Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1)=[CH2:2].C12BC(CCC1)CCC2.C1C[O:24]CC1>>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH2:2][OH:24])=[CH:11][C:7]1=2
Reactant: C1CCOC1
Reactant: C=Cc1ccc2ccsc2c1
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc2ccsc2c1
Temperature: 60 °C
Yield: 99 %

Procedure:
A solution of 6-vinylbenzo[b]thiophene (2.124 g, 13.3 mmol) in 80 mL THF was added to a solution of 9-borabicyclo[3.3.1]nonane (9-BBN) (5.21 g, 21.3 mmol) in 80 mL THF, rinsing with 5 mL THF. The solution was heated at 60° C. for 2.5 h and then a solution of H2O2 (36 mL, 35%)/NaOH (36 mL. 0.5 M)/H2O (9 mL) was added slowly. The reaction was then heated to 85° C. for 1 h, cooled to room temperature and 50 mL H2O was added. The mixture was extracted with ethyl acetate (3×50 mL), the combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (2.338 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20]C(=O)C)[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[OH-].[Na+]>CO.O>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[C:12](=[O:18])[NH:11][N:10]=2)=[C:6]([Cl:19])[CH:5]=1
Reactant: CC(=O)Nc1cc(Cl)c(Sc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(Sc2c(Cl)cc(N)cc2Cl)n[nH]c1=O
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of N-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylsulfanyl)-phenyl]-acetamide (84) (4.0 g, 10.7 mmol) in methanol (15 mL) and water (15 mL) was treated with powdered sodium hydroxide (2.14 g, 53.5 mmol). The reaction was then heated to reflux for 18 h. At this time, the reaction was cooled to 25° C., diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried with magnesium sulfate, filtered and concentrated under vacuum to afford 6-(4-amino-2,6-dichloro-phenylsulfanyl)-4-isopropyl-2H-pyridazin-3-one (85) (3.5 g, 99%) as a light tan solid. The material was used without further purification; ES(+)-HRMS m/e calcd for C13H13Cl2N3OS (M+H)+ 330.0229, found 330.0229. Exact Mass=329.0156; Molecular weight=330.24
Reaction SMILES: Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]([F:34])([F:33])[C:28]1[CH:32]=[CH:31][NH:30][N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[Cl:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:30]1[CH:31]=[CH:32][C:28]([C:27]([F:34])([F:33])[F:26])=[N:29]1)[C:11]([C@@H:12]([N:14]1[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]1=[O:23])[CH3:13])=[CH:10]2
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](c1cc2cccc(Cl)c2nc1-n1ccc(C(F)(F)F)n1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (S)-2-(1-(2,8-dichloroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.2000 g, 0.539 mmol), 3-(trifluoromethyl)pyrazole (0.0733 g, 0.539 mmol), cesium carbonate (0.351 g, 1.08 mmol) and in DMF (1.80 mL, 0.539 mmol) was stirred at 100° C. After 2 h, The mixture was cooled to room temperature. To the cooled mixture was added water (30 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×1), dried over MgSO4, 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 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 10 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 10 min as eluent to give 2-((S)-1-(8-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1 H, s), 8.51 (1 H, d, J=2.2 Hz), 8.25 (1 H, dd, J=8.4, 1.0 Hz), 8.08 (1 H, dd, J=7.7, 0.9 Hz), 7.63-7.85 (5 H, m), 6.92 (1 H, d, J=2.7 Hz), 5.94-6.05 (1 H, m), 1.83 (3 H, d, J=7.0 Hz); LC-MS (ESI) m/z 471.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2NC=N[C:7]=2[CH:6]=1)[NH2:4].C(C1C=C2C([CH2:20][CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)=CC=1)#N>>[NH2:4][C:3](=[N:2][OH:1])[C:5]1[CH:6]=[C:7]2[C:8]([CH2:20][CH2:21][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:23]2)=[CH:12][CH:13]=1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2C1
Product: CC(C)(C)OC(=O)N1CCc2ccc(C(N)=NO)cc2C1
Yield: 80 %

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from tert-butyl 7-cyano-3,4-dihydroisoquinoline-2(1H)-carboxylate obtained in step 1 (1.50 g; 5.81 mmol). The solvent was evaporated in vacuo and further freeze dried to give the title compound as an off-white solid (1.35 g, 80%). 1H NMR (DMSO-d6) δ 9.54 (s, 1H), 7.46 (m, 2H), 7.14 (d, J=8 Hz, 1H), 5.74 (bs, 2H), 4.49 (s, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.76 (t, J=5.9 Hz, 2H), 1.49 (s, 9H). HPLC (Method A), Rt 2.40 min (Purity: 99.4%). LC/MS (Method B): 292.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(#N)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1
Reactant: Cc1cccc(N)c1
Reactant: COC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)CNc1cccc(C)c1
Yield: 130.5 %

Procedure:
A mixture of m-toluidine (55.0 g), methyl chloroacetate (85.0 g) and sodium bicarbonate (86.2 g) in acetonitrile (400 ml) was heated at reflux for 2 days under nitrogen. Ethyl acetate (250 ml) was added and the mixture was washed with water (2×250 ml), dried and evaporated to give an oil (120 g), a sample of which (1.4 g) was purified by FCC eluting with System A (3:7) to give the title compound (0.8 g) as a solid, m.p. 40°.
Reaction SMILES: [CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22]>>[CH:1]1([NH:9][C:10]2[O:11][CH2:12][C:13]3[CH:19]=[C:18]([NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])[CH:17]=[CH:16][C:14]=3[N:15]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCCC1)=N2
Reactant: CC(C)N=C=O
Product: CC(C)NC(=O)Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Yield: 19.7 %

Procedure:
Prepared from N2-cyclooctyl-4H-benzo[d][1,3]oxazine-2,6-diamine (210 mg, 0.81 mmol) and isopropyl isocyanate (76 mg, 0.89 mmol) according to the procedure described for Example 16. Obtained the title compound as an off-white foam (55 mg, 20%), MS (ISP) m/e=345.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-amino-5-methoxy-benzoic acid (8.0 g, 47.8 mmol) in toluene (100 mL) was added a solution of phosgene (20%, 50.0 mL) in toluene and triethyl amine (13.40 mL). The reaction mixture was heated at 80 C. for 1.5 h. The precipitated product was filtered and washed with hexanes and toluene and dried to give 9.00 g of 6-methoxy-1H-benzo[d][1.3]oxazine-2,4-dione as a light brown solid. This was used directly for the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].Cl>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([C:19](=[O:22])[CH2:20][CH3:21])[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: CCC(=O)CC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)C(C(=O)CC)C(=O)OC
Temperature: 2 °C
Yield: 104.4 %

Procedure:
5.21 g=5.02 ml (39.2 mmol) of 3-oxo-pentanoic acid methyl ester were dissolved in 30 ml of CH2Cl2, the solution was cooled to 2° C. and 3.81 g (39.2 mmol) of anhydrous magnesium chloride were added in small portions. Then, 6.21 g=6.34 ml (78.4 mmol) of pyridine were added to this suspension between 2° C. and 5° C., followed by 3.89 g=3.67 ml (41.2 mmol) of propionyl chloride. The reaction mixture was warmed up to RT and 1 hour later poured into crashed ice, acidified with HCl (25%) to pH 1-2 and extracted twice with Et2O. The organic phases were dried over magnesium sulfate, filtered and evaporated to give 7.62 g of title compound as light yellow oil. MS: 185.1 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.Cl[CH2:30][CH:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:30][CH:31]2[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(O)c2)c1N
Reactant: CC1(C)OCC(CCl)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCC3COC(C)(C)O3)c2)c1N
Temperature: 150 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (75 mg, 0.2 mmol) and 4-chloromethyl-2,2-dimethyl-[1,3]dioxolane (36 mg, 0.24 mmol) were dissolved in DMF (4 ml) was added K2CO3 and the mixture stirred at 150° C. for 2 h in microwave oven. The solvent was removed, residue was dissolved in EtOAc, washed by water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (EtOAc:Hex =3:1) and the product was obtained as a colorless oil (18 mg, 18%). HPLC (4 minute gradient) tR 2.57 min; MS m/z 491.11 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:26](=[O:27])[N:25]3[CH:21]([CH2:22][CH:23]([O:28][C:29]4[CH:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:32]=[C:31]([O:41][CH3:42])[N:30]=4)[CH2:24]3)[C:20](=[O:43])[NH:19][C:18]3([C:44]([NH:46][S:47]([C:50]4([CH3:53])[CH2:52][CH2:51]4)(=[O:49])=[O:48])=[O:45])[CH:16]([CH2:17]3)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=CC=1.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:42][O:41][C:31]1[N:30]=[C:29]([O:28][CH:23]2[CH2:22][CH:21]3[N:25]([C:26](=[O:27])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]4[C:18]([C:44]([NH:46][S:47]([C:50]5([CH3:53])[CH2:52][CH2:51]5)(=[O:48])=[O:49])=[O:45])([NH:19][C:20]3=[O:43])[CH2:17]4)[CH2:24]2)[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:32]=1
Reactant: COc1ccc(CN2CCCCCC=CC3CC3(C(=O)NS(=O)(=O)C3(C)CC3)NC(=O)C3CC(Oc4cc(-c5ccccc5)nc(OC)n4)CN3C2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5(C)CC5)CC4C=CCCCCCNC(=O)N3C2)cc(-c2ccccc2)n1
Yield: 16 %

Procedure:
Compound 4a was dissolved in a 1:2 mixture of TFA:DCM (12 ml) and stirred at RT for 1 h. NaHCO3 was added and the organic layer was dried, filtered and evaporated. The afforded residue was purified by preparative HPLC which gave the pure title compound (36 mg, 16% over two steps), MS (M+H)+639.
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].O=[C:7]([CH2:29][CH2:30][CH3:31])[CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1)[C:9](OCC)=[O:10]>CO>[CH2:29]([C:7]1[N:5]=[C:3]([SH:4])[N:2]=[C:9]([OH:10])[C:8]=1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:19][CH:20]=1)[CH2:30][CH3:31]
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: NC(N)=S
Agent: [Na]
Solvent: CO
Product: CCCc1nc(S)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
5.7 g of sodium are dissolved in 150 ml of methanol, and 19 g of thiourea are added to this solution. The mixture is stirred for 5 minutes and 58 g of ethyl 3-oxo-2-[(2'-cyano-4-biphenylyl)methyl]hexanoate, prepared in Example 4, are added. The mixture is then heated to reflux for 10 hours and the methanol is evaporated off under vacuum. The residue is taken up with water and washed with ether, the aqueous phase is neutralised by adding dilute hydrochloric acid and the crystals obtained are filtered off and washed with water and with ether to give 26 g of 6-n-propyl-2-mercapto-4-hydroxy-5-[(2'-cyano-4-biphenylyl)methyl]pyrimidine in the form of crystals of melting point 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH2:14]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([O:13][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([CH2:14][CH3:15])=[CH:17][CH:18]=2)=[C:2]([Cl:1])[CH:7]=1)([CH2:11][CH3:12])[CH3:10]
Reactant: CCc1ccc(CO)cc1
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(COc2ccc(OC(C)CC)cc2Cl)cc1
Reaction time: 48 h
Yield: 60.7 %

Procedure:
A mixture of 0.74 g of 2-chloro-4-sec-butoxyphenol, 0.50 g of p-ethylbenzyl alcohol, 1.00 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 100 mg of tetrahydrofuran was stirred at room temperatur for 48 hours. The reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.71 g of 1-sec-butoxy-3-chloro-4-(4-ethylbenzyloxy)-benzene. Yield, 60%. nD22.6 1.5529.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[N:38][CH:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[N:38][CH:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (900 mg, 2.90 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K14) (1.16 g, 2.90 mmol) according to the general procedure M. Obtained as a light yellow foam (790 mg, 43%).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>O=[Pt]=O.C(O)(=O)C>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: O=C(O)Cc1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC1CCNCC1
Yield: 96.6 %

Procedure:
A mixture of 4-pyridylacetic acid hydrochloride (5 g, 28.8 mmol), glacial acetic acid (100 mL) and PtO2 (0.5 g) was hydrogenated at 50 psi overnight. The solvent was decanted from the catalyst and concentrated in vacuo. Azetroped with toluene twice then washed with ether to give 5 g (97%) of white solid. MS(ESI) 144.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:34]1[CH:35]=[CH:36][O:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccoc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccoc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. furan-3-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 23 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-3-sulfonamide (percentage yield: 89%), was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])[CH2:28][CH2:27]1)=O)(C)(C)C.[ClH:38]>>[ClH:38].[CH3:18][O:17][C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:34]3[CH2:35][CH2:36][N:32]([CH:29]4[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]4)[C:33]3=[O:37])=[CH:3][CH:4]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNC2=O)CC1
Reactant: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: Cl
Product: COc1nn(-c2ccccc2)c2cc(N3CCN(C4CCNCC4)C3=O)ccc12

Procedure:
The title compound was prepared according to the procedure as described in Example 57 reacting 6-bromo-3-methoxy-1-phenyl-1H-indazole and 4-(2-oxo-imidazolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester, followed by de-protection with HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]3[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11]2)=[CH:6][C:5]=1[O:19][CH:20]([CH3:22])[CH3:21])([O-])=O.O.NN>C(O)C.[Pd]>[CH2:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([O:19][CH:20]([CH3:22])[CH3:21])[CH:6]=2)[CH2:15][CH2:14][N:13]2[CH2:16][CH2:17][CH2:18][C@H:12]12
Reactant: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1N
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A mixture of 1.38 g of (8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine, 2.72 g of hydrazine hydrate and 240 mg of 10% palladium-on-carbon (240 mg, 5 mol %) in 30 ml of ethanol is heated at 80° C. (bath) for 1 h 30. The mixture is filtered on Clarcel and the filtrate is concentrated under vacuum, so as to obtain 1.23 g of 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)aniline in the form of a purple oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][O:19][CH3:20]>>[CH3:20][O:19][CH2:18][CH2:17][N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: COCCBr
Product: COCCn1cc(C#Cc2ccnc(C)c2)nc1C

Procedure:
The title compound, MS: m/e=256.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromoethyl-methylether.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]#[N:19])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1.[NH4+].[OH-:35].OO>CO.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:33]=[CH:32][C:11]3[N:12]([C:28]([CH3:29])([CH3:30])[CH3:31])[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=4[N:23]4[CH:27]=[N:26][CH:25]=[N:24]4)[C:18]([NH2:19])=[O:35])=[N:14][C:10]=3[CH:9]=2)=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: CC(C)(C)n1c(-c2cc(C#N)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Agent: OO
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)n1c(-c2cc(C(N)=O)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a round bottom flask is added 3-[5-(2-amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzimidazol-2-yl]-4-1,2,4-triazol-1-yl-benzonitrile (Example 7) (200 mg, 0.46 mmol) in MeOH (5 mL), followed by the addition of NH4OH (2 mL) and H2O2 (1 mL) (30% in water). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with EtOAc (20 mL), washed with water (10 mL), brine (5 mL), dried under anhydrous Na2SO4 (500 mg), filtered and concentrated. The residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (89 mg, 42%) as a white solid. LCMS (ESMS): m/z 454.73 (M++1)
Reaction SMILES: Br.[CH2:2]([N:5]1[CH:9]=[C:8]([CH3:10])[S:7][C:6]1=[NH:11])[CH:3]=[CH2:4].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH:21]=1)[C:18](Cl)=[O:19]>>[CH2:2]([N:5]1[CH:9]=[C:8]([CH3:10])[S:7]/[C:6]/1=[N:11]\[C:18](=[O:19])[C:17]1[CH:21]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[O:22][CH3:23])[CH:3]=[CH2:4]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: C=CCn1cc(C)sc1=N
Agent: Br
Product: C=CCn1cc(C)s/c1=N\C(=O)c1cc(Cl)ccc1OC

Procedure:
A mixture of Example 232A (0.5 g) and 5-chloro-2-methoxybenzoylchloride (0.57 g) were processed according to the method of Example 227B to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 2.28 (d, J=1.4 Hz, 3H), 3.78 (s, 3H), 4.77 (d, 2H), 5.13 (dq, J=16.9, 1.3 Hz, 1H), 5.24 (dq, J=10.5, 1.4 Hz, 2H), 5.94-6.07 (m, 1H), 7.11 (d, 1H), 7.23 (q, J=1.4 Hz, 1H), 7.43 (dd, 1H), 7.68 (d, 1H); MS (ESI+) m/z 323 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 80.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.