Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([OH:12])[C:10]=1[OH:11])=[O:5])[CH3:2].[CH2:25](O)[CH2:26]O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]2[O:12][CH2:25][CH2:26][O:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c(O)c(C(=O)OCC)n1Cc1ccccc1
Reactant: OCCO
Solvent: C1CCOC1
Product: CCOC(=O)c1c2c(c(C(=O)OCC)n1Cc1ccccc1)OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
ADC01 (2.9 g, 16.9 mmol) was slowly added to a solution of N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylic acid diethyl ester (2.6 g, 7.7 mmol), ethylene glycol (0.5 g, 8.5 mmol), and PH02 (4.4 g, 16.9 mmol) in dry tetrahydrofuran (150 ml) at 0° C. The reaction mixture was allowed to warm to 25° C., stirred for 3 h, and then was refluxed for 21 h. The reaction mixture was then allowed to cool to 25° C. and was concentrated by rotary evaporator to remove the tetrahydrofuran. The residue was diluted with diethyl ether and allowed to stand overnight to enable the tributylphosphine oxide to precipitate out. The tributylphosphine oxide was then removed by filtration and the residue purified by chromatography on silica gel (eluant: ethyl acetate/hexane=3/1) to give 6-benzyl-2, 3-dihydro-6H-[1,4]dioxino[2,3-c]pyrrole-5,7-dicarboxylic acid diethyl ester as a colourless solid in 2.3 g (85%) yield as characterized by 1H NMR, 13C NMR, HRMS, and elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:14]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
5-Chloro-2-nitrobenzoic acid (20.1 g,; 0.10 mol), is dissolved in anhydrous methanol (100 ml) and anhydrous hydrogen chloride gas is bubbled into the reaction mixture for 4 hours at room temperature. The reaction mixture is then poured into water and the aqueous mixture triturated with hexane, the hexane layer decanted, dried (anhd. MgSO4) and the solvent removed under vacuum to afford 11.7 g of methyl 5-chloro-2-nitrobenzoate, mp 50°-51° C.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11]CC)=[O:10])=[N:5]1.[OH-].[Na+]>CO>[F:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]1
Reactant: CCOC(=O)c1ccn(CCF)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccn(CCF)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 18.8 %

Procedure:
To a solution of ethyl 1-(2-fluoroethyl)-1H-pyrazole-3-carboxylate (0.1 g) in methanol (5 ml) was added 2M sodium hydroxide (5 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue dissolved in water (20 ml) and acidified to pH=4 using 2M hydrochloric acid then extracted with ethyl acetate (20 ml), dried over sodium sulphate and evaporated to give the title compound (16 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[S:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[S:21].NCCC(O)=O>C(O)(=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1/[CH:13]=[C:25]1/[C:23](=[O:24])[NH:22][C:20](=[S:21])[S:19]/1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C=O)c1Cl
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\SC(=S)NC2=O)c1Cl

Procedure:
To a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]benzaldehyde (209 mg, 0.75 mmols) and rhodanine (104 mg, 0.78 mmols) in 15 mL of acetic acid is added β-alanine (48 mg, 0.54 mmols). The solution is heated at reflux for one hour. During this time a thick precipitate forms. The mixture is filtered hot, washing with an additional 5 mL of [[2- [(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2-thioxo-4-thiazolidinone as a fluffy orange solid; mp 274°-276° C. dec.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([CH:18]=[O:19])=[C:11]1[CH:15]([CH3:16])[CH3:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure C. To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 2.08 g, 8.04 mmol) in DMF (15 ml) was added K2CO3 (3.32 g, 24.1 mmol) and benzyl bromide (1.91 ml, 16.1 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13]Cl)=[CH:5]2.[F:15][C:16]([F:25])([F:24])[C:17]1[N:22]=[CH:21][N:20]=[C:19]([OH:23])[CH:18]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][O:23][C:19]1[CH:18]=[C:17]([C:16]([F:25])([F:15])[F:24])[N:22]=[CH:21][N:20]=1)=[CH:5]2
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: ClCc1cc2cc(Br)ccc2nc1Cl
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: FC(F)(F)c1cc(OCc2cc3cc(Br)ccc3nc2Cl)ncn1
Temperature: 70 °C

Procedure:
6-Bromo-2-chloro-3-(chloromethyl)quinoline (0.60 g, 2.1 mmol), 6-(trifluoromethyl)-4-pyrimidinol (0.34 g, 2.1 mmol), DIEA (0.54 ml, 3.1 mmol) and sodium iodide (0.31 g, 2.1 mmol) were suspended in CAN (50 mL) and heated to 70° C. for 1 h. The reaction was cooled, diluted with water (100 mL) and extracted with EtOAc (200 mL). After drying with magnesium sulfate the organic was evaporated to dryness under reduced pressure. Purification using low pressure silica chromatography (0-10% methanol in DCM gradient) to give the desired 6-bromo-2-chloro-3-((6-(trifluoromethyl)pyrimidin-4-yloxy)methyl)quinoline. Step 2 and 3: The product from step 1 was taken through a procedure similar to that described in steps 3 and 4 of Example 9, to provide the titled compound, o-tolyl-3-((6-(trifluoromethyl)pyrimidin-4-yloxy)methyl)quinolin-2-amine. (ESI, pos. ion) m/z: 411 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38].[H-].[Na+].[CH2:41](Br)[C:42]#[CH:43].C1(C)C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:41][C:42]#[CH:43]
Reactant: C#CCBr
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-ol (150 mg, 22.89 mmol, 1.0 equiv.) was slowly added to a slurry of NaH (48 mg, 45.78 mol, 8 equiv.) in DMF (1.4 mL) in a flame dried flask pre-cooled to 0° C. 80% propargyl bromide in toluene (36 □L, 27.47 mmol, 1.2 equiv.), cooled to 0° C., was added slowly. The ice bath was removed and the reaction was allowed to stir at room temperature for an additional 2 hours. The reaction was then re-cooled to 0° C., 0.5 mL of ice cold water was added, and the reaction was concentrated under reduced pressure. The remaining residue was redissolved in dichloromethane, then partially purified via silica gel chromatography (10% MeOH in DCM) to remove all the salts. After partial purification, 2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxahentetracont-40-yne (s-13e) was obtained as a brown oil that was taken on to the next step without full purification.
Reaction SMILES: Cl.C(=N)([O:4]CC)C.[O-]CC.[Na+].[Na].[NH:13]([C:17]1[S:18][CH:19]=[C:20]([C:22](NN)=[O:23])[N:21]=1)[C:14]([NH2:16])=[NH:15]>C(O)C>[NH:13]([C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:23])=[O:4])[N:21]=1)[C:14]([NH2:16])=[NH:15]
Reactant: CCOC(C)=N
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)O)cs1
Reaction time: 60 h
Yield: 128.9 %

Procedure:
37.1 g (0.3 mol) of ethyl acetimidate hydrochloride was dissolved in 200 ml absolute ethanol. A solution of sodium ethoxide (6.9 g (0.3 mol) sodium in 300 ml absolute ethanol) was added. The resulting precipitate of sodium chloride was removed by filtration and to the clear filtrate was added 20.0 g (0.1 mol) of 2-guanidino-4-thiazole carboxylic acid hydrazide. The slurry was stirred at 25° for 60 hours, during which time complete dissolution occurred. The clear, pale orange solution was concentrated in vacuo to a soft solid which was triturated in 10:1 ethyl acetate-ethanol to give 24.0 g (88%) of crude 2-guanidino-4-thiazole carboxylic acid 2-acetiminohydrazide, with a broad melting point, 150° to 178° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1>O>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:11]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: Clc1ccc(CBr)cc1
Solvent: O
Product: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Yield: 90.3 %

Procedure:
According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 29.0 mmol, 5.00 g, Example 1 Step 1) and 4-chlorobenzyl bromide (1.2 eq, 34.0 mmol, 7.10 g) according to the procedure described for Example 1 Step 2. After concentration of the solvent, water was added. The aqueous phase was extracted with AcOEt and the combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recrystallized with pentane/Et2O 50/50 to afford 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (26.2 mmol, 7.82 g, 91%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:21][C:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: O=C(Nc1cc(Br)ccc1O)c1ccc(C(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2nc3cc(Br)ccc3o2)cc1
Yield: 66.5 %

Procedure:
Intermediate 42 (1 g, 2.77 mmol) was dissolved in 1,4-Dioxane and added Phosphorus oxychloride (0.76 ml, 8.3 mmol). This mixture was refluxed for 2 h. 1,4-Dioxane removed on rotavapour to obtain the residue. Residue was washed with water to obtain solid. Solid was filtered and dried to obtain the titled compound (630 mg) as an off-white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.35 (d, J 8.2, 2H), 7.93 (d, J 1.5, 1H), 7.79 (d, J 8.3, 2H), 7.52-7.49 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[S:11][C:12]([S:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][N:14]=2)[CH:3]=1.[N:25]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CCCCO>[OH:33][CH2:32][CH2:31][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]3[S:11][C:12]([S:15][C:16]4[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=4)=[CH:13][N:14]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: Cc1nc(Cl)cc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)n1
Reactant: OCCN1CCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Nc2ncc(Sc3ccnc(C(=O)O)c3)s2)cc(N2CCN(CCO)CC2)n1
Temperature: 115 °C
Yield: 69 %

Procedure:
To a stirring solution of 4-(2-(6-chloro-2-methylpyrimidin-4-ylamino)thiazol-5-ylthio)picolinic acid (104 mg, 0.274 mmol) and 2-(piperazin-1-yl)ethanol (195 mg, 1.50 mmol) in n-BuOH (2 mL) was added i-Pr2NEt (0.20 mL, 1.15 mmol). The reaction was then heated to 115° C. in a sealed reaction vessel overnight. The reaction was cooled to room temperature and the solid collected by filtration, the filter cake was washed with n-BuOH then air dried to give the title material (89.5 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.59 (1H, s), 8.27 (1H, d, J=5.05 Hz), 7.71 (1H, s), 7.53 (1H, d, J=2.02 Hz), 7.07 (1H, dd, J=5.05, 2.02 Hz), 6.03 (1H, s), 4.45 (1H, t, J=4.67 Hz), 3.49 (6H, s), 2.41 (2H, t, J=6.32 Hz), 2.33 (3H, s). LC/MS (M+H)+: 474. HPLC ret. time (Condition I): 1.097 min.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[CH:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:14][C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(CO)C(=O)O
Reactant: NC1CCCC1
Product: CC(C)(CO)C(=O)NC1CCCC1

Procedure:
Prepared as in Example 24a from hydroxypivalic acid and cyclopentyl amine as an orange oil (32%). 1H NR (400 MHz, DMSO-d6) δ 1.00 (s, 6H), 1.32-1.40 (m, 2H), 1.43-1.49 (m, 2H), 1.57-1.65 (m, 2H), 1.73-1.81 (m, 2H), 3.34 (d, J=4.0 Hz, 2H), 3.98 (m, 1H), 4.87 (t, J=4.0 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H). MS 186 (MH+).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3]>[O-2].[Cr+3].[Cu+2]>[CH3:8][C@H:7]1[CH2:9][C:10](=[O:11])[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CCO
Agent: [Cr+3]
Agent: [Cu+2]
Agent: [O-2]
Product: CC(C)[C@@H]1CC[C@@H](C)CC1=O

Procedure:
156 g of purified citronellol ([α]D20 = +2.3) was reacted with 7.8 g of copper-chromium oxide (CuO:Cr2O3 = 50:50) at 260° C for 2 hours under a hydrogen pressure of 2.5 kg/cm2.G to afford menthone (menthone 59 wt%, iso-menthone 41 wt%). The product was converted to the enol acetate having a specific rotation, [α]D20, of +55. The optical purity of the product was 80% of that of the starting material. The product was hydrogenated in the same manner as described in Example 4. From the resulting menthol mixture, menthol was isolated. The menthol had a specific rotation, [α]D20, of +39 and an optical purity of 80%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>C(Cl)Cl>[OH:17][C:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cncc(C(F)(F)F)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a slightly cloudy solution of 3-bromo-5-(trifluoromethyl)pyridine (2.20 g, 30% purity, 2.92 mmol) in dry methylene chloride (15.0 mL) at −78° C. was added a 1.6 M solution of n-butyllithium in hexanes (1.99 mL). After being stirred for 30 min at −78° C., a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (0.534 g, 2.65 mmol) in dry methylene chloride (3.0 mL) was added dropwise. The reaction was stirred at −78° C. for 1.5 h and quenched with aqueous NH4Cl. The resulting solution was extracted with methylene chloride three times. The combined organic layers were dried, filtered and concentrated. The residue was purified by column chromatography on silica gel (50:50 EtOAc/hexanes) to give 330 mg (25%) of desired product as a yellow oil. LC-MS calculated for C16H21F3N2O3: (M+H) 347; found 247.1 (M-Boc+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH3:27][N:28]([CH3:31])[CH:29]=O>O1CCCC1>[CH3:27][N:28]([CH3:31])/[CH:29]=[CH:14]/[C:13]([C:11]1[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:26][CH:25]=2)[CH:12]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: COc1ccc(Cn2cc(C(C)=O)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(=O)/C=C/N(C)C)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.6 %

Procedure:
460 mg (1.3 mmol) of 1-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-ethanone were dissolved in 25 ml of dry tetrahydrofuran and 15 ml of dimethylformamide di-tert-butylacetale (62 mmol) were added to the resulting solution. The reaction was heated at 70° C. under stirring for 6 hours. The solvent was then evaporated in vacuo and the residue diluted with dichloromethane and washed with water. The organic layer was finally dried over sodium sulphate and evaporated, giving 500 mg (96%) of the title compound as an oil.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].I[CH2:29][CH3:30]>>[CH2:29]([N:15]1[C:16]([CH3:27])=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14]1)[CH3:30]
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Reactant: CCI
Product: CCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC)cc2)c1C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-iso-propoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodpropane.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[CH:14])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1I>>[C:1]([C:5]1[CH:15]=[C:8]2[N:9]=[CH:10][C:11]([C:13]#[C:14][C:21]3[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=3[F:23])=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(F)c(I)c1
Reactant: C#Cc1cnc2cc(C(C)(C)C)nn2c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cc(F)ccc3F)cn2n1

Procedure:
The title compound, a white solid, MS: m/e=312.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2) and 1,4-difluoro-2-iodobenzene.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>ClCCl.O1CCOCC1>[CH3:17][O:16][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:13][CH2:12]1)=[O:15]
Reactant: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 1-(2-tert-butoxy-2-oxoethyl)piperidine-4-carboxylate (3.0 g, 12 mmol) in dichloromethane (9 mL) was added hydrochloric acid in 1,4-dioxane (4 M) and stirred at ambient temperature for 24 h. The final product was formed as a white solid, which was washed with ether and filtered (2.3 g). 1H NMR (400 MHz, DMSO-d6) δ 4.09 (s, 2H), 3.64 (s, 3H), 3.46 (br. s., 2H), 3.11 (br. s., 2H), 2.67 (br. s., 1H), 1.82-2.12 (m, 4H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][CH:48]1[CH2:49][CH2:50][N:45]([C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:44])[CH2:46][CH2:47]1)=[N:4][C:5]=2[NH:22][CH2:23][CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCN(C(=O)c5ccccc5)CC4)nc32)[C@H](O)[C@@H]1O
Yield: 70.3 %

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino)-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (310 mg, 0.63 mmol) (example 1), 1-benzoyl-4-piperidinone (128 mg, 0.63 mmol), sodium triacetoxyborohydride (200 mg, 0.90 mmol) and acetic acid (45 mg, 0.74 mmol). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (92:8:0.4) to give the title compound (300 mg) as an oil. MS: 679 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].[C:32](Cl)([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[C:17]([C:16]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[N:14][N:13]2[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:9][CH2:10][NH:11][C:12]=12)#[N:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccc(O)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 7-(2-aminophenyl)-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carbonitrile (730 mg, 2.21 mmol) in THF (30 mL) was added K2CO3 (610 mg, 4.42 mmol), CbzCl (564 mg, 3.32 mmol). After stirring at 65° C. for 16 hr, the mixture was concentrated in vacuum. The residue was partitioned between 150 mL of DCM and 150 mL of brine. Organic layers were separated from aqueous layers, dried over Na2SO4 and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 370 mg (62%) of benzyl 2-(3-cyano-2-(4-hydroxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.33 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.44-7.28 (m, 7H), 7.17 (t, J=7.6 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.59 (d, J=7.6 Hz, 1H), 5.82-5.77 (m, 1H), 5.17 (s, 2H), 3.25-3.18 (m, 1H), 2.97-2.87 (m, 1H), 2.36-2.24 (m, 1H), 2.08-2.00 (m, 1H).