Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH2:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:20]1[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=1.[H-].[Na+].O>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[N:13]=[C:12]([NH:18][C:20]2[S:21][C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(Nc2ncc(C#N)s2)n1
Temperature: 75 °C
Reaction time: 8.5 h

Procedure:
4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-6-ethylpyridin-2-amine 12-1 (0.159 g, 0.60 mmol) was dissolved in 2 mL THF. 2-Chloro-1,3-thiazole-5-carbonitrile (0.103 g, 0.72 mmol) and sodium hydride (60% dispersion in mineral oil) (0.057 g, 2.38 mmol) were added and the solution was heated to 75° C. After 4 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.043 g, 0.30 mmol) and sodium hydride (0.014 g, 0.60 mmol) were added. After 5.5 hours more 2-chloro-1,3-thiazole-5-carbonitrile (0.086 g, 0.60 mmol) and sodium hydride (0.029 g, 1.19 mmol) were added. After 8.5 hours the solution was allowed to cool to room temperature. H2O was added and the reaction was concentrated in vacuo (to remove THF). 1N HCl was added to adjust to neutral pH. The resulting precipitate was filtered and washed with water to afford the desired compound 12-2 as a yellow solid. 1H NMR (DMSO-d6) δ 12.23 (s, 1H), 8.25 (s, 1H), 6.70 (s, 1H), 6.83 (s, 1H), 4.73 (bs, 2H), 2.79 (q, 2H, J=7.63 Hz), 1.32 (t, 3H, J=7.63 Hz), 0.94 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCCCOc1ccc2ccccc2c1
Reaction time: 168 h

Procedure:
A mixture of 2-naphthol (28.8 g), 8-chloro-1-octanol (32.8 g), potassium carbonate (40 g) and dimethylformamide (200 ml) was stirred at 60°-65° for 7 days. Water and ether were then added. The a solution was washed with aqueous potassium hydroxide, dried and evaporated. The residue was chromatographed on silica gel, eluting with 95:5 dichloromethane:methanol, and the product so obtained was crystallized from hexane, to give the title compound, mp 67°-9°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:16]([O:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: Clc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
2.54 g 3-Bromo-5-chloro-phenol was dissolved in 50 mL acetone. Subsequently were added 8.04 g potassium carbonate, 1.52 mL benzyl bromide and 0.86 g tetrabutylammonium iodide. The mixture was refluxed for 2 h., cooled to room temperature and filtrated, and the filtrate was concentrated to dryness. The residue was chromatographed over a short column of silica, eluting with DCM/PA 1:4, and the pink color of the product fractions (at the front) was removed with active carbon. After filtration and evaporation, 3.11 g (90%) of a pale yellow oil was obtained. 1H NMR (400 MHz, CDCl3) δ 5.03 (s, 2H), 6.92 (t, J=2 Hz, 1H), 7.03 (t, J=2 Hz, 1H), 7.12 (t, J=1.5 Hz, 1H), 7.31-7.45 (m, 5H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH:17]=O)([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([BH3-])#N.[Na+]>CO>[C:8]([O:12][C:13](=[O:30])[C@H:14]([CH3:29])[N:15]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:16][CH2:17][NH:2][C@@H:3]([C:5]([NH2:7])=[O:6])[CH3:4])([CH3:9])([CH3:10])[CH3:11]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(CC=O)C(=O)OCc1ccccc1
Reactant: C[C@@H](N)C(N)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](NCCN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The D-alanine amide hydrochloride, (45) (2.5 g) (20.18 mmol) was dissolved in methanol, followed by the aldehyde (44) (3.30 g, 10.27 mmol) and triethylamine (1.40 mL, 1.0 g, 10.07 mmol). Sodium cyanoborohydride (0.86 g, 13.7 mmol) was added and the solution was kept stirring at room temperature overnight. The solution was evaporated under vacuum. The residue was taken up in chloroform:methanol (98:2) and flash chromatographed silica gel to yield the titled product (46): (2.48 g, 61%). 1H-NMR CDCl3) δ7.33 (s, 5H), 6.00 (br s, 1H), 5.20 (d, 2H), 4.67-3.00 (m, 4H), 2.77 (t, 2H), 1.83-1.23 (s/m, 13H).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([NH:13][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCN
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into a 500 mL two-neck flask, dodecylamine (18.69 g) and DMAP (N,N-dimethyl-4-aminopyridine) (3.67) were added and nitrogen substitution was carried out. Subsequently, dichloromethane (150 mL) and potassium carbonate (16.67 g) were added to this. In a state in which this flask was cooled in an ice bath, a solution obtained by mixing dichloromethane (150 mL) and octanoic acid chloride (17.94 g) was dropwise added. After the dropwise addition was finished, the temperature was raised to room temperature, and the reaction was carried out for 4 hours. The end of the reaction was confirmed by gas chromatography, and 50 mL of saturated aqueous solution of ammonium chloride was added. After the resultant was stirred for 10 minutes, extraction was carried out with dichloromethane (100 mL), and the obtained organic phase was washed with 1M aqueous solution of hydrochloric acid (50 mL), saturated aqueous solution of sodium hydrogencarbonate (50 mL), and saturated aqueous solution of sodium chloride (50 mL). Removal of the solvent by reduced-pressure distillation was carried out using an evaporator, and recrystallization was carried out with dichloromethane-hexane. The yield of the object N-dodecyloctanoic acid amide was 89% (20.13 g, 89.42 mmol) in terms of dodecylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[C:6]([CH:12]([N:50]1[C:46](=[O:56])[C:47]3[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:49]1=[O:51])[CH3:13])=[N:7]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cccc(F)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethanol (0.2875 g, 0.9497 mmol) in tetrahydrofuran (9.497 mL, 0.9497 mmol) were added triphenyl-phosphine (0.7473 g, 2.849 mmol), phthalimide (0.4192 g, 2.849 mmol), and diisopropyl azodicarboxylate (0.5518 mL, 2.849 mmol). The reaction mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 20 min and 50% isocratic of EtOAc for 5 min as eluent to give 2-(1-(5-chloro-3-(3-fluorophenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (1H, dd, J=8.4, 1.4 Hz), 8.09 (1H, dd, J=7.6, 1.4 Hz), 7.91 (1H, dd, J=8.4, 7.6 Hz), 7.73-7.80 (2H, m), 7.60-7.68 (2H, m), 7.31-7.38 (1H, m), 7.14-7.24 (2H, m), 7.00-7.09 (1H, m), 6.04-6.13 (1H, m), 1.77 (3H., d, J=6.7 Hz); LC-MS (ESI) m/z 432.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (150 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and water was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo. After purification by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v), the corresponding product was obtained as white solid (21.42 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.41 (m, 10H), 7.09 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]([F:30])([F:29])[O:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:23](/[CH:22]=[CH:21]/[C:20]3[CH:26]=[CH:27][CH:28]=[C:18]([O:17][C:16]([F:15])([F:29])[F:30])[CH:19]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1cccc(OC(F)(F)F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC(F)(F)F)c3)nc2n(CC)c1=O
Yield: 59.8 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 1.00 g (5.05 mmol) of 5,6-diamino-1,3-diethyluracil and 1.29 g (5.56 mmol) of 3-trifluoromethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.19 g (yield 60%) of Compound 142 as white needles.
Reaction SMILES: [CH2:1]([N:8]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC=CC=1.Cl>O>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][C:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)N(Cc1ccccc1)C(=O)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)N1Cc1ccccc1
Yield: 75 %

Procedure:
34.1 g. (0.1 moles) of diethyl N-benzyl-N-(chloroacetyl)-amino-malonate prepared according to Example 19 and 18.2 ml. (13.2 g., 0.13 moles) of triethyl amine in 100 ml. of benzene are stirred at room temperature for 8 hours. The mixture is shaken with 100 ml. of water, 50 ml. of a 10% aqueous hydrochloric acid solution and again with 100 ml. of water. The organic phase is dried with magnesium sulfate, filtered and from the filtrate benzene is distilled off. The oily residue is distilled at 149° to 150° C., under a pressure of 0.1 mmHg. 23 g. (75%) of the named compound are obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:9][C:10]1[CH:15]=[C:14]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:13]=[CH:12][N:11]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OCC(F)(F)F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: FC(F)(F)COc1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 2,2,2-trifluoroethanol (2.61 g, 26.10 mmol) in tetrahydrofuran (12 ml) was added dropwise to a suspension of sodium hydride (1.31 g, 32.60 mmol) in tetrahydrofuran (48 ml) at 0° C. The mixture was stirred at 0° C. for 30 min and a solution of 4,6-dichloropyrimidine (3.6 g, 24.16 mmol) in tetrahydrofuran (12 ml) was added at 0° C. The reaction mixture was stirred at ambient temperature for 3 h and poured into sat. aqueous ammonium chloride and extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The orange residue was purified by column chromatography (10-40% ethyl acetate/hexanes) to afford 4-chloro-6-(2,2,2-trifluoroethoxy)pyrimidine (2.0 g, 2.41 mmol, 38.9% yield) as a pale yellow oil. MS (LC/MS) R.T.=2.78; [M+H]+=213.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH3:29][NH:30][CH3:31].C(O)C>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:30]([CH3:31])[CH3:29])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and 2.0 M dimethylamine in ethanol (4.60 ml, 9.30 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-dimethylaminopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (308 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:23][C:24]#[N:25])[CH2:16][N:15]([S:17]([CH:20]4[CH2:22][CH2:21]4)(=[O:19])=[O:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[N:26]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[N:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.C(#N)C.O>[CH:20]1([S:17]([N:15]2[CH2:16][C:13]([CH2:23][C:24]#[N:25])([N:11]3[CH:12]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:35][C:34]5[CH:33]=[CH:32][C:31]([N:26]6[CH:30]=[CH:29][CH:28]=[N:27]6)=[CH:37][CH:36]=5)[N:7]=4)[CH:9]=[N:10]3)[CH2:14]2)(=[O:19])=[O:18])[CH2:22][CH2:21]1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CN(S(=O)(=O)C2CC2)C1
Reactant: Nc1ccc(-n2cccn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(-n5cccn5)cc4)n3)cn2)CN(S(=O)(=O)C2CC2)C1

Procedure:
A mixture of (3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(cyclopropylsulfonyl)azetidin-3-yl)acetonitrile (30 mg, 0.08 mmol), 4-(1H-pyrazol-1-yl)aniline (18.9 mg, 0.119 mmol), and p-toluenesulfonic acid (12 mg, 0.067 mmol) in dry 1,4-dioxane (0.6 mL) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC to give the desired product as a racemic mixture (17.6 mg, 44%). LCMS (M+H) 502.0.
Reaction SMILES: [I:1]I.[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][C:11]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[C:6]2[CH:5]=[N:4]1.[OH-].[K+].[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOCC>[I:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[NH:3][N:4]=1
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]ncc23)CC1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3[nH]nc(I)c23)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
I2 (0.920 g, 3.63 mmol) was added to tert-butyl 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.55 g, 1.81 mmol) and KOH (0.305 g, 5.44 mmol) (crushed by motar and pestle) in DMF (10 mL). The resulting mixture was warmed to 60° C. and stirred for 2 hours. Ether (20 mL) and saturated Na2SO3 (10 mL) were then added. The organic layer was separated, washed with brine and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (hexane:ethyl acetate, 3:1) to give tert-butyl 4-(3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.45 g, 58%) as a solid. MS APCI (+) m/z 430.0 detected. 1H NMR (400 Hz, DMSO-d6) δ 8.31 (d, J=5.2 Hz, 1H), 6.63 (d, J=5.6 Hz, 1H), 3.63 (m, 4H), 3.18 (m, 4H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[C:12]([NH:19][C:20]2[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][NH:16]3)=[C:12]([NH:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:11]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Reactant: N[C@H]1CC[C@H](N)CC1
Product: CCOC(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3[nH]cnc23)c1

Procedure:
570 mg of trans 1,4-diaminocyclohexane are heated to its melting point (70° C.) and 158 mg of the product obtained in stage 1 above are added. 32 mg of the expected product are thus obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:22]([O:25][C@@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:24])[CH3:23]>CS(C)=O>[C:22]([O:25][C@@H:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[C:15](=[O:17])[C:16]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=[N:10][C:11]=2[N:12]([CH3:19])[C:13]1=[O:18])(=[O:24])[CH3:23]
Reactant: CC(=O)O[C@@H](C)CCCCBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a stirring suspension of 7-benzyl-3-methylxanthine (0.512 g, 2 mmol) in dimethyl sulfoxide (10 ml) was added 95% sodium hydride (50.5 mg, 2.0 mmol) in one portion. After stirring for 30 minutes, (S)-5-acetoxy-1-bromohexane (0.490 g, 2.2 mmol) was added neat. After stirring at room temperature for 12 hours, the reaction was quenched by addition of water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate to give (S)-1-(5-acetoxyhexyl)-7-benzyl-3-methylxanthine (0.700 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].[O-2].[Al+3].[O-2].[O-2].[Al+3]>ClCCl.CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Yield: 172 %

Procedure:
(cis)-N,N-Dibenzyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12d (2.44 g, 5.83 mmol) was dissolved in 30 mL mixture solvent of dichloromethane and methanol (V/V=1:2) followed by the addition of palladium/carbon (1.22 g, 10%) and 0.1 mL acetic acid, filled with hydrogen three times. The reaction mixture was reacted at 3 atmosphere for 12 hours. The resulting solution was added with 4 g alkaline aluminum oxide (200-300 mesh) and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (2.38 g, yield: 98.0%) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.[Na+].[I-]>CN(C=O)C.O>[CH:23]1([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C3CCCC3)CC2)nc1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of 2.21 g of methyl 6-piperazinylnicotinate (compound 6), 3.18 g of sodium carbonate and 1.64 g of cyclopentyl bromide in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 150 ml of water and extracted with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; ethyl acetate) afforded 1.73 g of methyl 6-(4 -cyclopentyl-1-piperazinyl)nicotinate (yield 60%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:18](I)[CH2:19][CH3:20]>CC(C)=O>[O:11]=[C:9]([CH3:10])[C:3](=[N:2][O:1][CH2:18][CH2:19][CH3:20])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCON=C(C(C)=O)C(=O)OCC
Yield: 81.2 %

Procedure:
To a suspension of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer) (15 g.) and potassium carbonate (19.8 g.) in acetone (75 ml.) was added dropwise n-propyl iodide (16.2 g.) with stirring, and the mixture was stirred at ambient temperature for 1.5 hours. The insoluble substance was collected by filtration and washed with acetone. The washings and the filtrate were combined and evaporated to dryness under reduced pressure. To the resultant residue was added water and the aqueous solution was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 3-oxo-2-n-propoxyiminobutyrate (syn isomer) (15.4 g.), oil.