Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].Cl.CC(C)=O.C.[CH3:23][N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1>>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:9]=2[CH:8]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (2.0 g) is taken in N-methyl-piperazine (12 ml) and N-methyl piperazine.HCl (4.6 g). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled to 70-75° C. and acetone and activated charcoal are added. The reaction mixture is stirred for 30 minutes and filtered. The water is added at 45-50° C., the mixture is cooled up to room temperature and the precipitated solid is filtered off and washed with acetone-water mixture.
Reaction SMILES: Cl.[CH:2]([NH:5][CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)([CH3:4])[CH3:3].[CH:27](=O)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C([BH3-])#N.[Na+].Cl>C(#N)C.C(O)(=O)C>[CH:2]([N:5]([CH:6]([CH3:26])[CH2:7][C:8]1[C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[C:14]=12)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:3])[CH3:4]
Reactant: COc1ccc2c(c1)CCC1CCNC(=O)C(CC(C)NC(C)C)=C21
Reactant: CCCCCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.66 ml of glacial acetic acid are added dropwise to the ice-cooled mixture of 5.0 g of slow moving 1-(2-isopropylaminopropyl)-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one hydrochloride, 15.2 g of heptaldehyde, 2.52 g of sodium cyanoborohydride and 53 ml of acetonitrile. The mixture is stirred at room temperature for 2 hours, cooled, acidified to pH=1 with concentrated hydrochloric acid and evaporated to remove the acetonitrile. The residue is diluted with water, the solution washed with diethyl ether, basified to pH=10-11 with 3 N aqueous sodium hydroxide and extracted with chloroform. The extract is dried, evaporated and the residue crystallized from ethanol-water (5:2) to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate melting at 102°-104°.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1)=[N:9][C:10]=2[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[CH:2]([CH3:4])[CH3:3].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[OH:59][C@@H:60]([CH3:65])[CH2:61][C:62](O)=[O:63]>CN(C)C=O>[NH2:33][C:30]1[N:31]=[CH:32][C:27]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:62](=[O:63])[CH2:61][C@@H:60]([OH:59])[CH3:65])[C@H:16]([CH3:20])[CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)=[CH:28][N:29]=1
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reactant: C[C@H](O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@H](C)O)[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Temperature: 40 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
5-{9-Isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (230 mg, 0.5 mmol), dicyclohexylcarbodiimide (160 mg, 0.77 mmol), 1-hydroxybenzotriazole (70 mg, 0.51 mmol), and (S)-3-hydroxybutyric acid (107 mg, 1.0 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred at 40° C. for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (167 mg, 61%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.Cl.N1C=NC=N1.O>CN(C)C=O>[N:12]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(-n3cncn3)ccnc2c1

Procedure:
3.27 g of 4-chloro-quinoline, 1.38 g of 1H-1,2,4-triazole and 0.21 g of 1H-1,2,4-triazole hydrochloride are mixed in 10 ml of dimethyl-formamide for 1 hour at 80° C. The reaction mixture is added to 50 ml of water, neutralized with cc. aqueous ammonia, the precipitate is filtered, washed with water and recrystallized from 15 ml of ethanol. 2.47 g /63%/ of 4-(1H-1,2,4-triazole-1-yl)-quinoline (Substance 1) are obtained. M.p.:147°-149° C.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12](Cl)=[O:13]>ClCCl>[CH3:1][NH:2][C:12](=[O:13])[CH2:11][C:5]1[C:4]([F:3])=[CH:9][CH:8]=[CH:7][C:6]=1[F:10]
Reactant: CN
Reactant: O=C(Cl)Cc1c(F)cccc1F
Solvent: ClCCl
Product: CNC(=O)Cc1c(F)cccc1F

Procedure:
25 ml of methylamine solution (33% in ethanol) are diluted with 90 ml of dichloromethane. While cooling, 9.52 g (50 mmol) of 2,6-difluorophenylacetyl chloride dissolved in 10 ml of dichloromethane are added dropwise in such a manner that the temperature of the reaction mixture does not exceed 10°. The reaction mixture is stirred for a further hour at 10° and then extracted three times with water. The organic phase is dried over magnesium sulphate and concentrated. The crude product is recrystallised from dichloromethane/petroleum ether and yields 8.57 g (92.6% of the theoretical yield) of 2,6-difluorophenylacetic acid methylamide of m.p. 163-164°.
Reaction SMILES: [CH2:1]([OH:29])[C@@H:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].CN(C)C=O>O>[Si:35]([O:29][CH2:1][C@@H:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Yield: 63.9 %

Procedure:
A mixture of (25R)-Cholest-5-ene-3β,26-diol (6.24 g, 15.4 mmol), imidazole (4.21 g, 61 mmol) and tert-butyldimethylsilylchloride (2.34 g, 15.4 mmol) and dimethylformamide was heated to 60° C. for 1.5 hours, then poured into water (300 ml) and extracted with diethyl ether (5×100 ml). Flash chromatography afforded (25R)-26-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (5.09 g). Melting point: 93.5° C. The 1H-NMR spectrum (CDCl3, d) showed characteristic signals at: 0.01 (s, 6H), 0.63 (s, 3H), 0.90 (s, 9H), 3.4 (m, 3H, H-26 and H-3), 5.32 (d, 1H, H-6). The 13C-NMR spectrum (CDCl3, d) showed characteristic signals at: 50.1 (C-9), 56.1 (C14), 56.7 (C-17), 68.5 (C-26), 71.7 (C-3), 121.6 (C-6), 140.7 (C-5). The mass spectrum showed characteristic peaks at: 516.5 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:11][OH:12]
Reactant: NO
Reactant: O=Cc1cnccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1cnccc1Cl
Temperature: 0 °C
Yield: 85.3 %

Procedure:
Combine 4-chloropyridine-3-carboxaldehyde (2.75 g, 0.020 mol) with hydroxylamine hydrochloride (1.38 g, 0.021 mol) and ice (50 g) in an ethanol/water (25 mL/25 mL) mixture. Add aqueous sodium hydroxide (2.00 g, 0.049 mol, in 25 mL of water) dropwise and stir for 3 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry the combined extracts over sodium sulfate and concentrate in vacuo which leaves the desired crude oxime (2.67 g, 88%). MS(ES): (M+1)+ 156.0, 158.0 m/z.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Yield: 99.4 %

Procedure:
A solution of 775 mg (2.75 mmol) of nitro compound from Example 215 in 20 mL of methanol with 10% palladium on carbon (150 mg) was introduced hydrogen via balloon at room temperature for 4 h. The catalyst was filtered off through Celite, and the filterate was concentrated under vacuum to give 690 mg of the title compound: 1H NMR (200 MHz, CDCl3) 8 6.69 (d, 2H, J=8Hz), 6.58 (d, 2H, J=8Hz), 4.94 (bs, 1H, N-H), 3.89 (bt, 2H, J=5.0Hz), 3.40 (q, 2H, J=5.0Hz), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[C:27]1=[O:45])([CH3:25])[CH3:24]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[C:27](=[O:45])[N:26]([CH:23]([CH3:25])[CH3:24])[CH2:35][CH2:34]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CC(C)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCN(C(C)C)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=511.9/514.0.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]([C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)=[O:12])([CH2:4]3)[CH2:2]2.CCCCCC.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH:19]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:12])([CH2:4]3)[CH2:2]2
Reactant: COc1ccc(C(c2ccc(OC)cc2)c2cnccc2C(=O)NC23CC4CC(CC2C4)C3)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC1C3)C2)c1ccncc1C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
In 40 ml of methylene chloride was dissolved 2.5 g of Compound 1 obtained in Example 1, and the solution was cooled to from -5° to -15° C. Then, 20 ml of a hexane solution containing 1M boron tribromide was added thereto. The mixture was stirred at room temperature for two hours and thirty minutes. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.63 g of the desired compound as a solid.
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(C)(=O)=O.[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:16]([C:23]1([OH:29])[CH2:28][CH2:27][N:26]([CH2:5][CH2:6][C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(C#CCCS(C)(=O)=O)c1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cccc(C#CCCN2CCC(O)(Cc3ccccc3)CC2)c1
Yield: 20.7 %

Procedure:
A mixture of 1-mesyl-4-(3-methylphenyl)but-3-yne (344 mg, 1.45 mmol), 4-benzyl-4-hydroxy-piperidine (332 mg, 1.73 mmol) and K2CO3 (598 mg, 4.34 mmol) in 15 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×20 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a brown oil (100 mg, 20%) 1H NMR (CDCl3) 1.37 (s, 1 H) , 1.55 (m, 2 H) 1.75 (m, 2 H), 2.30 (s, 3 H), 2.41 (m, 2 H), 2.60 (m, 3 H), 2.75 (m, 5 H), 7.11-7.31 (m, 9 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][C@@H:17]([N:19]1[C:28](=[O:29])[CH2:27][C:22]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][C:20]1=[O:30])[CH3:18]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:18][C@@H:17]([N:19]2[C:28](=[O:29])[CH2:27][C:22]3([CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:21][C:20]2=[O:30])[CH3:16])[CH2:13][CH2:14]1
Reactant: Fc1ccc(F)c(N2CCNCC2)c1
Reactant: C[C@@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Product: C[C@@H](CN1CCN(c2cc(F)ccc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 31.7 %

Procedure:
A mixture of 1-(2,5-difluorophenyl)piperazine (20 mg, 0.10 mmol) and (S)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (20 mg, 0.082 mmol) was heated with stirring at 160° C. for 5 hours. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (10.8 mg, 0.026 mmol, 32%): ESI-MS m/z 406 (MH+).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][C:22]=1[F:31]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][C:22]=1[F:31]
Reactant: O=C(Cl)Cc1ccc(Cl)c(F)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)c(F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(4-chloro-3-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.70-11.79 (m, 1H), 8.39-8.44 (m, 1H), 7.88-8.05 (m, 2H), 7.71-7.76 (m, 1H), 7.63 (s, 4H), 7.57 (t, J=8.1 Hz, 1H), 7.44 (dd, J=10.5, 1.9 Hz, 1H), 7.25 (dd, J=8.3, 1.9 Hz, 1H), 3.75 (s, 2H); MS (ESI+) M/Z 442 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1[N:20]=[C:19](Cl)[C:18]2[N:22]=[CH:23][N:24]([C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[C:17]=2[N:16]=1>>[C:1]1([C:7]2([CH2:13][NH:14][C:19]3[C:18]4[N:22]=[CH:23][N:24]([C:17]=4[N:16]=[CH:15][N:20]=3)[C@@H:25]3[O:29][C@H:28]([CH2:30][OH:31])[C@@H:27]([OH:32])[C@H:26]3[OH:33])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCC1(c2ccccc2)CCCCC1
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC4(c5ccccc5)CCCCC4)ncnc32)[C@H](O)[C@@H]1O
Yield: 42.4 %

Procedure:
(1-Phenylcyclohexyl)methylamine (1.80 g, 8 mmol) as prepared below, and 6-chloropurine riboside (2.36 g, 8 mmol) are reacted as described in Example 1. The solvent is removed under reduced pressure, and the residue dissolved up in CHCl3 and washed with water and dried (MgSO4). The solvent is removed under reduced pressure and the residual white foam is purified on silica gel chromatography eluting with 10% MeOH in CH2Cl2 to give N6-((1-phenylcyclohexyl)methyl)adenosine (1.49 g, 42%) as a white glass m.p. 87°-9° C. Found: C, 62.22; H, 6.96; N, 15.70%. C23H29N5O4 calculated requires: C, 62.87; H, 6.61; N, 15.95%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:16]=[C:15]2[C:10]([NH:11][C:12]([CH3:26])=[C:13]([C:24]#[N:25])[CH:14]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[Br:27][CH2:26][C:12]1[NH:11][C:10]2=[N:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=[C:15]2[CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:13]=1[C:24]#[N:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C#N)C(c2ccccc2Cl)c2cn(C(=O)OC(C)(C)C)nc2N1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)n1cc2c(n1)NC(CBr)=C(C#N)C2c1ccccc1Cl
Reaction time: 1 h

Procedure:
A solution of 4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (22.9 g), di-t-butyl dicarbonate (19.4 g) and dimethylaminopyridine (0.5 g) in tetrahydrofuran (200 ml) was stirred at room temperature for 30 minutes. The reaction mixture was ice-cooled and the precipitated crystals were collected by filtration to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (21.8 g) as white crystals. 2-(t-Butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-methyl-2H-pyrazolo[3,4-b]pyridine (5.0 g), N-bromosuccinimide (2.5 g) and azobisisobutyronitrile (66 mg) were suspended in benzene (50 ml) and the suspension was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (2:1)) and crystallized from ethyl acetate to give 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine as white crystals. To a suspension of sodium hydride (32 mg) in DMF (10 ml) was added morpholine (70 μl) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 6-bromomethyl-2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.36 g) and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water, and the precipitated crystals were collected by filtration and washed with hexane to give 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (450 mg) as white crystals. A solution of 2-(t-butoxycarbonyl)-4-(2-chlorophenyl)-5-cyano-4,7-dihydro-6-(morpholin-4-yl)methyl-2H-pyrazolo[3,4-b]pyridine (440 mg) in trifluoroacetic acid (5 ml) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and 4M hydrochloric acid-dioxane solution was added. The precipitated crystals were collected by filtration and washed with ethyl acetate to give the title compound (250 mg) as pale-yellow crystals.
Reaction SMILES: [C:1]([C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C1COCC1>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:25]=[CH:24][C:12]([O:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(COc2ccc(C(=O)c3ccccc3)cc2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccc(C(O)c3ccccc3)cc2)o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of methyl 5-((4-benzoylphenoxy)methyl)furan-2-carboxylate (330 mg, 1.0 mmol) in methanol (5 mL) and THF (5 mL) was cooled to 0° C. NaBH4 (58 mg, 1.53 mmol) was added in one portion and the reaction was stirred at 0° C. for 2 hours. The reaction was quenched by addition of water (0.75 mL). The mixture was stirred for 10 minutes and the majority of the solvent was removed in vacuo. The residue was partitioned between EtOAc and water and the aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound (325 mg, 96.1%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(C(C)=O)C.[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)C(F)(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Temperature: 75 °C
Reaction time: 108 h
Yield: 74.4 %

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.29 g) and hexamethylphosphoric acid triamide (2.07 g) was heated at 70-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization form ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148-149° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h
Yield: 86.8 %

Procedure:
A suspension of diethyl 2-t-butyloxycarbonylaminomalonate (5.0 g), potassium carbonate (3.0 g), and ethyl 2-bromoacetate (3.9 g) in DMF (20 mL) was stirred at 50° C. for 4 hours. The reaction mixture was cooled, and then poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (5:1), to obtain the title compound (5.7 g, yield: 79%) as colorless oil.