Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:34][C:35]2[C:40]([C:41]#[N:42])=[CH:39][N:38]=[CH:37][CH:36]=2)=[N:14][C:15]([C:18]2[C:19]3[CH2:33][CH2:32][CH2:31][C:20]=3[N:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:22]=2)=[N:16][CH:17]=1)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:21]1[C:20]2[CH2:31][CH2:32][CH2:33][C:19]=2[C:18]([C:15]2[N:14]=[C:13]([NH:34][C:35]3[C:40]([C:41]#[N:42])=[CH:39][N:38]=[CH:37][CH:36]=3)[C:12]([O:11][CH2:10][CH2:9][OH:8])=[CH:17][N:16]=2)=[N:22]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1Nc1ccncc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnccc1Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1OCCO
Temperature: 25 °C

Procedure:
32.7 mg of 4-({5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]pyrimidin-4-yl}amino)nicotinonitrile 2-3-10 (0.034 mmol, 1.00 eq.) were dissolved in 0.58 mL dioxane and 0.085 mL 4 M hydrochloric acid in dioxane (0.341 mmol, 10.0 eq.) were added and stirred at rt over night. The reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM/isopropanol (4:1). The combined organic layers were washed with brine, dried over silicon filter and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (DCM/methanol (9:1)) to provide 8.7 mg (0.02 mmol, 54%) of analytically pure target compound.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:16]=1)=[O:3].[N+:17](=[CH2:19])=[N-:18]>CCOCC>[N+:17](=[CH:19][C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][C:8]=2[CH:16]=1)=[O:3])=[N-:18]
Reactant: C=[N+]=[N-]
Reactant: O=C(Cl)c1ccc2c(c1)sc1ccccc12
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccc2c(c1)sc1ccccc12

Procedure:
A solution of 7.9 g. of crude 3-chlorocarbonyldibenzothiophene in 700 ml. of ether was added with stirring to a solution of 2.7 g. of diazomethane in 180 ml. of ether in an ice bath. The solution was stirred for 7 hours and then the solvent was removed, on a steam bath, to yield the crude 3-diazomethylcarbonyldibenzothiophene (7.5 g.) which was used directly in the next step.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.Cl>C(O)=O>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1cccc(N)n1
Agent: Cl
Solvent: O=CO
Product: Nc1cccc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Temperature: 25 °C
Yield: 66.6 %

Procedure:
To a solution of 7-[2-tert-butoxycarbonylmethoxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (5.0 g) in formic acid (50 ml) was added conc. hydrochloric acid (2 ml), and the mixture was stirred at ambient temperature for an hour. After the solvent was removed by distillation under reduced pressure, the residue was dissolved in water (100 ml), followed by subjecting to column chromatography on a non-ionic adsorption resin, "Diaion HP-20" (200 ml). After the column was washed with water (600 ml), elution was carried out with 10% aqueous methanol. The eluates containing a desired compound were collected, evaporated to remove methanol under reduced pressure and then lyophilized to obtain 7-[2-carboxymethoxyimino-2-(6-aminopyridin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (3.0 g), mp 100° to 108° C. (dec.).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[NH:21][S:22]([CH2:25][C:26]([O:28]C)=O)(=[O:24])=[O:23])[N:6]=1.C(OCC)C.C(O)(C)C>CO>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[NH:21][S:22]([CH2:25][C:26]([NH:2][CH3:1])=[O:28])(=[O:24])=[O:23])[N:6]=1
Reactant: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reactant: CN
Solvent: CO
Solvent: CC(C)O
Solvent: CCOCC
Product: CNC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 552 h

Procedure:
Methylamine (4.2 g of a 33% solution in industrial methylated spirits) was added to a solution of the product of stage (a) (3 g) in methanol (60 ml) at room temperature. After standing for 23 days, the solution was run down under vacuum at less than 35° C. to give a brown oil. Trituration with a mixture of diethyl ether and isopropanol gave an off-white solid which was dried without heat to give 1.3 g of the desired product, mp 193°-198° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH:27]([F:29])[F:28])=[C:21]([CH3:30])[N:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][CH:27]([F:29])[O:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([C:8]2([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:34]4[CH:35]=[N:36][CH:37]=[C:32]([F:31])[CH:33]=4)[CH:7]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)=[N:20][C:21]=1[CH3:30]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1cc(C2(c3ccnc(Cl)c3)N=C(N)c3c(F)cccc32)nc(C)c1OC(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(C2(c3ccnc(-c4cncc(F)c4)c3)N=C(N)c3c(F)cccc32)nc(C)c1OC(F)F
Temperature: 90 °C
Yield: 13.9 %

Procedure:
A mixture of 3-(2-chloro-pyridin-4-yl)-3-(5-difluoromethoxy-4,6-dimethyl-pyridin-2-yl)-7-fluoro-3H-isoindol-1-ylamine 1 (0.14 g, 0.32 mmol), 5-fluoropyridine-3-boronic acid (0.068 g, 0.485 mmol), Pd(PPh3)4 (0.065 g, 0.056 mmol), aqueous Na2CO3 (2M, 1 mL, 2 mmol) in DME (4 mL) was degassed for 15 minutes using nitrogen and then heated in a sealed tube at 90° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and washed with saturated NaHCO3 solution (10 mL) and H2O (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (22 mg, 14%). 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (br. s., 1 H) 8.61 (d, 1 H) 8.48 (br. s., 1 H) 8.00 (d, 2 H) 7.85 (s, 1 H) 7.54-7.61 (m, 1 H) 7.51 (s, 1 H) 7.40 (d, 1 H) 7.16 (t, 1 H) 6.36 (s, 1 H) 2.51 (s, 3 H) 2.30 (s, 3 H).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([C:13](=[O:25])[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=[O:17])C1)=O)(C)(C)C.[C:26]([O:30][C:31]([N:33]1C(C(O)=O)C2C[CH:34]1[CH2:35][CH2:36]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31]([N:33]1[CH:10]([C:13](=[O:25])[NH:14][CH2:15][C:16]([C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)=[O:17])[CH:11]2[CH2:12][CH:34]1[CH2:35][CH2:36]2)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(Br)cc2)C1
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)NCC(=O)c1ccc(Br)cc1

Procedure:
Following the procedure used to prepare compound 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester, except that 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester was used instead of pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3]1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O1CCOCC1>[CH2:23]([N:3]1[C:4]2[C:9](=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:10][CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1Cc2cnccc2NC1=O)OCc1ccccc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1Cc2cnccc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of 1E (297 mg, 1 mmol) in THF (8 mL) and 1,4-dioxane (6 mL) was added benzyl alcohol (103 μL, 1 mmol) and triphenylphosphine (393.5 mg, 1.5 mmol), followed by diethyl azodicarboxylate (0.24 mL, 1.5 mmol). The reaction mixture was stirred at RT for 10 min. After this time, no starting material was detected by LC-MS. The reaction was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of methonal (0-5%) in EtOAc to give the title compound as a white solid (260 mg, 67%). LC/MS (method A): retention time=2.50 min, (M+H)+=388.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][CH:17]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH:29]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:12]1[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCCCC1CC(C=Cc2ccccc2)=NO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCNCC1CCCCC1CC(C=Cc2ccccc2)=NO1
Yield: 78.6 %

Procedure:
4-[3-(2-Phenylvinyl)-4,5-dihydroisoxazol-5-yl]butanal (23.4 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 28.7 mg (73.2%) of the target compound was obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1>N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]=[CH:8][CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCN1CC#CCN1CCCC1
Solvent: c1ccncc1
Product: O=C1CCCN1CC=CCN1CCCC1

Procedure:
A solution containing 24.7 g. (0.12 mole) of 1-(4-pyrrolidino-2-butynyl)-2-pyrrolidinone dissolved in 250 ml. of pyridine was hydrogenated in a bottle-type hydrogenator over 5 g. of 2% palladium-on-strontium carbonate catalyst. When the theoretical quantity of hydrogen was absorbed, the catalyst was removed by filtration and the solvent was removed under reduced pressure. Upon distillation and chromatographic separation, the product, N-[4-(1-pyrrolidinyl)-2-butenyl]-pyrrolidinone, was obtained as a clear oil distilling at 107° C. at 0.05 mm.
Reaction SMILES: C([C:3]1([OH:19])[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]([CH:11]=[CH:12][C:13]([OH:17])([CH3:16])[C:14]#[CH:15])=[C:4]1[CH3:18])#C.[OH-].[Na+]>>[OH:17][C:13]([CH3:16])([C:14]#[CH:15])[CH:12]=[CH:11][C:5]1[C:6]([CH3:9])([CH3:10])[CH2:7][CH2:8][C:3](=[O:19])[C:4]=1[CH3:18]
Reactant: C#CC(C)(O)C=CC1=C(C)C(O)(C#C)CCC1(C)C
Agent: [Na+]
Agent: [OH-]
Product: C#CC(C)(O)C=CC1=C(C)C(=O)CCC1(C)C

Procedure:
10 mL of 0.5M solution of ethynylmagnesium chloride (5 mmoles) in tetrahydrofuran (purchased from Aldrich Chemical Co., Milwaukee, Wis.) was added to a 100 mL 3-neck reaction flask fitted with an addition funnel and an adapter connected to an apparatus similar to that described by Johnson and Schneider [Org. Synth., 30, 18 (1950)] so that the mixture in the flask could be protected from atmospheric moisture, et al. throughout the course of the reaction. After sweeping the system briefly with a stream of nitrogen gas and placing the flask in an ice-water bath (0° C.), a solution of 600 mg (2.91 mmoles) of 4-oxo-beta-ionone (prepared as described in Example V) in 4.0 mL of anhydrous tetrahydrofuran was added rapidly to the stirred Grignard reagent. The resulting mixture was stirred at 0° C. for an additional 60 minutes; after which it was diluted with 5 mL of hexane and the excess organometallic reagent was destroyed by slow, dropwise addition of 6 mL of saturated aqueous ammonium chloride. Isolation of the product as described in the procedure of Example III afforded 703 mg of a mixture of products, the major component of which was shown by proton NMR analysis to be the named keto alkynol (characterized by a singlet at δ 1.158--ascribed to the two methyls bonded to C-4). The other product was shown to be a diyne-diol (i.e., the bis Grignard adduct obtained by addition of ethynylmagnesium chloride to both carbonyl groups in 4-oxo-beta-ionone). The systematic name of the latter by-product is 1-ethynyl-3-(3-hydroxy-3-methylpent-1-en-4-ynyl)-2,4,4-trimethylcyclohex-2-en-1-ol; and its proton NMR spectrum is characterized by a singlet at δ 1.02--ascribed to the two methyls bonded to C-4. Upon treatment with powdered NaOH in a non-polar organic solvent at room temperature, the latter diyne-diol was converted to the desired product, the named keto alkynol. As described by the following procedure, this transformation can be conducted without the need for separation of the above mixture of products.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=[O:5])[CH2:3]1.[NH3:13]>[Co]>[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([C:10]#[N:11])([CH3:9])[CH2:6][C:4](=[O:5])[CH2:3]1.[CH3:1][C:2]1([CH3:12])[CH2:8][C:7]([CH2:10][NH2:11])([CH3:9])[CH2:6][CH:4]([NH2:13])[CH2:3]1
Reactant: N
Agent: [Co]
Agent: CC1(C)CC(=O)CC(C)(C#N)C1
Product: CC1(C)CC(N)CC(C)(CN)C1
Yield: 48 %

Procedure:
EP-B 0 042 119 also discloses a Comparative Example in which isophoronenitrile and liquid ammonia are pumped into the top of a hydrogenation reactor charged with commercially available cobalt catalyst. The reaction system is kept at 270 bar with H2 ; a certain gas stream is set up and a certain amount of off-gas is withdrawn. The reaction mixture leaving the bottom of the reactor is then worked up by distillation. Despite approximately quantitative conversion of the isophoronenitrile, this embodiment produces only 48% of isophoronediamine, together with many by-products. EP-B 0 042 119 does not suggest passing a mixture containing isophoronenitrile, ammonia and organic solvent, instead of a mixture of isophoronenitrile and ammonia, over a trickle bed reactor at an essentially low pressure and without the need for a preliminary imine formation reaction.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=2)[CH2:34][CH2:33]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Yield: 62 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid obtained in Example 22, step 3 instead of 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid and 1-(4-fluorophenyl)piperazine (0.06 g, 0.35 mmol), the title compound (0.11 g, 62%) was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[C:35](=[O:41])[C:34]1=[O:42])=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:42]=[C:34]1[C:35](=[O:41])[N:36]([CH2:39][CH3:40])[CH2:37][CH2:38][N:33]1[C:31]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[C:7]([F:29])[N:8]([C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:9]=1)=[O:32]
Reactant: NCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(C(=O)NCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(F)n2)C(=O)C1=O

Procedure:
Crude 4-(3-aminopropyl)-2-fluoro-1-triphenylmethylimidazole was dissolved in CH2Cl2 and treated with 4-dimethylaminopyridine and a solution of 1-chlorocarbonyl-4-ethylpiperazine-2,3-dione in CH2Cl2. Work-up by chromatography gave 4-[3-(2,3-dioxo-4-ethylpiperazine-1-carbonylamino)propyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 : 1.25 (t, 3H); 1.85 (quintet, 2H); 2.25-3.7 (m, 6H); 4.05 (q, 2H); 6.25 (s, 1H); 7.05-7.5 (m, 15H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[C@@H:8]([O:18][Si](C(C)(C)C)(C)C)[C@H:7]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([Cl:44])=[N:30][C:31]=3[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([I:43])[CH:38]=2)[S:6]1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][NH:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[C@@H:8]([OH:18])[C@H:7]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([Cl:44])=[N:30][C:31]=3[NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([I:43])[CH:38]=2)[S:6]1)=[O:4]
Reactant: CNC(=O)[C@H]1S[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)[C@H]1S[C@@H](n2cnc3c(NCc4cccc(I)c4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
75 mg (0.09 mmol) of (2S,3S,4R,5R)-3,4-bis(tert-butyldimethylsilanyloxy)-5-[2-chloro-6-(3-iodobenzylamino)purin-9-yl]-tetrahydrothiophene-2-carboxylic acid methyl amide from the aforementioned Experimental Example 35 were dissolved in 5 mL of anhydrous tetrahydrofuran to which 0.25 mL (0.25 mmol, 1 mol tetrahydrofuran solution) of tetrabutylammonium fluoride was added. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was distilled under reduced pressure and the concentrate was purified by silica gel column chromatography using the eluant (dichloromethane:methanol=7:1) to obtain 33 mg (yield: 63%) of (2S,3S,4R,5R)-5-[2-chloro-6-(3-iodobenzylamino)purin-9-yl]-3,4-dihydroxytetrahydrothiophene-2-carboxylic acid methyl amide as white solids (see Table 3).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].N[CH2:6][CH2:7][CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:1]([NH2:4])[CH:2]=[CH2:3].[NH2:4][CH:7]([CH3:6])[CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: C=CCN
Product: CCO[Si](CC(C)N)(OCC)OCC
Temperature: 120 °C

Procedure:
A four-neck flask equipped with a reflux condenser, dropping funnel, stirring rod and thermometer was charged with 41 grams of triethoxy silane (0.25 mole) and a solution of chloroplatinic (IV) acid as a catalyst, in isopropyl alcohol in an amount to provide 2×10-5 mole of platinum. To the mixture heated in an oil bath maintained at a temperature of 120° C., 14 grams of allylamine (0.25 mole) was dropwise added over one hour from the dropping funnel. The mixture was maintained at 120° C. for 9 hours. After the completion of the reaction, the reaction mixture was subjected to gas chromatography analysis. It was found that gamma-aminopropyl triethoxy silane was obtained in a yield of 44% on an allylamine basis, while the yield of beta-aminopropyl triethoxy silane was 10% on an allylamine basis.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16](Cl)=[O:17].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:17]
Reactant: O=C(Cl)c1cnc2c(C(F)(F)F)cccc2c1O
Reactant: Nc1ccccn1
Product: O=C(Nc1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1O

Procedure:
Using the procedure of Step B of Example 1, 4-hydroxy- 8-trifluoromethyl-3-quinoline carboxylic acid chloride and 2-amino-pyridine were reacted to obtain N-[2-pyridinyl]-4 -hydroxy-8-trifluoromethyl-3-quinoline-carboxamide melting at 335°-336° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH3:1][C:2]1[N:3]([CH2:16][C:17]([CH3:26])([O:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc2c(N)nc3c(c2n1CC(C)(C)OCCS(C)(=O)=O)CCCC3
Yield: 64 %

Procedure:
A mixture of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 21, 1.70 g, 4.52 mmol) and platinum(IV) oxide (1.0 g) in trifluoroacetic acid (23 mL) was hydrogenated on a Parr apparatus at 50 psi (3.5×105 Pa) hydrogen pressure for 20 hours. The mixture was filtered through CELITE filter agent, which was washed afterwards with dichloromethane. The filtrate was concentrated under reduced pressure to afford an oil that was suspended in water (50 mL) and adjusted to pH 12 with 50% aqueous sodium hydroxide. A white solid formed that was isolated by filtration, washed with water, and recrystallized from ethanol. The crystals were isolated and dried under vacuum at 65° C. to afford 1.10 g of 2-methyl-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 226-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:8]2)=[C:4](C)[CH:3]=1.[Cl:24]C1C=C(Cl)C=CC=1CN1C2C(=CC=CC=2)C(C(O)=O)=N1.ClC1C=CC(CN2C3C(=CC=CC=3)C(C(O)=O)=N2)=C(C)C=1>>[Cl:24][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:8]1
Reactant: CCOC(=O)c1nn(Cc2ccc(Cl)cc2C)c2ccccc12
Reactant: O=C(O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12
Agent: Cc1cc(Cl)ccc1Cn1nc(C(=O)O)c2ccccc21
Product: CCOC(=O)c1nn(Cc2ccc(Cl)cc2Cl)c2ccccc12

Procedure:
The product was obtained using the method described for the preparation of compound 10a, but using as reagent 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, prepared as described in J. Med. Chem. (1976) 19, 778-783, (0.4 mol) instead of 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid.