Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CO.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([SH:31])[CH3:30]>C(O)(C)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:31][CH2:29][CH3:30])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: CCS
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCCO
Solvent: CC(C)O
Product: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Lit. Org. Lett. 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol, 0.07 mmol copper(I) iodide, 1.32 mmol cesium carbonate, 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37Cl}[M+H-Me2C═CH2]+, 42%), 258.1 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH2:1]([O:8][CH:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=COCC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)COC(C)OCc1ccccc1
Temperature: 40 °C

Procedure:
A 250 ml. round-bottom flask equipped with a magnetic stirrer, condensor, mantle, and addition funnel was charged with 52.5 g. of benzyl alcohol and 4 drops of 36% hydrochloric acid. The mixture was heated to 40° C. and 50 g. of isobutyl vinyl ether was added dropwise, over a one-half hour period. GLC analysis showed the reaction to be complete at this point. Saturated sodium carbonate solution was added to quench (10 ml.) and the organic phase was dried over sodium sulfate prior to distillation on a concentric tube column:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:21][CH:20]=[CH:19][N:7]2[C:8](=[O:18])[C:9]=1[C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)C>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[S:21][CH:20]=[CH:19][N:7]3[C:8](=[O:18])[C:9]=2[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: CC(N)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 110 °C

Procedure:
A mixture of 7-(1-aminoethyl)-6-(3,5-difluorophenyl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.040 g, 0.13 mmol), 2-amino-6-bromopurine (0.056 g, 0.26 mmol), and N,N-diisopropylethylamine (0.045 mL, 0.26 mmol) in ethanol (0.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH), to give the desired product. LCMS calculated for C19H15F2N8OS (M+H)+: m/z=441.1. Found: 441.1.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:28])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[CH2:1]([NH:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:28])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH:27]=[N:26][CH:25]=[N:24]3)=[CH:21][CH:22]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
11.1 ml of benzaldehyde and 10 g of Molecular Sieve 3A were added to 50 ml of a solution of 2.97 g of 4-amino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol. The mixture was refluxed by heating, for 150 minutes. Thereto was added 4.97 g of sodium borohydride in small portions, under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The Molecular Sieve 3A was removed by filtration and the filtrate was subjected to distillation to remove the solvent. To the residue was added water. The mixture was made acidic with hydrochloric acid and then washed with ethyl acetate. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, under ice-cooling, followed by extraction with methylene chloride. The extract was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluant:methylene chloride/methanol=50/1), followed by recrystallization from methylene chloride-ethyl acetate to obtain 2.92 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:2][CH2:3][N:4]1[CH:8]([OH:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]1[OH:14])[CH3:16]
Reactant: CCNCC
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: Cc1ccccc1
Product: CCN(CC)CCN1C(O)c2ccccc2C1O

Procedure:
25.4 g (0.10 mol) of N-(2-bromoethyl)phthalimide were dissolved together with four times the molar quantity of diethylamine (29.2 g; 0.40 mol) in 500 ml of toluene and refluxed for 8 hours. After the reaction, excess diethylamine and the solvent were removed under a vacuum in a rotary evaporator. The residue was combined with tert-butyl methyl ether and the precipitated salt removed by filtration. The ether phase was then completely evaporated off. Yield: 21.0 g (85.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:14]([C:15]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=3)[N:13]=[CH:12][C:11]=2[CH2:23][CH2:24][OH:25])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:25][CH2:24][CH2:23][C:11]1[CH:12]=[N:13][N:14]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[C:10]=1[O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:36])=[O:35]
Reactant: N#Cc1ccnc(-n2ncc(CCO)c2OCc2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a mixture of 2-[5-[(4-fluorophenyl)methoxy]-4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile (40 mg, 0.12 mmol), Et3N (26 mg, 0.26 mmol) in DCM (5 mL) was added MeSO2Cl (17 mg, 0.15 mmoL) at 0° C. The reaction mixture was then stirred for 2 h at r.t. Water was added and extracted with DCM and concentrated to afford the title compound (42 mg, 87%). [M+H] Calc'd for C19H17FN4O4S, 417; Found, 417.
Reaction SMILES: ClC1C(NC2C=CC=CC=2S(C(C)C)(=O)=O)=NC(NC2C=C3C(CN([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)C3=O)=CC=2OC(C)C)=NC=1.C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][CH3:54])=[O:51]>CN(C=O)C>[CH2:53]([O:52][C:50]([N:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)=[O:51])[CH3:54]
Reactant: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N(C1CCNCC1)C2
Reactant: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-piperidin-4-yl-2,3-dihydro-isoindol-1-one (Example 1, 15 mg, 0.025 mmol) and triethylamine (37.5 uL, 0.25 mmol) in DMF (0.5 mL), is added ethyl chloroformate (5.4 mg, 0.05 mmol). The mixture is stirred at room temperature for 1 hour. The crude reaction mixture is purified by mass-trigger preparative RP LC-MS to afford the title compound 446-{5-chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid ethyl ester (175) as a white solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.55 (d, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 7.82 (dd, 1H), 7.74 (t, 1H), 7.34 (t, 1H), 7.28 (s, 1H), 4.73 (m, 2H), 4.39 (s, 2H), 4.12 (m, 2H), 4.06 (q, 2H), 3.46 (m, 1H), 2.92 (m 2H), 1.76 (m, 2H), 1.68 (m, 2H), 1.29 (d, 6H), 1.20 (t, 3H), 1.17 (d, 6H); MS m/z 671 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7](=O)[CH2:8]Br)([O-:3])=[O:2].[NH2:14][C:15]([NH2:17])=[S:16]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[N:14]=[C:15]([NH2:17])[S:16][CH:8]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Product: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Yield: 93.1 %

Procedure:
A solution of 3-nitrophenacyl bromide (244 mg, 1.00 mmol) and thiourea (76.1 mg, 1.00 mmol) in DMF (2 mL) was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo to obtain a yellow solid that was then washed with H2O and dried to yield a yellow solid (206 mg). The solid was dissolved in DMSO and purified by SCX column (4×6 mL capacity), eluted with CH2Cl2 (4×6 mL), MeOH (4×12 mL) and then released by NH3 (7 N in MeOH, 4×6 mL) to give a light-yellow solid of 4-(3-aminophenyl)-thiazol-2-ylamine. 1H NMR (DMSO-d6, 400 MHz): δ=7.24 (brs, 2H), 7.35 (s, 1H), 7.65-7.69 (m, 1H), 8.10-8.13 (m, 1H), 8.23-8.26 (m, 1H), 8.62 (t, 1H, J=1.8 Hz). MS (ES+): m/z 223.12 (45) [M}+]. HPLC: tR=2.82 min (ZQ2000, polar—5 min). The combined CH2Cl2 and MeOH solution was concentrated in vacuo to give a yellow solid of 4-(3-aminophenyl)-1H-imidazole-2-thiol. 1H NMR (DMSO-d6, 400 MHz): δ=7.75 (t, 1H, J=8.0 Hz), 8.01 (d, 1H, J=0.8 Hz), 8.17-8.20 (m, 1H), 8.35-8.37 (m, 1H), 8.56 (d, 1H, J=1.6 Hz), 8.72 (t, 1H, J=1.8 Hz), 12.56 (s, 1H). MS (ES+): m/z 222.12 (15) [MH+]. HPLC: tR=2.97 min (ZQ2000, polar 5 min).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:12]1[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]2[CH:26]3[CH2:27][CH2:28][CH:23]2[CH2:24][CH2:25]3)=[O:18])=[CH:15][N:16]=1)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH:22]3[CH:26]4[CH2:25][CH2:24][CH:23]3[CH2:28][CH2:27]4)=[O:18])=[CH:15][N:16]=2)[CH2:3]1
Reactant: OCC1CO1
Reactant: CCS(=O)c1ncc(C(=O)NCCC2C3CCC2CC3)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCC1C2CCC1CC2)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for ten minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfinyl-5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained for 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-(5-[2-(bicyclo[2.2.1]hept-7-yl)ethylaminocarbonyl]thiazole-2-yloxy)propane.
Reaction SMILES: C12C[CH:4](C=C1)[C:3](=[O:8])N2.Cl.[NH2:10][C@@H:11]1[CH2:15][C@H:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12]1.[CH3:19]O>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:3]([NH:10][C@@H:11]1[CH2:15][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12]1)(=[O:8])[CH3:4]
Reactant: CO
Reactant: O=C1NC2C=CC1C2
Reactant: N[C@H]1C=C[C@@H](C(=O)O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@@H]1C=C[C@H](NC(C)=O)C1

Procedure:
The recent description of an unequivocal route to 2-azabicyclo[2.2.1]hept-5-en-3-one (1, referring to the corresponding number on the flow sheet) (Jagt et al., J. Org. Chem., 39, 564 (1974)) offers a unique starting point for the synthesis of carbocyclic aminonucleosides of known geometric configuration. Acidic hydrolysis of this compound to cis-4-aminocyclopent-2-ene carboxylic acid hydrochloride, followed by esterification of the carboxyl function in refluxing methanol and subsequent acetylation of the amino group in acetic anhydride-pyridine, gives methyl (±)-cis-4-acetamidocyclopent-2-ene carboxylate (2). Reduction of the methyl ester of 2 gives, after acetylation, acetate 3. Epoxidation of acetate 3 is stereoselective due to the syn-directing allylic amide group, giving only the cis-epoxide 4. Hydrolysis of the easily synthesized epoxide 4 and subsequent acetylation gives a mixture of 5, 6 and 6a.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[C@H:14]([C:15]#[C:16][Si](C)(C)C)[NH:13][C:12]1=[O:21])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:23].C(OCC)(=O)C>O1CCCC1.O.S([O-])([O-])(=O)=O.[Hg+2]>[C:15]([C@@H:14]1[NH:13][C:12](=[O:21])[C@H:11]1[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:16]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@H]1C#C[Si](C)(C)C
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
trans-3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone (1.2 g) is dissolved in a mixture of tetrahydrofuran (20 ml) and water (2 ml), and mercury sulfate (0.07 g) and concentrated sulfuric acid (catalytic amount) are added, followed by stirring at room temperature for 15 hours. The reaction mixture is poured into a mixture of ethyl acetate (150 ml) and water (100 ml) and the organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 0.60 g of trans-4-acetyl-3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[CH:15][C:16](=[O:18])[CH3:17].[H][H]>[C].[Pd].C(OCC)(=O)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(=O)C=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Yield: 56.3 %

Procedure:
To 350 ml of ethyl acetate were added 17 grams of 4-(2-fluorenyl)-3-buten-2-one and 2 grams of 10% palladium carbon powder, the mixture was warmed at 40°-50° C., and hydrogen was introduced in under ordinary pressure. When the absorption of hydrogen ceased, the catalyst was removed by filtration, the filtrate was concentrated, and ethyl acetate was removed therefrom. Crystals separated out therefrom were recrystallized from methanol to give 9.65 grams of 4-(2-fluorenyl)-butan-2-one, white crystals, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:5]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(-c2cc3nc(Cl)cc(Cl)n3n2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
There was dissolved, in 1,4-dioxane (5 mL), 5,7-dichloro-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (259 mg, 0.930 mM), morpholine (162 μL, 1.86 mM) was added to the resulting solution and then the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off from the reaction mixture, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (274 mg, yield: 90%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2/[CH:13]=[C:17](/[C:16](=[O:15])[CH3:25])\[C:18]([O:20][CH2:21][CH2:22][C:23]#[N:24])=[O:19]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)/C(=C/c1cccc2c(=O)cc(C)oc12)C(=O)OCCC#N
Yield: 92 %

Procedure:
1.50 g (7.97 mmol) of the compound from Example 5A, 1.86 g (9.57 mmol) of 2-cyanoethyl 3-oxobutanoate [Yamamoto, T., et al., Bioorg. Med. Chem. Lett. 16, 798-802 (2006)], 91 μl (1.59 mmol) of acetic acid and 158 μl (1.59 mmol) of piperidine are dissolved in 30 ml of anhydrous dichloromethane and stirred under reflux with a water trap overnight. The mixture is then washed with water, the organic phase is dried with magnesium sulfate, and the volatile components are removed in a rotary evaporator. 2.91 g (approx. 7.33 mmol) of the 2-cyanoethyl (2Z)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylidene]-3-oxobutanoate crude product obtained in this way are mixed with 0.990 g (9.00 mmol) of 4-amino-5-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)], taken up in 40 ml of 2-propanol and stirred at the reflux temperature overnight. After cooling, the resulting precipitate is filtered off and washed with a little diethyl ether. Drying under high vacuum results in 1.20 g (38% of theory) of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Br:11][CH2:12][CH2:13][CH2:14][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(I)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-iodophenol (1.0 g) in dimethylformamide (10 ml), 273 mg of sodium hydride and 0.603 ml of 1,3-dibromopropane were added under ice-cooling, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([CH3:18])[CH:17]=1)[NH:14][N:13]=[CH:12]2)[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:21](=[O:22])C1.C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][CH:47]([C:50]2[C:51](=[O:60])[NH:52][C:53]3[C:58]([CH:59]=2)=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:46][CH2:45]1>CN(C=O)C.C(Cl)Cl>[CH3:18][C:16]1[CH:17]=[C:9]([CH2:8][C@@H:3]([NH:2][C:21]([N:44]2[CH2:45][CH2:46][CH:47]([C:50]3[C:51](=[O:60])[NH:52][C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH2:48][CH2:49]2)=[O:22])[C:4]([O:6][CH3:7])=[O:5])[CH:10]=[C:11]2[C:15]=1[NH:14][N:13]=[CH:12]2
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: COC(=O)[C@H](N)Cc1cc(C)c2[nH]ncc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
To a solution of (R)-methyl 2-amino-3-(7-methyl-1H-indazol-5-yl)propanoate hydrochloride (2.69 g, 10 mmol) in DMF (20 mL) was added N,N′-disuccinimidyl carbonate followed by triethylamine (5.6 mL, 40 mmol). After 20 min, 3-(piperidin-4-yl)quinolin-2(1H)-one (2.28 g, 10 mmol) was added at once. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with CH2Cl2 (250 mL), washed with water (2×100 mL), 1 M sodium hydroxide (30 mL) and then with 1.0 M hydrogen chloride (100 mL). The organic phase was dried (Na2SO4) and then purified by flash chromatography using 5% methanol in dichloromethane to give (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate in 68% yield. MS (ESI) 488 (M+H) ; Rf=2.14.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH:15]C(=O)C2C=CC=CC=2)=[N:13][C:11]1=[O:12]>N>[CH2:1]=[C:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:25]=[CH:24][C:14]([NH2:15])=[N:13][C:11]1=[O:12]
Reactant: C=C1[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@H](CO)[C@H]1O
Agent: N
Product: C=C1[C@H](n2ccc(N)nc2=O)O[C@H](CO)[C@H]1O
Yield: 96.1 %

Procedure:
A solution of 139 mg (0.5 mmol) of 2'-deoxy-2'-methylidene-4-N-benzoylcytidine in 10 ml of methanolic ammonia was stirred at room temperature for 6 hours to cause reaction and the solvent distilled off under reduced pressure. The residue was developed through a silica gel column (1.6×10 cm, 20% ethanol-chloroform being used as a solvent for elution), fractions containing the desired compound collected, 2 ml of 1N hydrochloric acid added, and the solvent distilled off under reduced pressure. The residue was crystallized from acetone-methanol to obtain 115 mg (yield 83%) of 2'-deoxy-2'-methylidenecytidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C.CCOC(C)=O>[CH2:60]([NH:67][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([C:14]2[O:15][C:16]([CH3:17])=[C:12]([CH2:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[N:13]=2)=[CH:26][CH:25]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3ccccc3)cc2)nc1CS(=O)(=O)c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
Benzoic acid 29 (150 mg, 0.34 mmol) was dissolved in anhydrous DMF (5 mL), DIEA (0.12 mL, 0.69 mmol) and HBTU (171 mg, 0.45 mmol) were successively added and the reaction mixture was stirred at 20° C. for 10 min. Benzylamine (0.16 mL, 1.4 mmol) was added and the reaction mixture was stirred at 20° C. for 1 h. The mixture was diluted with EtOAc (150 mL), washed with H2O (3×50 mL), washed with brine (50 mL) and dried. The solvent evaporated and the residue was purified by column chromatography, eluting with a gradient (50-100%) of EtOAc/pet. ether followed by a gradient (1-4%) MeOH/DCM, to afford amide 57 (117 mg, 66%) as a white solid: mp (DCM/MeOH) 234-237° C.; 1H NMR δ □ (t, J=5.9 Hz, 1H, CONH), 8.01 (br d, J=8.6 Hz, 2H, H-2, H-6), 7.87 (br d, J=8.7 Hz, 2H, H-3, H-5), 7.85 (dt, J=8.8, 2.1 Hz, 2H, H-2′, H-6′), 7.72 (dt, J=8.7, 2.1 Hz, 2H, H-3′, H-5′), 7.34 (s, 2H, H-2″, H-6″), 7.33 (s, 2H, H-3″, H-5″), 7.22-7.28 (m, 1H, H-4″), 4.74 (s, 2H, CH2SO2), 4.49 (d, J=5.9 Hz, 2H, CH2NH), 2.21 (s, 3H, CH3); 13C NMR δ□ 165.3, 158.0, 150.0, 139.4, 137.7, 135.6, 132.2 (2), 130.3 (2), 128.6, 128.2 (2), 128.1, 128.0 (2), 127.2 (2), 126.7, 125.6, 125.3 (2), 52.6, 42.6, 9.7; MS m/z 526.5, 528.5 (MH+, 100%). Anal. calcd for C25H21BrN2O4S: C, 57.15; H, 4.03; N, 5.33. Found: C, 57.34; H, 3.74; N, 5.50%.