Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[C:16]([OH:17])[C:11]=3[CH2:10][O:9]2)=[CH:4][CH:3]=1.[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:19]([O:23]/[N:24]=[N+:25](/[N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([O:17][C:16]1[C:11]2[CH2:10][O:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[CH3:18])=[O:30])\[O-:26])[CH2:20][CH2:21][CH3:22]
Reactant: Cc1ncc2c(c1O)CO[C@H]2c1ccc(Cl)cc1
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)Oc1c(C)ncc2c1CO[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-ol (346 mg, 1.32 mmol), 1-[(Z)-butoxy-NNO-azoxy]-L-proline (306 mg, 1.32 mmol), and triethylamine (369 mL, 2.65 mmol) in CH2Cl2 (10 mL) was added BOP-Cl (438 mg, 1.72 mmol). After stirring at rt over night, the mixture was purified by flash chromatography (Biotage 40+M) using 40-50% EtOAc/hexane gradient, affording the title compound: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m, 2H), 6.19 (s, 1H), 5.21 (dd, J=2.4, 14.1 Hz, 1H), 5.07 (dd, J=1.9, 14.2 Hz, 1H), 4.78 (dd, J=4.5, 14.1 Hz, 1H), 4.20 (t, 6.7 Hz, 2H), 3.93-3.88 (m, 1H), 3.73-3.68 (m, 1H), 2.54-2.48 (m, 1H), 2.47 (s, 3H), 2.26-2.15 (m, 3H), 1.76-1.70 (m, 2H), 1.45-1.38 (m, 2H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:13][CH2:12]2)[NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[CH2:18]([CH2:22][C:23](=O)[CH3:24])[C:19]([CH3:21])=O>C(O)C>[CH:11]1([C:4]2[NH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([N:1]3[C:23]([CH3:24])=[CH:22][CH:18]=[C:19]3[CH3:21])[N:3]=2)[CH2:13][CH2:12]1
Reactant: COC(=O)c1[nH]c(C2CC2)nc1N
Reactant: CC(=O)CCC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1[nH]c(C2CC2)nc1-n1c(C)ccc1C
Yield: 95.6 %

Procedure:
A suspension of methyl 4-amino-2-cyclopropylimidazole-5-carboxylate (Example 40, 5.72 g, 0.032 mol) in ethanol (40 mL) was treated with acetic acid (25 mL) and the mixture refluxed to effect solution. To the hot solution was added acetonylacetone (5.41 g, 0.047 mol) and the whole stirred and refluxed for 18 hours. The solvent was removed under reduced pressure and the residue purified by flash chromatography eluting with a gradient of CH2Cl2 to 20% EtOAc in CH2Cl2 to afford 7.93 g of the title compound methyl 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole-5-carboxylate. 1H-NMR (CDCl3) 5.85 (s, 2H), 3.68 (s, 3H), 2.0 (s, 6H), 1.80-2.0 (m, 1H), 1.0-1.18 (m, 4H).
Reaction SMILES: Br[C:2]1[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[CH2:27]([O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:27]([O:34][C:35]1[C:40]([C:2]2[C:3]([C:25]#[N:26])=[C:4]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:5]=[C:6]([C:8]([CH3:10])([CH3:11])[CH3:9])[CH:7]=2)=[CH:39][CH:38]=[CH:37][N:36]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)c(C#N)c(C#Cc2ccc(NS(C)(=O)=O)cc2)c1
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: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(C#Cc2ccc(NS(C)(=O)=O)cc2)c(C#N)c(-c2cccnc2OCc2ccccc2)c1
Yield: 64.1 %

Procedure:
step 3—A sealed tube containing 94 (0.290 g, 0.67 mmol), 2-benzyloxy-3-pyridine boronic acid (0.184 g, 0.80 mmol, 141), Pd(PPh3)4 (0.220 g, 0.07 mmol) and Na2CO3 (0.609 g, 2.01 mmol) in MeOH (9 mL) and DCM (3 mL) was irradiated in a microwave reactor at 125° C. for 30 min. The organic volatiles were removed under reduced pressure. The residue was partitioned between DCM and water then the aqueous layer was further extracted with DCM. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 0.230 g (64%) of N-{4-[3-(2-benzyloxy-pyridin-3-yl)-5-tert-butyl-2-cyano-phenylethynyl]phenyl}-methanesulfonamide (96) as a light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1>C(OCC)C.C(OCC)(=O)C.[Cl-].[NH4+]>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:5]2([OH:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCC(O)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of N-methyl-piperidin-4-one (1.50 g, 13.3 mmol) in diethyl ether (10 mL) was degassed under a nitrogen stream. The solution was cooled to 0° C. in an salt ice bath. To the stirring solution was added 4-fluorophenylmagnesium bromide (1.74 g, 14.6 mmol) dropwise over 5 min. A solid formed partway through the addition, and additional diethyl ether was added (2 mL). The reaction was then stirred at 0° C. for 2 h. To the suspension was added aqueous ammonium chloride (15 mL). The biphasic solution was diluted with ethyl acetate (40 mL) and additional saturated aqueous ammonium chloride (20 mL). The layer was separated, and the organic extract washed with brine (50 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum to give I-293 (965 mg, 32% yield) as a brown powder. The product was taken on without further purification. 1H NMR (400 MHz, DMSO-d6): 7.51-7.48 (m, 2H), 7.13-7.09 (m, 2H), 4.80 (s, 1H), 2.52-2.53 (m, 3H), 2.36-2.30 (m, 2H), 2.19 (s, 3H), 1.94-1.87 (m, 2H), 1.57-1.54 (m, 2H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)CC>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCO
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].CCN(CC)CC.[CH2:28]([N:35]=[C:36]=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH2:28]([NH:35][C:36]([NH:20][C@H:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:2][CH3:3])[N:5]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)NCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.360 g, 1 mmol) and Et3N (0.42 mL, 3 mmol) in 10 mL CH2Cl2 is added benzyl isocyanate (0.12 mL, 1 mmol). The mixture is stirred at room temperature for 18 hours. The product is isolated by filtration to afford 0.425 g (96% yield) of the desired product which is used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27]([CH:24]4[CH2:26][CH2:25]4)=[O:28])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.4 %

Procedure:
A mixture of 4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-amine (150 mg, 0.47 mmol) produced in Example 2, cyclopropanecarbonyl chloride (0.13 mL, 1.40 mmol) and pyridine (5 mL) was stirred at room temperature for 6 hr. To the reaction mixture was added cyclopropanecarbonyl chloride (0.085 mL, 0.94 mmol) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→100/0), and 1N aqueous sodium hydroxide solution (0.5 mL), methanol (5 mL) and tetrahydrofuran (10 mL) were added to the crude product. The mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to the obtained residue. After neutralization with 1N hydrochloric acid, the resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (145 mg, 80%) as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14](OS(C(F)(F)F)(=O)=O)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.[CH2:30]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:31]#[CH:32]>[Cu]I.C(NCC)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:29])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[C:14]([C:32]#[C:31][CH2:30][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCN1CCOCC1
Agent: [Cu]I
Solvent: CCNCC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1C#CCN1CCOCC1
Yield: 38.5 %

Procedure:
Operating analogously to what described in example 74 starting from trifluoro-methanesulfonic acid 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazin-5-yl ester (2 g, 4.27 mmoles), prepared as described in example 73, 4-prop-2-ynyl-morpholine (640 mg, 5.12 mmoles), prepared as described in example 137, diethylamine (40 ml), bis(triphenylphosphine)PdCl2 (60 mg, 0.0854 mmole) and CuI (16 mg, 0.0854 mmole), 728 mg of the title compound were obtained (yield: 38.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6](O)[CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[BrH:13]>>[Br:13][CH:6]([C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)C(O)c1ccc(Cl)cc1
Reactant: Br
Product: CC(C)C(Br)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of p-chloro-α-isopropylbenzyl alcohol (33.08 g) in 48% hydrobromic acid (330 mL) is stirred at room temperature for 1 hour and extracted with hexanes. The combined organic extracts are washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a yellow oil (42.98 g) which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[O:40])[N:36]([CH3:38])[N:37]=1>O1CCCC1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:40])[N:36]([CH3:38])[N:37]=1
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(Cl)cnc21
Temperature: -20 °C
Yield: 29.5 %

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (629, 0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was, cooled to −20° C. 2M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise to the mixture, then stirred to −5° C. After the reaction was cooled to −20° C., 5-(3-chloro-benzylamino)-2-methyl-2 H-pyrazole-3-carbaldehyde (648, 0.050 g, 0.20 mmol) in 2 mL of tetra.hydrofuran was added at once to the mixture. The reaction was stirred to 0° C. and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hlexane gave the desired compound (649, 0.033 g, 30%). (ESI) [M+H+]+=558.3, 560.9.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[C:27]([C:30]1[CH:60]=[CH:59][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=3)[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)(O)=[O:28]>CN(C=O)C>[N:1]1([C:27]([C:30]2[CH:60]=[CH:59][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:56])[F:55])[CH:48]=4)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: C1CCNCC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Piperidine (0.04 mmol), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL), 1-hydroxybenzotriazole hydrate (0.45 mmol) in DMF (0.15 mL) were added to a solution of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (0.040 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 17 h, loaded onto Varian™ SCX column, and washed with CHCl3/CH3OH 1:1 (5 mL) and CH3OH (5 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 1{-4-(piperidinocarbonyl)benzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1572) (14.3 mg, 66%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 545 (M++H, C29H35F3N4O3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:10])[Cl:9])[N:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([Cl:24])([Cl:23])[S:21]Cl>C1C=CC=CC=1>[CH3:1][N:2]([S:21][C:20]([Cl:24])([Cl:23])[Cl:19])[C:3]1[S:7][N:6]=[C:5]([C:8]([Cl:11])([Cl:9])[Cl:10])[N:4]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CNc1nc(C(Cl)(Cl)Cl)ns1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(SC(Cl)(Cl)Cl)c1nc(C(Cl)(Cl)Cl)ns1
Yield: 23 %

Procedure:
To a 3-neck flask equpped with condenser, thermometer and stirring bar was added 11.6 g (0.05 mole) 5-methylamino-3-trichloromethyl-1,2,4- thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 20 hours and filtered hot. The filtrate was evaporated under vacuum to give a beige solid which was refluxed in 400 milliliters of ligroin and filtered. The ligroin was cooled, filtered and the filtrate evaporated to 20 milliliters and filtered. The resulting solid was recrystallized again from ligroin to obtain 4.4 g (23% yield) of product; mp=106° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([Mg]Br)([CH3:13])=[CH2:12].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][C:11]([CH3:13])=[CH:12]2
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(Br)c2[nH]1
Temperature: -55 °C
Reaction time: 1 h

Procedure:
27.0 g of 2-bromonitrobenzene are placed in 400 ml of THF. The medium is placed under nitrogen and is cooled to −55° C. and then 800 ml of 0.5M isopropenylmagnesium bromide in THF are added dropwise. The medium is left stirring for 1 hour and then it is poured into a saturated NH4Cl solution. Extraction is carried out with ether, the extract is evaporated and then the residue is taken up in DCM. Washing is carried out with a saturated NaCl solution. The organic layer is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (1/9, v/v) mixture. 10.7 g of the expected compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[NH2:17][CH2:16][CH2:15][NH:18][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOc1cc(Cl)nc2ccccc12
Reactant: NCCN
Product: CCOc1cc(NCCN)nc2ccccc12
Yield: 66.6 %

Procedure:
2-Chloro-4-ethoxyquinoline (1.119 g, 5.39 mmol) and ethylenediamine (10.8 ml, 162 mmol) were heated at 60° C. for 50 h, then evaporated to dryness. The residue was purified by flash chromotography on silica gel, eluting with 0-14% ‘10% ammonia in methanol’ in dichloromethane, to give 2-(2-aminoethylamino)-4-ethoxyquinoline (0.830 g, 67%). This material (0.820 g, 3.54 mmol) was dissolved in concentrated hydrochloric acid (25 ml) and gently refluxed for 16 h. The mixture was then cooled in an ice bath, and the precipitate filtered off and dried in vacuo to give the title compound as an off-white powder (0.861 g, 88%); δH (CD3OD) 3.2-3.35(2H, m, under methanol), 3.84 (2H, t), 6.35 (1H, s), 7.46 (1H, t), 7.7-7.9 (2H, m), 8.1 (1H, d), MS (ES+) 204 (50%, MH+) and 187 (100).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32](O)=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:41]C=2C=1.C(Cl)CCl.N>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:25]=[C:24]4[C:20]([N:21]=[CH:22][NH:23]4)=[C:19]([N:26]4[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([NH2:41])=[O:33])[CH2:27]4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(=O)O)C4)c4nc[nH]c4n3)cc2)CC1
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCCC(C(N)=O)C4)c4nc[nH]c4n3)cc2)CC1
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To a solution of 1-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-9H-purin-6-yl)piperidine-3-carboxylic acid (40 mg, 0.086 mmol) and HOBt (30 mg, 0.196 mmol) in DMF (2 mL), EDC (35 mg, 0.183 mmol) was added. After being stirred for 90 min, NH3 (0.5 M in dioxane, 1.00 mL, 0.500 mmol) was added. The mixture was stirred for 2 h. More EDC (52 mg, 0.271 mmol) was added. It was stirred for another 20 h. The mixture was then purified by HPLC to give the titled compound (30 mg). MS 464.3 (M+H); UV 204.8, 273.8 nm.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: Cl
Product: O=C(c1ccc2cccnc2c1O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 8-hydroxyquinoline-7-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O.O.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:2]3[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=3[CH3:8])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
A mixture of 20.50 g (0.100 mole) of 5-bromo-6-methyl-2,4(1H, 3H)pyrimidinedione, 26.96 g (0.100 mole of 1-(4-chlorophenyl)-piperazine, 10.35 g (0.110 mole) of potassium fluoride dihydrate and 41.40 g (0.300 mole) of potassium carbonate in 200 ml of dimethylsulfoxide was heated at 80° for 72 hours. The reaction mixture was cooled and poured into 1 l of ice water. The solid was collected, washed with water, and recrystallized from ethanol to give 6.05 g of the product as a dull yellow solid.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[CH3:11].[CH3:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=1)=O>CO>[CH3:11][C:10]1[C:9](=[O:12])[N:8]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:7]2=[N:6][C:5]=1[CH:4]=[C:19]([CH3:18])[C:21]1[CH:22]=[C:23]([O:31][CH3:32])[C:24]([O:29][CH3:30])=[C:25]([O:27][CH3:28])[CH:26]=1
Reactant: Cc1nc2c(C)cccn2c(=O)c1C
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C)=Cc2nc3c(C)cccn3c(=O)c2C)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75 ml of absolute methanol is added 2.0g of 2,3,9-trimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, followed by 4.2g of 3,4,5-trimethoxyacetophenone. The mixture is stirred and heated under reflux for 97 hours to yield the title compound.