47.8 μl DIPEA (0.2793 mmol) was added. The reaction was allowed to stir at room temperature overnight then LCMS was used to confirm product formation and the absence of starting material. The reaction was then quenched with 10-20 mL 1 M citric acid and desired product was extracted into 10 mL ethyl acetate. The organic layers were washed with 10 mL 1M citric acid, brine and dried while stirring with MgSO4. Concentration under vacuum provided crude intermediate (2) that was used in the next reaction without further purification. MS: m/z (M+Na) calc: 1452.59, obs: 1452.4.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)(C(C)(C)C)(C)C.[CH3:21][O:22][C:23](=[O:35])[C:24](=[N+]=[N-])[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1.C(C(CC)(CC)C)C.FC(F)(F)C(O)=O>CC(C)(CC)C>[ClH:31].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:24]([C@@H:12]2[CH2:13][C@@H:9]([OH:8])[CH2:10][NH:11]2)[C:23]([O:22][CH3:21])=[O:35])[CH:30]=[CH:29][C:28]=1[Cl:31]
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CCC(C)(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCC(C)(C)C
Product: COC(=O)[C@H](c1ccc(Cl)c(Cl)c1)[C@@H]1C[C@@H](O)CN1
Product: Cl
Reaction time: 16 h
Yield: 35 %

Procedure:
A stirred solution of (R)-3-(tert-butyldimethylsilyloxy)-N-(tert-butoxycarbonyl)pyrrolidine (1.00 g, 3.32 mmol) and dirhodium(II) tetrakis[(S)—N-[p-(dodecylphenyl)sulfonyl]prolinate] {Rh2(R-DOSP)4} (125 mg, 0.07 mmol) in 2,2-dimethylbutane was stirred under reflux. Diazo-(3,4-dichlorophenyl)acetic acid methyl ester (1.63 g, 6.64 mmol) in a 1:4 mixture of trifluorotolune: 2,2-diethylbutane was added via syringe pump over a 3 hour period. The mixture was stirred under reflux for an additional 2 hours and then stirred at room temperature overnight. The mixture was then concentrated, diluted with dichloromethane (100 mL) and charged with trifluoroacetic acid (1.97 mL, 26.6 mmol). After 16 hours, the solution was concentrated, the residue dissolved in Et2O (100 mL), and extracted with 10% HCl (3×100 mL). The aqueous layers were basified with solid NaHCO3 (solid) and 1M NaOH to pH=8−9. The aqueous phase was then back extracted ethyl acetate (3×50 mL) and the organic phases were washed with brine (25 mL), dried with Na2SO4, and filtered. The extraction was reduced and purified by chromatography to afford the titled compound as a clear oil: 391 mg (35% yield). 1H NMR (500 MHz, CDCl3) δ 7.50 (s, 1H), 7.41-7.39 (d, J=8 Hz, 1H), 7.24-7.22 (m, 1H), 4.41 (m, 1H), 3.99 (m, 1H), 3.67 (s, 1H), 3.42 (d, J=9 Hz, 1H), 3.04 (dd, J=4.5, 7.5 Hz, 1H), 2.83 (m, 1H), 2.00 (m, 4H), 1.66 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 172.3 (C), 137.4 (C), 132.7 (C), 131.8 (C), 130.6 (CH), 130.5 (CH), 128.1 (CH), 72.3 (CH), 59.3 (CH2), 56.6 (CH), 54.8 (CH), 52.2 (CH3), 40.2 (CH2); IR (neat): 1753 cm−1; HRMS (ESI) m/z Calc'd for [C13H15Cl2NO3]+ (M+): 303.0429. Found: 303.0437.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH:4]([CH3:10])[N:3]1[CH2:11][C:12]#[CH:13].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][C@H:26]([C:30](O)=[O:31])[CH:27]([CH3:29])[CH3:28].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][CH:26]([CH:27]([CH3:29])[CH3:28])[C:30]([O:8][CH2:7][N:6]1[C:5](=[O:9])[CH:4]([CH3:10])[N:3]([CH2:11][C:12]#[CH:13])[C:2]1=[O:1])=[O:31]
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: C#CCN1C(=O)N(CO)C(=O)C1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#CCN1C(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2Cl)C(C)C)C(=O)C1C
Reaction time: 2 h

Procedure:
To a stirred solution of (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methanol (1.8 mmol), N-(2-chloro-4-trifluoromethylphenyl)valine (2.0 mmol) and dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph, eluting with 25% ether/hexane, to yield (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11](C(NCC(O)=O)=O)CS)=O)[C:3]([OH:5])=[O:4].[CH:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]([NH2:28])[C:22]=1[OH:29]>>[CH:21]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]([NH2:28])[C:22]=1[OH:29].[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6][C:7]1[N:24]=[CH:11][NH:10][CH:8]=1
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: Nc1ncc(O)c(N)n1
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
W3, W8, and W10 were further subcloned into a modified pGEX4T-1 plasmid (Pharmacia Biotech, Uppsala, Sweden) (where a NdeI cloning site was inserted between the BamHI and EcoRI sites) as NdeI-NotI fragments to generate glutathione S-transferase (GST) tagged fusion proteins. A similar strategy was used to generate fusion proteins without the (Gly4Ser)31inker (i.e., W4 (p27-p16), W7 (p2712-178-p16 fusion CDKi W9 (p2725-93-p16)). The nucleic acid and amino acid sequences of the p2725-93-p16 fusion CDKi, W9, without the HA tag and six histidine residues are provided in SEQ ID NO: 23 and SEQ ID NO: 24, respectively.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH2:22]([OH:24])[CH3:23].O1CCCC1.[H-].[Na+]>CCOCC.O>[Br:1][C:2]1[C:3]([Cl:21])=[C:4]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:5]([O:24][CH2:22][CH3:23])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1c(F)c([N+](=O)[O-])cc(Br)c1Cl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c([N+](=O)[O-])cc(Br)c(Cl)c1CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of the compound (200 mg) obtained in Example 519c, ethanol (36 μl) and tetrahydrofuran (5 ml), sodium hydride (content, 60%; 25 mg) was added under ice cooling. The reaction mixture was stirred at 0° C. for 2 h and then water and ether were added. The organic layer was washed with water and a saturated aqueous sodium chloride solution sequentially, then dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give 197 mg of the titled compound (yield, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C(O)(=O)C.CCO>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(NN=Cc1ccc(C(F)(F)F)cc1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and 4-trifluoromethylbenzaldehyde (0.35 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give beige solid 0.58 g, in 94% yield, mp: 260.5° C. 1H NMR (CD3OD) δ 8.35 (s, 1H), 7.99 (d, 2H), 7.83 (d, 2H), 7.70 (d,2H), 6.87 (d, 2H). 13C NMR (CD3OD) δ 167.0, 163.0, 147.7, 1139.6, 131.0, 129.1, 126.7, 126.6, 124.5, 116.4. Anal. Calcd for C15H11F3N2O2 ·¼H2O: C, 57.60; H, 3.54; N, 8.95, F; 18.22. Found: C, 57.71; H, 3.77; N, 8.67, F; 18.43.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH:22](C)[C:23]3C=CC=CC=3)=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:30])=[O:10].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH2:17][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]2=[CH:13][C:12]=1[CH3:30])=[O:10]
Reactant: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)OC(C)c2ccccc2)n1C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CCn2c1cc(C)c2C(=O)c1ccc(SC)n1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 86.2 %

Procedure:
To a solution of (-)-α-methylbenzyl 5-(1-methyl-5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (3.0 g, 7.1 mmol) in CH2Cl2 (80 ml) at -78° C. under N2 atmosphere was slowly added a 1.0M solution of boron tribromide in CH2Cl2 (15.6 ml, 15.6 mmol). The solution was stirred at -78° C. for 5 minutes and absolute ethanol (30 ml) was added slowly and warmed to room temperature then stirred at room temperature for 2 hours. The solution was washed with water (3×25 ml.) and brine (1×25 ml.), dried over anhydrous sodium sulfate, filtered and rotovapped at 20° C. to an orange solid and chromatographed on a flash silica gel column (5×15 cm) eluted with 50% ether/hexane. The resulting crude product was crystallized from hot EtOH to afford 2.12 g (86% yield) of (-)-ethyl 5-(1-methyl- 5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. [α]D25 =-127.4 (CHCl3, C=1.06); m.p. 113°-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C:4]([F:32])([F:31])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][C:28](=[O:30])[CH3:29])[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].[N+](=C)=[N-].O1C=C[CH2:40][CH2:39][CH2:38]1.CC1C=CC(S(O)(=O)=O)=CC=1>CCOCC.O1CCOCC1>[CH3:1][O:2][C:3](=[O:33])[C:4]([F:31])([F:32])[CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([O:27][CH:28]4[CH2:29][CH2:40][CH2:39][CH2:38][O:30]4)[CH2:18][CH2:19]2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(F)(F)C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95 %

Procedure:
The difluoroester (5) (880 mg, 1.9 mmol) was treated with 2% KOH--MeOH (30 ml) at room temperature for 2 hr. The usual work-up (ether for extraction) gave a crude acid. This in ether (10 ml) was treated with etheral solution of diazomethane until the gas evolution was ceased. This solution was concentrated under reduced pressure to leave the residue. This is dioxane (10 ml) was treated with 2,3-dihydropyran (516 μl) and TsOH (10 mg) at room temperature for 3 hr. The usual work-up (ether for extraction) gave a crude product, which was applied to a column of silica gel (200 g). Elution with n-hexane-ether (15:1) provided the THP-ester (6) (907 mg, 95%), amorphous. 1H-NMR δ: 0.70 (3H, s, 18-H3), 1.03 (3H, s, 19-H3), 1.10 (3H, d, J=6 Hz, 21-H3), 3.53 (2H, m, THP), 3.86 (3H, s, --CO2CH3), 3.93 (1H, m, 3-H), 4.73 (1H, m, THP), 5.36 (1H, m, 6-H). 19F-NMR δ: +40.0. MS m/z: 424 (M+ -DHP), 406, 391.