Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>CC#N>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:39][CH:38]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC#N
Product: O=C1C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
4-Chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (40 mg, 0.1 mmol) and 4-morpholinoaniline (36 mg 0.2 mmol) were mixed in MeCN (1 ml). The reaction mixture was heated in a microwave reactor at 150° C. for 15 mins and then evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 5 g/25 ml), eluting with DCM, then MeOH/DCM (1:99) and a product mixture was obtained. It was further purified by re-chromatography (ISOLUTE SI, 5 g/25 ml), eluting with EtOAc/heptane (10:90, then 25:75), to give the title compound (14 mg, 26%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.96-2.99 (m, 4H), 3.78-3.81 (m, 4H), 4.86 (s, 2H), 6.47-6.51 (m, 2H), 6.50 (t, J=74 Hz, 1H), 6.57-6.60 (m, 2H), 7.09-7.13 (m, 7H), 7.17-7.22 (m, 1H), 7.52-7.57 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 42.8, 49.4, 66.6, 109.7, 115.3, 115.8 (t, J=259 Hz), 119.6, 123.5, 124.7, 127.9, 128.9, 129.3, 130.6, 131.2, 131.5, 149.1, 151.2, 159.3; Mass Spectrum: M−H+ 540.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[CH:22]1([CH2:27][C:28](Cl)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl>C(=S)=S>[CH:22]1([CH2:27][C:28]([C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC3CCCC3)ccc2c1
Yield: 59.1 %

Procedure:
Following the procedure described in Step 2 of Example 1, 2-(6-methoxy-2-naphthyl)-1-benzofuran (6.00 g, 21.9 mmol) was acylated with 2-cyclopentylacetyl chloride (3.51 g, 23.9 mmol) using tin (IV) chloride (2.8 mL, 24 mmol) in carbon disulfide (120 mL). Purification by flash chromatography (Biotage apparatus) using 10-25% chloroform in hexane and 0.5-1% ethyl acetate in hexane as eluants furnished the title compound as a yellow gum (4.98 g); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (d, 3H, J=8.7 Hz), 7.8 (d, 1H, J=8.7 Hz), 7.7-7.8 (m, 1H), 7.35-7.5 (m, 3H), 7.2-7.35 (m, 1H), 3.95 (s, 3H), 2.75 (d, 2H, J=7.7 Hz), 2.1-2.3 (m, 1H), 1.5-1.75 (m, 2H), 1.3-1.5 (m, 4H), and 0.8-1.1 ppm (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[F:10][C:11]([F:35])([F:34])[CH2:12][O:13][C:14]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][C:15]=1[C:16](OCC(F)(F)F)=[O:17]>>[F:10][C:11]([F:34])([F:35])[CH2:12][O:13][C:14]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][C:15]=1[C:16]([NH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH2:1][CH3:2])=[O:17]
Reactant: CCN1CCCC1CN
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: CCN1CCCC1CNC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Using the synthetic method illustrated in Example 23, 1-ethyl-2-aminomethyl pyrrolidine and 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate are reacted to provide a white solid, 2,5-bis(2,2,2-trifluoroethoxy)-N-[(1-ethyl-2-pyrrolidyl)methyl]benzamide, m.p. 78° -80° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:12]2)[O:8][N:7]=1.[ClH:35]>O>[Cl:35][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[CH2:12]2)[O:8][N:7]=1
Reactant: Nc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2.59 g (37.6 mmol) of sodium nitrite in 10 ml of water was added dropwise at 0° C. to a solution of 8.00 g (18.8 mmol) of the amine from Example 22A in 200 ml of concentrated hydrogen chloride solution. After the addition had ended, the mixture was stirred at 0° C. for 1 h and then at RT for 2 h. The reaction mixture was diluted with 1 N aqueous hydrogen chloride solution and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 5.83 g (70% of theory)
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[CH2:22]([N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>S(Cl)(Cl)=O>[CH2:22]([N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)O)c1
Reactant: Nc1ccn(Cc2ccccc2)n1
Solvent: O=S(Cl)Cl
Product: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccn(Cc3ccccc3)n2)c1
Temperature: 70 °C
Reaction time: 21 h
Yield: 45 %

Procedure:
3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoic acid (0.672 mmol) is dissolved in thionylchloride (1.2 ml) and heated to 70° C. for 1 hour. After cooling to room temperature, the solvent is removed in vacuo. The residue is dissolved in dichloromethane (1.2 ml) and ethyldiisopropyl-amine (167 μl) is added and 1-benzyl-1H-pyrazol-3-ylamine (1.2 eq) is added. The solution is stirred 21 hours at room temperature. The reaction solution is extracted with water. The organic layer is washed with brine and dried over MgSO4 and the solvent is removed in vacuo. N-(1-Benzyl-1H-pyrazol-3-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide is isolated after column chromatography (heptan /ethylacetate) as yellow oil in a yield of 45%; HPLC (method B): 3.63 min; LC-MS (method B): 2.74 min, 462.2 (MH+); 1H-NMR (DMSO-d5, 500 MHz): δ [ppm] 10.78 (s, 1), 7.79 (d, 1H, J=2.2 Hz), 7.468 (dd, 1H, J=3 Hz, J=4.9 Hz), 7.359-7.269 (m, 4H), 7.245-7228 (m, 2H), 7.174-7.139 (m, 2H), 7.11 (dd, 1H, J=1.1 Hz, J=4.9 Hz), 6.648 (d, 1H, J=2.2 Hz), 5.256 (s, 2H), 4.678 (sep, 1H, J=6 Hz), 4.223 (t, 2H, J=6.9 Hz), 3.049 (t, 2H, J=6.9 Hz), 1.262 (d, 6H, J=6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8]2=[O:15].[OH-].[NH4+:21]>>[NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:8]([NH2:21])=[O:15])[C:11](=[CH:12][CH:13]=1)[C:10]([NH2:9])=[O:14]
Reactant: [NH4+]
Reactant: Nc1ccccc1Oc1ccc2c(c1)C(=O)NC2=O
Agent: [OH-]
Product: NC(=O)c1ccc(Oc2ccccc2N)cc1C(N)=O

Procedure:
5-(2-Aminophenoxy)-isoindole-1,3-dione (0.1 g, 0.38 mmol) in conc. ammonium hydroxide (aq) was stirred at 60° C. for two hours. The reaction mixture was evaporated in vacuo (cold in order not to make the imide again). The crude mixture was used without any purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].S(=O)(=O)(O)O.[CH2:12]([C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1)[CH3:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:6][C:14]1([CH2:12][CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CCC1=CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1(CC)CCCCC1
Temperature: 30 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 43.0 g (0.5 mol) of methacrylic acid, 0.5 g (5 mmol) of sulfuric acid and 100 g of toluene. Separately 110.2 g (1.0 mol) of 1-ethylcyclohexene, prepared by the same procedures as described in Reference Example 3, was dissolved in 100 g of toluene. The obtained solution of 1-ethylcyclohexene in toluene was dropwise added to the content in the flask over a period of about 3 hours, while the content was maintained at a reaction temperature of about 30° C. Then the content was stirred for 15 hours at the same temperature. After completion of the reaction, the residual catalyst was neutralized by adding 40.0 g (50 mmol) of a 5% aqueous sodium hydroxide solution, and the neutralized liquid was washed with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 68.6 g (yield: 69.9%) of the object 1-ethylcyclohexyl methacrylate was obtained.
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.C([O:18][C:19](=[O:25])[C:20](OCC)=[O:21])C>O>[N+:13]([C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH2:12][C:20](=[O:21])[C:19]([OH:25])=[O:18])([O-:15])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)C(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To a cooled mixture prepared by adding 13.6 g. of sodium to 300 ml. of ethanol is added a solution of 100 g. of 4-chloro-2-nitrotoluene and 84 g. of diethyloxalate in 150 ml. of ethanol while maintaining the temperature below 20° C. The resulting mixture is refluxed for one hour, cooled, 400 ml. of water added and the resulting mixture refluxed for 90 minutes. The ethanol is then evaporated to a small volume and the resulting precipitate contains tan and black material and the black material is mechanically separated and discarded and the remainder (filtrate plus tan precipitate) used in the next step.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](S)[CH:5]=[C:4]([CH3:9])[N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([OH:1])[N:7]=1)[NH2:12]
Reactant: Cc1cc(S)nc(O)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(NN)nc(O)n1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
The product obtained in Step 1 (3.0 g) was suspended in 30 ml of ethanol at room temperature. Hydrazine monohydrate (3.17 g) was added dropwise to this suspension and the mixture was refluxed for two hours. After cooling to room temperature, the formed crystals were collected by filtration and washed with 20 ml of ethanol, giving 2.6 g of the objective compound as red crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH:13](OC)(OC)OC.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=[CH:13]1.[C:20]([OH:26])([C:22]([F:25])([F:24])[F:23])=[O:21]
Reactant: COC(OC)OC
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cnc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of diamine 248 (1.14 g, 6.80 mmol) in CH2Cl2 (10 mL) was added trimethyl orthoformate (5 mL, 46 mmol, 6.7 eq) (or any other acylating agent of choice, 6 eq) followed by TFA (0.43 mL, 5.6 mmol, 0.8 eq) and the mixture was stirred at room temperature for 2 h. Precipitate was collected by filtration, washed with CH2Cl2 and dried to afford the title compound 249 as TFA salt (1.23 g, 62% yield). 1H NMR: (CDCl3) δ (ppm): 8.57 (d, J=1.8 Hz, 1H), 8.20 (dd, J=1.8, 9.2 Hz, 1H), 8.18 (s, 1H), 7.54 (d, J=9.2 Hz, 1H), 3.94 (s, 3H). LRMS: (calc.) 177.2; (obt.) 178.1 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:18])([C:16]#[CH:17])[CH3:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:18])([C:16]#[C:17][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=3)[CH3:15])[CH2:10][CH2:9]2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1cccc(Br)n1
Reactant: C#CC(C)(O)C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Product: Cc1cccc(C#CC(C)(O)C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1
Yield: 41 %

Procedure:
According to the Method B detailed for Examples 218-226 starting from Compound 312c and using 2-bromo-6-methylpyridine the title compound was prepared. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc 1:1 affording the title product as a yellow oil. Yield: 41%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:5][O:4][CH2:3][CH2:2][O:6][C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Yield: 93.7 %

Procedure:
1-bromo-2-methoxyethane(5.8 mmol), dimethyl 5-hydroxyisophthalate(5 mL), K2CO3 (6 mmol) in DMF(10 mL) were stirred for 12 h at 60° C., then the solution was poured into water and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated to give dimethyl 5-(2-methoxyethoxy)isophthalate (93.7%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[N:17][CH:18]=2)[N:3]=1.[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]1)#[CH:33].F[B-](F)(F)F.CCN(C(C)C)C(C)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:43]([C:40]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:32]#[C:33][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[N:3]=2)[CH2:41][CH2:42]1)(=[O:44])[NH2:45]
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 4-(5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A70 (0.208 g, 0.453 mmol), 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.079 g, 0.42 mmol), CuI (0.003 g, 0.02 mmol), PdCl2(PPh3)2 (0.017 g, 0.024 mmol) and t-Bu3PH.BF4 (0.009 g, 0.03 mmol) under a nitrogen atmosphere was added dioxane (6.0 mL) and DIPEA (0.23 mL, 1.3 mmol). The mixture was stirred at 85° C. for 4 hours and then concentrated under reduced pressure. Purification by silica gel column chromatography (Biotage Isolera, 0-100% EtOAc in Petroleum Benzine 40-60° C., 0-20% MeOH in EtOAc) gave the title compound A78 (0.118 g, 46%). LCMS-D: rt 3.645 min; m/z 607.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([O:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:23][CH2:22][CH2:21][CH2:20]4)[N:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:29][C:30]1[N:31]=[CH:32][S:33][CH:34]=1>>[CH3:29][C:30]1[N:31]=[C:32]([C:2]2[C:3]3[N:11]=[N:10][N:9]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]5([O:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23]5)[N:14]=4)[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[S:33][CH:34]=1
Reactant: C[Si](C)(C)OC1(c2cccc(Cn3nnc4c(Cl)nc(N)nc43)n2)CCCC1
Reactant: Cc1cscn1
Product: Cc1csc(-c2nc(N)nc3c2nnn3Cc2cccc(C3(O[Si](C)(C)C)CCCC3)n2)n1
Yield: 20 %

Procedure:
Prepared from 7-chloro-3-{6-[1-trimethylsilyloxy-1-cyclopentyl]pyridin-2-ylmethyl}-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 4-methylthiazole by the method described for Example 30 to give the title compound (0.105 g, 20%); NMR δH (400 MHz, DMSO) 7.77 (1H, t, J 7.9 Hz), 7.72 (1H, s), 7.44 (1H, d, J 7.9 Hz), 7.35 (2H, br s), 7.14 (1H, d, J 7.4 Hz), 5.82 (2H, s), 2.56 (3H, s), 1.84 (2H, m), 1.73 (2H, m), 1.64 (2H, m), 1.40 (3H, m), −0.10 (9H, s); (M+H)+ 481.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 95.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added N,N-dimethyl-1,2-ethanediamine (0.022 mL, 0.20 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH [7]+NH4OH[3]) provided the title compound as a white solid (20 mg, 95%). LC-MS m/z 524 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 2.14 (s, 6H), 2.33 (s, 3H), 2.37 (m, 2H), 3.22 (m, 2H), 4.09 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16](O)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)O)CC1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
4-(2-Carboxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 3.9 mmol, according to the procedure described in J. Med. Chem., 41(14), 2492, 1998) was dissolved in THF (50 ml) and cooled down to 0° C. 2M Borane solution in THF (3.9 ml, 7.8 mmol) was added slowly and the mixture was stirred for 20 h at room temperature. Water was added and solvents were concentrated in vacuo. The residue was dissolved in EtOAC, basified with NaHCO3, washed with brine, dried and concentrated in vacuo to yield the title compound (938 mg, 99%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]2[CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([Cl:22])[C:20]=3[O:21][C:11]=2[C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:19]1[C:20]2[O:21][C:11]3[C:10](=[O:23])[N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[CH2:13][C:12]=3[CH2:14][C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC2=C(Oc3c(Cl)cccc3C2)C1=O
Yield: 90.2 %

Procedure:
A solution of (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (2 g, 5.71 mmol) and lithium hydroxide monohydrate (0.312 g, 7.40 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (50 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(5-chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (1.73 g, 93.6%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1>>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18]2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: C1=CCNCC1
Reactant: CC#CCOc1cc(Cl)ncn1
Product: CC#CCOc1cc(N2CC=CCC2)ncn1
Reaction time: 2 h
Yield: 100.9 %

Procedure:
0.3 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 0.41 g of 1,2,3,6-tetrahydropyridine were mixed and left for 2 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.38 g of 1-(6-(2-butynyloxy)pyrimidin-4-yl)-1,2,3,6-tetrahydropyridine (hereinafter, referred to as Compound (54)).
Reaction SMILES: [Br-].N[CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Br:22]C(C)[CH2:24][CH2:25][CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O>>[Br-:22].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:6])[CH3:7]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Product: C[N+](C)(CCCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
The title compound is prepared by an analogous procedure to (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) by replacing N-(4-bromoethyl)-phthalimide with N-(4-bromopentyl)-phthalimide.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].O.[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: CC(C)(C)NN
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a suspension of t-butyl hydrazine hydrochloride (6.2 g, 0.05 mole), water (30 mL) and toluene (60 mL) at 0° C. to 5° C. was added 50% sodium hydroxide (4.0 g,0.05 mol). To the above reaction mixture was then added, separately and simultaneously, 50% sodium hydroxide (4.0 g,0.05 mol) and 3-chlorobenzoyl chloride (8.8 g, 0.05 mol) from two dropping funnels. After addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and room temperature for 30 minutes. The resultant precipitate was collected by suction-filtration and washed with water (100 mL) and dried in air to give 9.0 g (79% yield) of 1-(3-chlorobenzoyl)-2-t-butyl hydrazine as a white solid. mp 116°-118° C.