Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=2)[CH:3]=1.[NH2:22][C@@H:23]1[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]1[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.CCOC(C)=O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:22][C@@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH:19]([CH3:21])[CH3:20])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)c1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Temperature: 140 °C
Yield: 25.3 %

Procedure:
To a solution of 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (250 mg, 807 μmol) in NMP (3.2 mL) was added tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) and the mixture heated to 140° C. Over the next 36 h three additional portions of tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (174 mg, 807 μmol) were added at 12 h intervals. At 48 h the mixture was cooled, diluted with EtOAc, and washed with water and brine (2×). The organic layer was concentrated onto silica and purified by chromatography (70% to 100% EtOAc in hexanes) to give tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 25%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 11.49 (s, 1H), 8.22 (s, 1H), 8.06 (br. s, 1H), 7.29 (t, J=9.4 Hz, 1H), 6.70 (dd, J=8.9, 3.0 Hz, 1H), 6.07 (br. s, 1H), 5.50 (br. s, 1H), 5.35 (br. s, 1H), 4.26 (br. s, 1H), 4.03 (m, 2H), 3.92 (d, J=11.4 Hz, 1H), 3.68 (d, J=11.5 Hz, 1H), 3.61 (t, J=11.8 Hz, 1H), 3.41 (m, 1H), 2.24 (d, J=11.2 Hz, 1H), 1.81 (m, 1H), 1.49 (s, 9H), 1.35 (d, J=6.9 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>O1CCCC1.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:37][Si:38]([C:41]#[C:42][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1)([CH3:40])[CH3:39]
Reactant: Brc1ccc2ccsc2c1
Reactant: C#C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)C#Cc1ccc2ccsc2c1

Procedure:
In tetrahydrofuran (15 ml) was dissolved 6-bromobenzo[b]thiophene (2.13 g), followed by the addition of triphenylphosphine (787 mg), triethylamine (40 ml), N,N-dimethylformamide (15 ml), trimethylsilylacetylene (1.47 g) and palladium acetate (225 mg). The resulting mixture was refluxed for 5 hours. After the reaction mixture was allowed to cool down, it was diluted with methylene chloride (150 ml). The diluted mixture was washed with water (twice) and saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (only hexane), whereby the title compound (1.38 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3]1.[CH3:17][N:18]([CH3:20])[NH2:19].C(O)C>C(O)(=O)C.O>[CH3:17][N:18]([CH3:20])[N:19]=[CH:7][C:5]1[C:4]([C:9]2[O:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc(C=O)c(-c2ccc([N+](=O)[O-])o2)n1
Reactant: CN(C)N
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN(C)N=Cc1cn(C)nc1-c1ccc([N+](=O)[O-])o1
Yield: 96 %

Procedure:
Stir together 2 g of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde, 0.65 g of N,N-dimethylhydrazine, 2 drops of glacial acetic acid and 30 ml of ethanol for 4 hours at room temperature. Add 30 ml of water dropwise thereto to obtain a 96% yield of 1-methyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-dimethylhydrazone [m.p. 164° to 165° C].
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:46][C:47](=[O:59])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:17][S:18][CH2:19][C@H:20]([NH:28][C:29]([O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[C:21]([O:23]C(C)(C)C)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CC(OC)(C)C>[C:47]([O:46][C@H:16]([CH2:15][O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:17][S:18][CH2:19][C@@H:20]([C:21]([OH:23])=[O:22])[NH:28][C:29](=[O:30])[O:31][CH2:32][CH:33]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)(=[O:59])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC

Procedure:
A solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diyl didodecanoate (11) in 40% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of tert-butyl group (2 hr). The reaction mixture was diluted in MTBE, washed three times with 1M citric acid (adjusted to pH3), and once with 1:2 1N HCl/brine. The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used without further purification.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]([OH:29])[CH2:14][N:15]2[CH2:20][CH2:19][N:18](C3C=CC(OC)=CC=3)[CH2:17][CH2:16]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:30]1([O:40][CH2:41]C2OC2)[C:39]2CCCC[C:34]=2[CH:33]=[CH:32][CH:31]=1.COC1C=CC=CC=1N1CCNCC1>>[C:1]1([O:11][CH2:12][CH:13]([OH:29])[CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:39][C:30]=3[O:40][CH3:41])[CH2:19][CH2:20]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cc2c(c(OCC3CO3)c1)CCCC2
Reactant: COc1ccc(N2CCN(CC(O)COc3cccc4c3CCCC4)CC2)cc1
Agent: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3c2CCCC3)CC1

Procedure:
1-[3-(5,6,7,8-tetrahydronaphth-1-yloxy)-2-hydroxyprop-1-yl]-4-(4-methoxyphenyl)-piperazine from 1-(5,6,7,8-tetrahydronaphth-1-yloxy)-2,3-epoxypropane and 1-(4-(methoxyphenyl)-piperazine; yield 72% of theory; m.p. 83°-84°C. (recrystallized from isopropanol); m.p. of the dihydrochloride 230°-231°C. (decomp.).
Reaction SMILES: [F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C:16](=[CH:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(=O)C.O>CC(C)=O>[F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C:16]([CH2:17][CH2:18]3)=[CH:15][C:14](=[O:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Yield: 99.6 %

Procedure:
A solution of 14α-fluoro-3β-hydroxyandrost-5(6)-en-17-one (93 mg), prepared as described in (i) above, in acetone (20 ml) was treated with Jones reagent (0.10 ml) at 0°-5° for 5 min. Excess Jones reagent was destroyed by the addition of isopropanol (0.2 ml) and water (5 ml) was added. The organic solvents were then evaporated off in vacuo and the aqueous residue was extracted with chloroform. The chloroform was evaporated in vacuo and the thus-obtained residue dissolved in warm methanol (10 ml). The resulting solution was treated with one drop of 2 N aqueous sodium hydroxide and warmed on a steam bath for 5 min. The orange solution so obtained was neutralized with acetic acid, water was added, and the organic solvents were evaporated of in vacuo. The residue was extracted with chloroform, and the solution was washed with sodium bicarbonate and water, and then dried. Evaporation of the chloroform in vacuo gave a solid (92 mg) which was chromatographed by p.l.c. (silica gel) eluting with ethyl acetate:hexane (1:1). Recovery of the major band gave the title compound (68 mg), which crystallised from acetone as prisms (58 mg) m.p. 216°-217°; [α]D24 +181° (c 0.69, CHCl3); λmax (ethanol) 239 nm (ε12,900); νmax 1740, 1660 and 1615 cm-1 ; the PMR spectrum included signals at δ1.05 (3H, s, 18-Me), 1.22 (3H, s, 19-Me) and 5.8 (1H, s, 4-H); FMR φ*+164.5 ppm (broad multiplet ca 90 Hz wide). (Found: C, 74.82; H, 8.23; F, 6.30, C19H25O2F requires C,74.97; H,8.28; F,6.24%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:40]1[N:39]=[CH:38][N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: Cc1cc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)ncn1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (137 mg, 0.5 mmol) and 3-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K41) (172 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][OH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH2:11][O:20][CH2:19][CH2:18][O:17][CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Reactant: COCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)OC
Reaction time: 3 h

Procedure:
A mixture of 0.30 g (about 1 mmol) methyl N-(5-chlorothiophen-2yl)carbonyl-aziridine-2-carboxylate and 0.29 ml (3.7 mmol) 2-methoxyethanol in 4 ml methylene chloride is slowly combined with 0.16 ml boron trifluoride etherate and stirred for 3 h. The reaction mixture is concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20->40/60). Rf value: 0.05 (silica gel; methylene chloride/methanol 80/20)
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:1])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: N
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 28% aqueous ammonia (19.3 g, 317 mmol, 4.0 eq) and toluene (30 mL) was dropwise added a 4-chloromethylbenzoyl chloride (15.0 g, 79.3 mmol)/toluene (30 mL) solution under ice-cooling. The mixture was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with water (9 mL) and toluene (9 mL), and dried in vacuo at 40° C. to give the title compound (13.36 g, yield 99.3%) as white crystals.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([C:22](Cl)=[N:23][OH:24])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:27]=[C:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:29]([O:31][CH3:32])=[O:30].C1COCC1>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([C:22]2[CH2:27][C:28]([CH2:33][C:34]([O:36][CH3:37])=[O:35])([C:29]([O:31][CH3:32])=[O:30])[O:24][N:23]=2)[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(Cl)=NO
Reactant: C=C(CC(=O)OC)C(=O)OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1(C(=O)OC)CC(c2cc(OCc3ccccc3)ccc2C)=NO1
Reaction time: 2 h

Procedure:
Triethylamine (3.06 mL) was added to a mixture of 5-(benzyloxy)-N-hydroxy-2-methylbenzenecarboximidoyl chloride (6.05 g), dimethyl 2-methylenesuccinate (3.09 mL), and THF (100 mL) at room temperature, and the obtained mixture was stirred at 70 C for 2 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (6.80 g).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:10]=1)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C1COCC1>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH2:36][CH2:37]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OCCCN4CCCC4)c23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OCCCN4CCCC4)c23)c1
Yield: 72.1 %

Procedure:
A mixture of 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-(3-pyrrolidin-1-ylpropoxy)quinazoline (0.68 g), 10% palladium on charcoal catalyst (0.16 g), ethanol (13 ml) and THF (13 ml) was stirred under 5 atmospheres pressure of hydrogen for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated under methanol. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.405 g); NMR Spectrum: (DMSOd6) 1.65 (br s, 4H), 2.1 (m, 2H), 2.4 (br s, 4H), 2.55 (t, 2H), 3.8 (s, 3H), 4.4 (t, 2H), 6.7 (m, 2H), 6.75 (m, 1H), 7.48 (d, 1H), 8.3 (d, 1H), 8.4 (s, 1H), 10.05 (s, 1H).
Reaction SMILES: C([C@:9]1([OH:43])[C@@:13](C(=O)C2C=CC=CC=2)([OH:14])[C@H:12]([CH2:23][O:24]C(=O)C2C=CC=CC=2)[O:11][C@@H:10]1[N:33]1[C:37]2[N:38]=[CH:39][NH:40][C:41](=[O:42])[C:36]=2[CH:35]=[N:34]1)(=O)C1C=CC=CC=1>CO.N>[C@H:10]1([N:33]2[C:37]3[N:38]=[CH:39][NH:40][C:41](=[O:42])[C:36]=3[CH:35]=[N:34]2)[O:11][C@@H:12]([CH2:23][OH:24])[C@H:13]([OH:14])[C@@H:9]1[OH:43]
Reactant: O=C(OC[C@@H]1O[C@H](n2ncc3c(=O)[nH]cnc32)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: CO
Product: O=c1[nH]cnc2c1cnn2[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Reaction time: 24 h
Yield: 100.4 %

Procedure:
1-(2′,3′,5′-O-Tribenzoyl-β-L-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 21 (152 mg, 0.26 mmole) was dissolved in MeOH saturated with NH3 at 0 C (75 mL). The resulting solution stood at room temperature for 24 h and concentrated. The residue was dissolved in water (30 mL), washed with EtOAc (3×15 mL). After evaporation of the water, the crystalline solid was soaked in acetonitrile (2 mL), filtered, and dried under vacuum to give 1-β-L-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one 22 as a white crystalline solid (70 mg, 99%).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]2=[O:31])[CH2:10]1)C1C=CC=CC=1.Cl.CN1C2C=CC=CC=2N(CC2OCCNC2)C1=O.[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]\[C:54]([OH:56])=[O:55]>C(O)(C)C>[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]\[C:54]([OH:56])=[O:55].[C:25]1([N:18]2[C:19]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[N:16]([CH2:15][CH:11]3[O:12][CH2:13][CH2:14][NH:9][CH2:10]3)[C:17]2=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ncccc2n1-c1ccccc1
Agent: Cl
Agent: Cn1c(=O)n(CC2CNCCO2)c2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Product: O=c1n(CC2CNCCO2)c2ncccc2n1-c1ccccc1

Procedure:
19 g of 4-benzyl-2-(1-phenyl-2,3-dihydro-imidazo(4,5-b)pyridin-2-on-3-yl-methyl)-morpholine hydrochloride are treated in accordance with part (a) of Example 2. The oil obtained is dissolved in hot isopropanol. A hot solution of maleic acid in isopropanol is added. The salt precipitates slowly. Recrystallization from isopropanol gives 5 g of 2-(1-phenyl-2,3-dihydro-imidazo-(4,5-b)pyridin-2-on-3-yl-methyl)-morpholine maleate, m.p. 190° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@@:6]12[CH2:13][CH2:12][C@@H:11]1[CH2:10][CH2:9][CH2:8][C:7]2=O)[CH3:2].[Cl:16][C:17]1[C:18]([CH3:25])=[C:19]([NH:23]N)[CH:20]=[CH:21][CH:22]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.O.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C@:6]12[CH2:13][CH2:12][C@H:11]1[CH2:10][CH2:9][C:8]1[C:20]3[C:19]([NH:23][C:7]=12)=[C:18]([CH3:25])[C:17]([Cl:16])=[CH:22][CH:21]=3)[CH3:2]
Reactant: CCOC(=O)C[C@@]12CC[C@@H]1CCCC2=O
Reactant: Cc1c(Cl)cccc1NN
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C[C@]12CC[C@H]1CCc1c2[nH]c2c(C)c(Cl)ccc12
Yield: 43.1 %

Procedure:
cis-2-Oxobicyclo[4.2.0]octane-1-acetic acid ethyl ester (3.7 g, 18.87 mmol) prepared by the process of Ziegler et al, J. Am. Chem. Soc., 104, 7181 (1982) and 3-chloro-2-methylphenylhydrazine (2.95 g, 18.87 mmol) were dissolved in 50 mL of toluene and refluxed under nitrogen with azeotropic removal of water for 48 hours. The toluene was removed and 13 mL of acetic acid and 2.78 mL (22.64 mmol) of borontrifluoride etherate was added to the residue. The reaction mixture was then allowed to reflux under nitrogen for 30 minutes. The reaction mixture was then poured into 50 mL of water and extracted with 4×30 mL of ether. The combined organic layers were washed with 4×30 mL of 1N HCl, 1×30 mL of 1N NaOH, and 1×30 mL of brine. The ether layers were dried over MgSO4 and concentrated in vacuo affording 5.7 g of crude product. Flash chromatography (70 mm column, 5% ethyl acetate/petroleum ether eluant) afforded 2.7 g (45%) of cis-7-chloro-1,2,2a,3,4,9-hexahydro-8-methyl-9bH-cyclobuta[a]carbazole-9b-acetic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([N:9]([C:19]2[CH:23]=[C:22]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])[S:21][C:20]=2[C:30]([OH:32])=[O:31])[C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([CH3:18])[CH2:14][CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][O:34][P:35]1(=[O:42])[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:29][C:26]([CH3:27])([CH3:28])[C:25]#[C:24][C:22]1[S:21][C:20]([C:30]([OH:32])=[O:31])=[C:19]([N:9]([CH:6]2[CH2:5][CH2:4][CH:3]([NH:2][CH:38]3[CH2:39][CH2:40][P:35]([O:34][CH3:33])(=[O:42])[CH2:36][CH2:37]3)[CH2:8][CH2:7]2)[C:10]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH3:18])[CH2:16][CH2:17]2)=[O:11])[CH:23]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C2CCC(N)CC2)CC1
Reactant: COP1(=O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COP1(=O)CCC(NC2CCC(N(c3cc(C#CC(C)(C)C)sc3C(=O)O)C(=O)[C@H]3CC[C@H](C)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(N-(4-aminocyclohexyl)-4-methylcyclohexanecarboxamido)-5-(3,3-dimethylbut-1-ynyl)thiophene-2-carboxylic acid hydrochloride (40 mg, 0.083 mmol) and 1-methoxy-1-oxo-1λ5-phosphinan-4-one (27 mg, 0.166 mmol) were dissolved in 2 mL of DMF. Sodium triacetoxyborohydride (35 mg, 0.166 mmol) was added. The reaction mixture was allowed to stir at room temperature over 18 hours, and then diluted with EtOAc, washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid) to give title compound (38.6 mg): MS (m/z): 591.3 [M+H]−; HPLC retention time: 3.28 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[NH:39]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[N:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([C:32]([N:42]5[CH2:41][C@H:40]([CH3:44])[NH:39][C@H:38]([CH3:37])[CH2:43]5)=[O:34])=[CH:35][CH:36]=4)[CH:25]=[CH:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=C(O)c1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C(=O)c2ccc(Cn3ccc4ncnc(Nc5ccc(OCc6cccc(F)c6)c(Cl)c5)c43)cc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
To a solution of 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoic acid (120 mg) in N,N-dimethylformamide (2.4 mL) were added cis-2,6-dimethylpiperazine (95 mg) and 1H-1,2,3-benzotriazol-1-ol (65 mg), and the mixture was stirred at room temperature for 15 min. N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (92 mg) and triethylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL×3). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=10/0→9/1). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (3/7) was added to the residue and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (85 mg) as white powder crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:28]=[C:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[S:23][C:1]([C:3]2[N:4]=[C:5]([CH2:9][O:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1

Procedure:
tert-Butyl 3-[(2-cyano-6-pyridyl)]methoxypropanoate (2.62 g, 10 mmol) and methyl thiosalicylate (1.85 g, 11 mmol) were dissolved in toluene (30 ml), and triethylamine (1.70 ml, 12 mmol) were added thereto. The reaction mixture was refluxed under nitrogen atmosphere for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The titled compound (2.92 g, 71%) was given from the fraction eluted with ethyl acetate-hexane (1:2, v/v) and recrystallized from ethyl acetate-isopropyl ether.