Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].[F:9][C:10]1[CH:11]=[C:12]([C:41]2[C:42]([C:47]#[N:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:40])[N:19]([C@H:30]2[CH2:33][C@@H:32]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]>CS(C)=O.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[NH:3][C:4](=[O:7])[O:5][N:48]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:18](=[O:40])[N:19]([C@H:30]2[CH2:33][C@@H:32]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[CH2:31]2)[C:20]2[N:21]([N:26]=[C:27]([CH3:29])[N:28]=2)[C:22]=1[CH2:23][CH2:24][CH3:25]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2nc(C)nn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2C[C@@H](OCC(C)(C)O)C2)c2nc(C)nn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (1.16 g), sodium hydrogen carbonate (1.87 g) and dimethyl sulfoxide (2 mL) was stirred at 60° C. for 30 min, a solution of 3′-fluoro-4′-({4-[cis-3-(2-hydroxy-2-methylpropoxy)cyclobutyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (606 mg) in dimethyl sulfoxide (3 mL) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (216 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (202 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=50/50→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (542 mg, 81%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[Cl:39][C:40]1[CH:54]=[CH:53][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)=[O:45])=[CH:42][CH:41]=1>>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([OH:45])([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:46]2[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=2)=[CH:53][CH:54]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(1,1-Bis(4-chlorophenyl)hydroxymethyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using 4,4'-dichlorobenzophenone instead of benzophenone) to afford the product as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[CH:21]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.ClC1N=C(N2CCOCC2)C2C=C(CN3CCN(C4CC4)CC3)SC=2N=1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:27]3[CH2:28][CH2:29][N:24]([CH:21]4[CH2:23][CH2:22]4)[CH2:25][CH2:26]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Agent: Clc1nc(N2CCOCC2)c2cc(CN3CCN(C4CC4)CC3)sc2n1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(C4CC4)CC3)cc2n1
Yield: 79.1 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (254 mg) and 1-cyclopropylpiperazine di-HCl (352 mg) was reacted under the reductive amination conditions described for 2-chloro-6-(4-cyclopropyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine, to give the title compound (279 mg) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2)cc1
Yield: 78.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-4-carbonyl chloride (0.098 g; 0.445 mmol), and triethylamine (0.131 mL; 0.934 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 10% ethyl acetate in dichloromethane) furnished 0.125 g (79%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].I[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].CN(C)C=O>O1CCCC1.ClCCl>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10]
Reactant: CC(C)CCI
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCN1C(=O)C2CC2C1=O
Reaction time: 0.08 h

Procedure:
Sodium hydride (0.11 g) was added to a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.3 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere at room temperature. The suspension was stirred for 5 minutes and 1-iodo-3-methylbutane (0.53 g) was then added in one portion to the reaction mixture. After stirring for two hours at room temperature, dimethylformamide (5 ml) was added and the reaction mixture was stirred for a further 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and then partitioned with water (20 ml). The aqueous phase was extracted with dichloromethane (20 ml) and the combined organic extracts were washed with water (2×20 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by chromatography on silica gel (50 g) using 25% ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH:7]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH2:22])[C:16]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)(C)(C)C.O>Cl.O1CCOCC1>[NH2:22][C:17]1[C:16]([N+:23]([O-:25])=[O:24])=[C:15]([CH2:7][C:6]([OH:26])=[O:5])[CH:20]=[C:19]([F:21])[CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1cc(F)cc(N)c1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(F)cc(CC(=O)O)c1[N+](=O)[O-]
Temperature: 40 °C

Procedure:
To the 2-(3-Amino-5-fluoro-2-nitro-phenyl)-malonic acid di-tert-butyl ester (140 g) in 500 mL of 4N HCl in dioxane was added 50 mL of water and heated to 40° C. for 2 days. The solution was extracted with ethyl acetate (3×'s) and the ethyl acetate washed with water (3×'s) and brine. The organic fraction was dried over MgSO4 and was concentrated to give 78 g of crude (66% pure by LC/MS); 1H NMR (500 MHz, DMSO) δ 12.40 (brs, 1H), 7.04 (s, 2H), 6.68 (dd, J=10.9 2.8 Hz, 1H), 6.47 (dd, J=10.9, 2.8 Hz, 1H), 3.80 (s, 2H).
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.0074 g (0.11 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.020 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-285) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16]>C1COCC1.CCCCCC>[CH3:16][Si:15]([CH3:18])([CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccccc1[Si](C)(C)C
Temperature: -78 °C

Procedure:
In a 10 ml volume double neck flask substituted with argon gas, was laid 2 ml of a THF solution containing 0.32 mmol/L of o-bromotoluene obtained in the step 2 of Example 1, followed by cooling at −78° C. in an atmosphere of argon gas. To the solution, while stirring using a magnetic stirrer, 0.34 ml of a n-hexane containing 1.58 mol/L of n-butyl lithium was slowly drop wise added and stirred at −78° C. for 30 min. Subsequently, 0.59 ml of a THF solution containing 0.96 mmol/L of chlorotrimethylsilane was slowly drop wise added and stirred at −78° C. for 60 min. After reaction, the resulting solution was analyzed using GC (CBP column 1; 0.25 mm×25 m; starting temperature 50° C.; rate of temperature increase 10° C./min). As a result, o-trimethylsilyltoluene was obtained with a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20]CC)=O)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:23][NH2:24].C(OC(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([NH:24][CH3:23])=[O:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: CN
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(Br)cn2)CC1

Procedure:
The process is performed as described in Example 1 (step 1.4.). Starting with 2.20 g (5.91 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(5-bromo-2-pyridyl)-1-piperazinecarboxylate, obtained in step 3.3. of Example 3, and 14.80 ml (29.55 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after crystallization from diisopropyl ether, 1.974 g of pure product are obtained in the form of a white solid.
Reaction SMILES: N1C=CC=CC=1.N1CCCCC1.[C:13](O)(=O)[CH2:14][C:15]([OH:17])=[O:16].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])C=O>O>[F:20][C:21]1[CH:22]=[C:23](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=C(O)CC(=O)O
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 0.6 h
Yield: 88.1 %

Procedure:
A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90° C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 90° C. for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40 minute period, then cooled to 25° C. with strong stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40° C. for 24 hours and 40 minutes, affording 13.7 kg of the crystalline product.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>O1CCCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:5]2[C:4]([CH3:3])=[C:8]([CH3:9])[N:7]=[CH:6]2)=[CH:17][CH:16]=1
Reactant: Clc1cccc(Oc2ccc(CBr)cc2)c1
Reactant: Cc1nc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncn(Cc2ccc(Oc3cccc(Cl)c3)cc2)c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
While stirring thoroughly, 1.91 g of 80% strength sodium hydride is introduced into a solution of 6.04 g of 4,5-dimethylimidazole in 80 ml of tetrahydrofuran. Upon completion of the exothermic reaction, the mixture is kept for 3 hours at 60° C., and then cooled. A solution of 17.85 g of p-(3-chlorophenoxy)-benzyl bromide in 20 ml of tetrahydrofuran is then added. The reaction batch is stirred for 12 hours at 20° C., then poured into about 750 ml of ice water and extracted by shaking with methyl tert-butyl ether. The extract is washed twice with 5% strength aqueous sodium hydroxide solution and twice with water. After the extract has been dried over sodium sulfate, the solvent is removed under reduced pressure and the residue is chromatographed over silica gel 60 with acetone/ethyl acetate (2:1). There is obtained 12.1 g (65%) of N-[p-(3-chlorophenoxy)-benzyl]-4,5-dimethylimidazole as a resin-like liquid which slowly crystallizes on standing.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[I:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[NH:10][N:9]=1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[I:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:9]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(I)c2c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
Cesium carbonate (25.3 g, 77.6 mmol) was added to 3-iodo-5-nitro-1H-pyrazolo[3,4-b]pyridine (15 g, 52 mmol) in DMF (500 mL). Then 1-(chloromethyl)-4-methoxybenzene (10.57 mL, 77.58 mmol) was added, which was stirred at room temperature for 16 hours. Water (1 L) was then added to the reaction mixture, which resulted in a precipitate. The solids were collected by filtration and transferred into a flask with the aid of i-PrOH. The concentrate was triturated with EtOAc/Et2O (3:1 EtOAc/Et2O, 750 mL) to give 3-iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (12.1 g, 29.5 mmol, 56.9%) as a solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][NH:25][CH2:11][CH:9]([OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2)=[CH:18][CH:17]=1
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(CCCN)cc1
Product: Cc1ccc(CCCNCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-trifluoromethylphenylglyoxal and 3-(4-methylphenyl)propanamine. Recrystallization of the chromatographed material from hexane gave the title compound m.p. 96-98. τ(CDCl3) 8.0-8.5 (2H, m), 7.7 (3H, s), 7.0-7.5 (6H, m+2H, disappears with D2O), 5.3 (1H, dd), 2.9 (4H, s), 2.3-2.7 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][O:19]C(=O)C)[C@@:14](C(=O)C)([OH:15])[C@@:12]2(C(=O)C)[OH:13])=[C:4](Cl)[N:3]=1.[NH3:30]>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:30])[C:5]2[N:6]=[CH:7][N:8]([C:9]=2[N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(N)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
The 6-position of 2-amino-6-chloro-9-(2,3,5-O-triacetyl-β-D-ribofuranosyl)-9H-purine was aminated by ammonia to give 2-aminoadenosine. In the same manner as Example 1 [METHOD 1], 2-aminoadenosine was methylated to give 2-amino-2'-O-methyladenosine (Compound 30) and 2-amino-3'-O-methyladenosine (Compound 31).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO.ClCCl>[CH3:18][N:19]([C:2]1[N:7]=[C:6]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1CCNC1
Reactant: Cc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Reactant: CNc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(N(C)c2ccccc2)nc(N2CCCC2)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2,4-dichloro-6-methyl-5-nitropyrimidine (208 mg, 1.0 mmol, 1.0 eq. in 2 mL each of EtOH and THF) is added of pyrrolidine (78 mg, 1.1 eq) in 1.0 mL of EtOH. The resulting solution is stirred for 1 hour at −78° C., then for 2 hours at 0° C. N-methylaniline (0.432 mL, 4.0 eq.) is added dropwise and the reaction is stirred overnight. The resulting mixture is diluted with dichloromethane, washed with 0.1N HCl, saturated NaCl, dried (MgSO4), and filtered. Solvent is removed by evaporation and the residue is purified by chromatography to provide the target compound (r).
Reaction SMILES: N1C=CC=CC=1.[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH:22]([OH:24])[CH3:23])[CH:16]([CH2:19][O:20][CH3:21])[CH2:17][OH:18])#[N:8]>[O-2].[O-2].[O-2].[Cr+6].ClCCl>[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([C:22]([CH3:23])=[O:24])[CH:16]([CH2:19][O:20][CH3:21])[CH:17]=[O:18])#[N:8]
Reactant: COCC(CO)C(CCCCCCC#N)C(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(C=O)C(CCCCCCC#N)C(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a mixture of 1.874 g. of pyridine (dried over barium oxide) and 60 ml. of dichloromethane (dried over calcium chloride) was added in one portion 1.237 g. of chromium trioxide (dried over phosphorus pentoxide). The mixture was stirred at room temperature for 15 mins. then 0.255 g. of 3-(6-cyanohexyl)-2-methoxymethyl-1,4-pentanediol in 5 ml. of dry dichloromethane was added in one portion. The reaction mixture was stirred at room temperature for 0.5 hr., at the end of which the supernatant was decanted into a separatory funnel. The residue was washed several times with diethyl ether (total 150 ml.). The combined organic solutions were washed three times with 20 ml. portions of 5% aqueous potassium hydroxide solution, twice with 20 ml. portions of 5% hydrochloric acid, once with 20 ml. of sodium bicarbonate and finally with 15 ml. of brine. Drying over anhydrous magnesium sulphate and removal of the solvent in vacuo gave the desired 3-(6-cyanohexyl)-2-methoxymethyl levulinaldehyde (0.195 g., 78% yield). Infra-red and proton NMR spectroscopy were in agreement with the proposed structure.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2.[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:18][CH2:17][Br:16]
Reactant: CC(C)=CCNc1ncnc2nc[nH]c12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)=CCNc1ncnc2c1ncn2CCBr
Yield: 70 %

Procedure:
Mixture of 6-[(3-methylbut-2-en-1-yl)amino]purine (2 g, 9.8 mmol), 1,2-dibromoethane (12.94 g, 6 ml, 69 mmol) and K2CO3 (2.5 g, 24 mmol) was stirred in 50 ml DMSO for 12 h. Reaction mixture was poured onto drift ice and after ice dissolution 30 ml ethyl acetate was added. Ethyl acetate layer was purified by charcoal and SiO2 and then it was evaporated in vacuo. The pure product was recrystallised from methanol; yellow solid was obtained. Yield: 70%. 1H NMR (DMSO-d6): 1.75 (3H, s), 1.59 (3H, s), 4.12 (2H, t, J=5.76), 4.10 (2H, s (br)), 4.6 (2H, t, J=5.76), 5.3 (1H, t, J=6.57), 8.1 (1H, s (br)), 8.3 (1H, s).
Reaction SMILES: C(OCO[CH2:6][CH3:7])C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([N:24]=[C:25]=[O:26])[CH:22]=[CH2:23].[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>C(OC)(C)(C)C.C1COCC1>[CH2:21]([NH:24][C:25](=[O:26])[C:7]#[C:6][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:22]=[CH2:23]
Reactant: CCOCOCC
Reactant: C[Si](C)(C)Cl
Reactant: C=CCN=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=CCNC(=O)C#C[Si](C)(C)C
Temperature: 0 °C

Procedure:
Preferred solvents include ethereals such as THF, diethoxymethane and t-butylmethyl ether. At about 0° C., a strong base is added dropwise over a period of about 15 minutes. Examples of strong bases are n-butyl lithium and lithium diisopropyl amide. While still maintaining the temperature near 0° C., a solution of allyl isocyanate in solvent is added dropwise over about 15 minutes. This is followed by the dropwise addition of trimethylsilyl chloride. After holding the reaction mixture at about 0 to about 10° C. for about 3 hours, the reaction is quenched with aqueous ammonium chloride and extracted with dichloromethane. The solvent is evaporated to yield the product, N-allyl-3-trimethylsilylpropiolic amide. ##STR8## wherein TMS is trimethylsilyl, the solvents are methylene chloride or DCE (1,2-dichloroethane), and the acid catalysts are aluminum chloride (AlCl3), ferric chloride (FeCl3) or methanesulfonic acid (MeSO3).