Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)#[N:7].[C:14](O)([CH3:17])([CH3:16])[CH3:15].[OH2:19].[OH-].[Na+]>S(=O)(=O)(O)O>[C:14]([NH:7][C:6]([CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)=[O:19])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#CC1CNCCN1
Reactant: CC(C)(C)O
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)NC(=O)C1CNCCN1
Reaction time: 2.5 h
Yield: 55 %

Procedure:
In 1029 g (8.40 moles) of an aqueous 80% sulfuric acid was dissolved 219.5 g (1.05 mole) of 2-cyanopiperazine sulfate with stirring while keeping the temperature below 40° C. Then, while maintaining the temperature of from 9° C. to 15° C., to the solution was added dropwise 187 g (2.52 moles) of tert-butyl alcohol over a period of 3 hours and further, the mixture was kept at the same temperature for 2.5 hours to complete the reaction. Then, after adding 3 liters of water to the reaction liquid thus obtained, the mixture was neutralized with an aqueous solution of 25% sodium hydroxide until pH thereof became 10. Then, the reaction liquid was extracted twice with one liter of chloroform, the extracts were combined with each other, and chloroform was removed from the mixed extract under reduced pressure to provide 106.8 g (yield 55%) of N-tert-butyl-2-piperazine carboxamide having a melting point of from 151° C. to 152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:7][C:4]=1[CH:5]=O.[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)(=[O:26])[CH3:25]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:7][C:4]=1/[CH:5]=[CH:25]/[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=1)=[O:26]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COCCOCCOc1cc(OC)c(C=O)cc1-c1cccs1
Product: COCCOCCOc1cc(OC)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-5-thiophen-2-yl-benzaldehyde (Ex-49A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 174–175° C., 61% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.23 (d, 2H, J=8.1 Hz), 8.05–8.11 (m, 3H), 7.91 (d, 1H, J=15.3 Hz), 7.72 (d, 1H, J=2.7 Hz), 7.52 (d, 1H, J=4.2 Hz), 7.11–7.15 (m, 1H), 6.86 (s, 1H), 4.39 (t, 2H, J=3.9 Hz), 3.99 (s, 3H), 3.89 (t, 2H, J=3.9 Hz), 3.64 (t, 2H, J=3.9 Hz), 3.48 (t, 2H, J=3.9 Hz), 3.25 (s, 3H). MS (ESI) m/z=483 ([M+H]+, 100%). Anal. Calcd. for C26H26O7S: C, 64.71; H, 5.43; S, 6.64. Found: C, 64.43; H, 5.34; S, 6.54.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:31](=[O:33])[CH3:32])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: CC(=O)Cl
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (56 mg, 0.18 mmol), (Example 88), in DCM (2 mL) were added triethylamine (384, 1.5 eq) and acetyl chloride (154, 1.2 eq). After stirring for 30 min at rt, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM and the combined organic phases dried over sodium sulfate and concentrated in vacuo. The residue was purified with the preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.25 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.41-7.31 (m, 2H), 7.26-7.12 (m, 2H), 5.60 (s, 2H), 2.63 (s, 3H); LC-MS method B, (ES+) 352.0, RT=9.09 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:4]([NH:6][CH3:7])=[S:5].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH2:21]=O>CO>[CH3:14][N:2]([CH3:1])[C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH2:21][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:4]([NH:6][CH3:7])=[S:5]
Reactant: CNC(=S)C(c1ccccn1)N(C)C
Reactant: C1COCCN1
Reactant: C=O
Solvent: CO
Product: CNC(=S)C(CN1CCOCC1)(c1ccccn1)N(C)C

Procedure:
A mixture of 19.5 g. of 2-dimethylamino-N-methyl-2-(2-pyridyl)thioacetamide in 200 ml. of methanol, 13 g. of morpholine and 4.5 g. of formaldehyde is heated at reflux for 48 hours. The mixture is concentrated in vacuo and the residue is recrystallized from isopropyl ether to give 2-dimethylamino-N-methyl-3-morpholino-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15][C:16]3[NH:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[O-]S([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[NH:1]([C:5]1[C:13]2[C:8](=[C:9]([CH2:14][S:15]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[N:17]=3)=[O:33])[N:10]=[CH:11][CH:12]=2)[S:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)Nc1csc2c(CSc3nc4ccccc4[nH]3)nccc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1csc2c(CS(=O)c3nc4ccccc4[nH]3)nccc12
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
To a solution of 83 mg (0.244 mmol) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylthio]benzimidazole (Ia-12) was dissolved in a mixture of 4 ml of CHCl3 and 2 ml of MeOH. To the solution was added 53 mg (1 equivalent) of 80% m-CPBA at -10° C., and the mixture was stirred for 1.5 hr. at the same temperature. By adding an appropriate quantity each of 10% Na2SO3 and saturated aqueous NaHCO3 to the solution, crystals separated out. The crystals were collected by filtration to give 72 mg of crude crystals. The crystals were recrystallized from a solution of CHCl3 - MeOH, whereby 53 mg (Yield : 60.9%) of 2-[(3-acetaminothieno[2, 3-c]pyridin-7-yl)methylsulfinyl]benzimidazole (Ic-27) was obtained as an objective compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[O:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=3[F:36])[CH:18]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16].[NH4+].[Cl-]>CO.O.C(OCC)(=O)C.[Fe]>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[O:26][C:27]3[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=3[F:36])[CH:18]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][Cl:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCCCl)c(OCCCCl)c4)sc23)c(F)c1
Temperature: 25 °C
Yield: 8.4 %

Procedure:
To a stirred suspension of nitro compound 333 (32 mg, 0.57 mmol) in a mixture of MeOH (2 mL) and water (1 mL) were added iron powder (16 mg, 0.29 mmol) and NH4Cl (2.8 mg, 0.05 mmol). The reaction mixture was heated to reflux for 2.5 hrs, cooled to room temperature, diluted with ethyl acetate, filtered, and rinsed with AcOEt. The filtrate was successively washed with sat. ammonium chloride, sat. NaHCO3, water, dried over anhydrous MgSO4, filtered, and concentrated to afford title compound 334 (25 mg, 83% yield) as a pale yellow solid. MS (m/z): 521.0 and 523.0 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[N:6]=[CH:5][C:4]=1[N:17]=O.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[NH2:17][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[NH2:2]
Reactant: [H][H]
Reactant: CC(C)c1ccc(-n2ncc(N=O)c2N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc(-n2ncc(N)c2N)cc1

Procedure:
6.0 g (22.5 mmol) of 5-amino-1-(4-isopropylphenyl)-4-nitroso-1H-pyrazole hydrochloride from Step 2.2 in 150 mL of ethanol was hydrogenated for 6 hours on 0.6 g of Pd/C (10%) at 8 bar of hydrogen pressure. The catalyst was filtered off, and the filtrate was concentrated to a total volume of about 20 mL. After the addition of 40 mL of a 3-molar ethanolic hydrochloric acid solution and agitation in an ice bath, the product crystallized out. Suction filtration and washing with 50 mL of ethyl acetate gave 5 g (17.2 mmol, 77% of the theoretical) of 4,5-diamino-1-(4-isopropylphenyl)-1H-pyrazole dihydrochloride as a colorless product.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1/[CH:13]=[N:15]/[C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nccn1Cc1ccccc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3nccn3Cc3ccccc3)cccc21
Yield: 100.1 %

Procedure:
The mixture of 1-benzyl-1H-imidazole-2-carbaldehyde (430 mg, 1.48 mmol), 4-aminoisobenzofuran-1(3H)-one (221 mg, 1.48 mmol) and magnesium sulfate (4.3 g) in acetonitrile was heated to reflux for 48 hr. Then the mixture was filtrated off and evaporated to remove the solvent. The crude was re-crystallized from isopropanol to obtain the title compound (470 mg, 65%). LC-MS (ESI) m/z: 318 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([O:15][C:8]2[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=[C:6]([CH:5]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:7]=2[F:16])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1F

Procedure:
In analogy to example 1.5, (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 1.4 was reacted with 1-tert-butyloxycarbonyl-4-hydroxy-piperidine to give (RS)-4-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. MS: 559.5 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH:2]=1.[I-].[CH3:14][N+]1C=CC=CC=1.[BH4-].[Na+]>>[CH3:14][N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH2:2]1
Reactant: C[n+]1ccccc1
Reactant: C#CCC(=NO)c1cccnc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Product: C#CCC(=NO)C1=CCCN(C)C1

Procedure:
Employing the general method of Example 6 above, 2.12 g (12.2 mmol) of 1-(3-pyridinyl)-3-butyne-1-one oxime were converted to the corresponding 1-methyl pyridinium iodide and subsequently reduced by the action of sodium borohydride to produce 1.2 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one oxime which was isolated as the ethanedioate salt, mp 55°-57° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:13][CH:12]=2)[C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(C)(C)Cc1ccc(C(=O)Cc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A solution of the product from step (b) (11.1 g) in trifluoroacetic acid (16 ml) was stirred at room temperature and triethylsilane (12.5 ml) added. The mixture was stirred overnight at room temperature, followed by 3 hours at 50° C. during which further portions of triethylsilane (3 ml each) were added after 1.5 hours and 2.5 hours, then poured into water (250 ml). The latter was extracted with ether (×2) and the combined extracts washed with water (×2), dried over MgSO4, and evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (1:4v/v). The eluate was evaporated under reduced pressure to give 11.0 g of the desired product.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>C(O)CC>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: CSc1ccc2cc3n(c2c1)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (50 mg, 0.19 mmol) in PrOH (2 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (105 mg, 0.58 mmol) and DIEA (185 mg, 0.96 mmol). The mixture was stirred at 100° C. for 4 h. The mixture was concentrated under vacuum and the residue was purified by preparative TLC to afford 1-isopropyl-7-(methylthio)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (45 mg, 57.7% yield) as a yellow oil. LC-MS MS (ESI) m/z 407.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12.N1[CH2:41][CH2:40][CH2:39][CH2:38]C1.C1(C=O)CC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:38][CH:39]3[CH2:41][CH2:40]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[CH:13][CH:12]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Reactant: C1CCNCC1
Agent: O=CC1CC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3F)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
Into a 50 mL round-bottom flask, was placed a solution of 3-[(2R)-2-([4-amino-3-[4-(2-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (50 mg, 0.11 mmol, 1.00 equiv) in methanol (10 mL), piperidine (50 mg, 0.59 mmol, 6.73 equiv), and cyclopropanecarbaldehyde (50 mg, 0.71 mmol, 5.54 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100:1, 50:1) to give 0.0179 g (32%) of the title compounds as an off-white solid. LC-MS (ES, m/z): 524 [M+H]+, 1HNMR (300 MHz, CDCl3, ppm) 8.396 (1H, s), 7.689˜7.628 (2H, m), 7.284˜7.085 (6H, m), 6.825˜6.798 (1H, d); 5.663 (2H, s); 4.868 (1H, d); 4.676 (2H, d); 3.708˜3.470 (2H, m); 2.060˜1.980 (5H, m); 1.226 (2H, t); 0.873 (2H, s).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[NH2:25][C:26]1[N:34]=[C:33]([C:35]([OH:37])=O)[N:32]=[C:31]2[C:27]=1[NH:28][C:29](=[O:45])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.NCC1CC1>CC(N(C)C)=O>[CH:13]1([CH2:12][NH:8][C:35]([C:33]2[N:32]=[C:31]3[C:27]([NH:28][C:29](=[O:45])[N:30]3[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:26]([NH2:25])[N:34]=2)=[O:37])[CH2:15][CH2:14]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nc(C(=O)O)nc2c1[nH]c(=O)n2Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (48.1 g, 126.8 mmol) was added to a solution of the product of Preparation 12, 6-amino-9-benzyl-8-oxo-8,9-dihydro-7H-purine-2-carboxylic acid (32.88 g, 115.3 mmol) and diisopropylethylamine (40.2 ml, 230.6 mmol) in dimethylacetamide (250 ml) and the reaction mixture stirred at room temperature for 1 hour. Aminomethylcyclopropane (12.5 ml, 144.1 mmol) was added and the reaction mixture stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and water added. The resultant precipitate was collected by filtration, azeotroped with toluene and triturated with methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Product: CN1CCN(C(=O)CN2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
22.3 Using general procedure A, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid was coupled with 1-methyl piperazine to give 4-chloro-N-[4-(2-{4-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-piperazin-1-yl}-2-oxo-ethyl)-thiazol-2-yl]-benzamide. White solid. MS 505.3 ([M+H]+)
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][OH:4].CO[C:21]([CH3:23])=[CH2:22].O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:22][C:21]1([CH3:23])[O:1][CH:2]([C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:12])([F:13])[F:11])[CH2:3][O:4]1
Reactant: O=C(NCc1ccccc1C(O)CO)C(F)(F)F
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)OCC(c2ccccc2CNC(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1.93 g of N-[2-(1,2-dihydroxyethyl)benzyl]-2,2,2-trifluoroacetamide and 20 ml of acetone were added 1.1 ml of 2-methoxyprop-1-ene and 140 mg of 4-methylbenzenesulfonic acid monohydrate under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 2.2 g of N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2,2,2-trifluoroacetamide.
Reaction SMILES: C(S(O)(=O)=O)(F)(F)F.[OH:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C1C(=O)N([I:25])C(=O)C1>CC#N>[OH:9][C:10]1[CH:17]=[CH:16][C:15]([I:25])=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1ccccc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81626.9 %

Procedure:
CF3SO3H (40 mL) was added dropwise to a solution of 2-hydroxy-benzonitrile (47.6 g, 0.400 mmol) in CH3CN (500 mL) at 0° C., and then stirred at 0° C. for 20 min, then NIS (108 g, 0.48 mmol) was added. The reaction mixture was stirred at rt overnight, concentrated, then diluted with H2O (300 mL) and extracted with EA (300 mL×3). The combined organic parts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification via FC (PE/EtOAc=5/1) afforded the title compound as a white solid (80 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](=O)[CH2:32][CH2:33][CH3:34]>CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][NH:20][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:17][CH:18]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CCCC=O
Agent: [Pd]
Solvent: CO
Product: CCCCNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (165 mg, 0.415 mmol) and butyraldehyde (50 mg, 0.69 mmol) in MeOH (4 mL) was heated at reflux for 30 minutes. The solution was allowed to cool to room temperature, 10% Pd/C (20 mg, 0.019 mmol) was added, and the mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 20 h. The mixture was filtered through Celite and the solvent from the filtrate was removed under reduced pressure. Purification of the crude material by column chromatography on silica gel (200:5:1 CH2Cl2/MeOH/NH4OH) afforded AMD9701 (16 mg, 8%) as a colourless foam. 1H NMR (CDCl3) δ0.87 (m, 3H), 1.24-1.49 (m, 4H), 1.68 (m, 1H), 2.02 (m, 2H), 2.26 (m, 1H), 2.56 (m, 2H), 2.79 (m, 2H), 3.68 (s, 2H), 3.73 (s, 2H), 3.97 (d, 1H, J=17 Hz), 4.08 (m, 1H), 4.17 (d, 1H, J=17 Hz), 7.18 (m, 5H), 7.35 (m, 2H), 7.42 (m, 1H), 7.58 (m, 2H), 8.69 (d, 1H, J=3.9 Hz); —C NMR (CDCl3) δ14.39, 20.84, 21.79, 23.77, 29.63, 32.57, 48.88, 49.53, 54.11, 60.58, 111.30, 119.11, 121.68, 122.04, 122.60, 128.47, 128.99, 135.09, 137.55, 138.30, 139.82, 147.33, 156.73, 157.89. ES-MS m/z 454 (M+H). Anal. Calcd. for C29H35N5.1.3H2O: C, 73.02; H, 7.94; N, 14.68. Found: C, 73.06; H, 7.70; N, 14.32.
Reaction SMILES: ClC[C:3]1([CH3:11])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH2:4]1.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][C:18]=1[OH:19].[C:27](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][C:18]=1[O:19][CH2:27][C:4]1[C:3]([CH3:11])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[CH3:10]
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: CC1=CC(C)(CCl)CC(C)=C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2c(C)cc(C)cc2C)c(F)c1
Yield: 51.4 %

Procedure:
2-Chloromethyl-2,4,6-trimethylbenzene (397 mg, 2.4 mmol), ethyl 3-fluoro-4-hydroxybenzenepropanoate (500 mg, 2.4 mmol) and potassium carbonate (358 mg, 2.6 mmol) were stirred in DMF (8 mL) at 50° C. for 3 hours. The reaction solution was poured into water (30 mL) and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate) to give the title compound (425 mg, yield 52%) as an oily matter.