Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]1([CH3:17])[CH3:16].[C:18](#N)[CH3:19].OO>O.O.O.O.O.S([O-])([O-])(=O)=O.C([NH3+])C[NH3+].[Fe+2].S([O-])([O-])(=O)=O.C1CCCCC1>[CH:19]1([O:6][N:7]2[C:12]([CH3:13])([CH3:14])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]2([CH3:17])[CH3:16])[CH2:18][CH2:10][CH2:9][CH2:8][CH2:16]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC#N
Agent: [Fe+2]
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of 0.404 g (1.1 mmol) of iron(II) ethylenediammonium sulfate tetrahydrate and 0.237 g (2.5 mmol) of methanesulfonic acid in 2 ml of water is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 38 ml of acetonitrile, and 24 ml of cyclohexane. The reaction mixture is heated to 50° C. A solution of 8.0 g (118 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture dropwise over 4 hours while the temperature is brought to and maintained at reflux. After the peroxide is added, the reaction mixture is allowed to cool slowly to room temperature. The reaction mixture is stirred overnight at ambient temperature. The lower layer is discarded, and the organic layer is concentrated and purified by flash chromatography to afford 3.9 g (53% yield) of the title compound, a yellow solid. GC assay is greater than 99%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1COCC1.CO>Cl.O1CCOCC1>[ClH:1].[ClH:1].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Cl)nc2)CC1
Yield: 277.1 %

Procedure:
A solution of tert-butyl [1-(6-chloropyridin-3-yl)-piperidin-4-yl)carbamate (1.211 g, 3.88 mmol) in HCl in Dioxane (4M, 5 mL), THF (5 mL) and MeOH (4 mL) was stirred at rt for 20 h. The reaction mixture was filtered, the residue washed with EtOAc and dried to give the title compound (1.02 g, 92%) as a solid; 1H NMR (500 MHz, CD3OD): 8.36 (d, 1H), 7.97 (dd, 1H), 7.68 (d, 1H), 4.05-3.96 (m, 2H), 3.51-3.41 (m, 1H), 3.18 (dt, 2H), 2.24-2.17 (m, 2H), 1.85 (dq, 2H); 13C NMR (CD3OD): 145.8, 136.7, 133.3, 130.7, 126.5, 47.1, 28.9; Mass Spectrum: M+H 212.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1I)[N:7]([CH3:12])[CH:6]=[C:5]2[C:13]1[C:14](=[O:30])[NH:15][C:16](=[O:29])[C:17]=1[C:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=2[O:20][CH:19]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.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>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:10]2[CH:9]=[C:8]3[C:4]([C:5]([C:13]4[C:14](=[O:30])[NH:15][C:16](=[O:29])[C:17]=4[C:18]4[C:22]5[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=5[O:20][CH:19]=4)=[CH:6][N:7]3[CH3:12])=[CH:3][C:2]=2[F:1])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cccc2c(C3=C(c4cn(C)c5cc(I)c(F)cc45)C(=O)NC3=O)coc12
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: [K+]
Solvent: COCCOC
Product: COc1cccc2c(C3=C(c4cn(C)c5cc(-c6ccc(Cl)cc6)c(F)cc45)C(=O)NC3=O)coc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.2 %

Procedure:
3-(5-Fluoro-6-iodo-1-methyl-1H-indol-3-yl )-4-(7-methoxy benzofuran-3-yl)-pyrrole-2,5-dione (0.020 g, 0.039 mmol), Pd(PPh3)4 (4.5 mg, 0.004 mmol), and 4-chloro-phenylboronic acid (15.1 mg, 0.097 mmol) were dissolved in dimethoxy ethane (DME) (4 mL), and the mixture was degassed for 1 min and stirred for 10 min at room temperature. A solution of K2CO3 (2 M, 0.049 mL, 0.098 mmol) was added. The mixture was degassed again for 1 min, and stirred at 85° C. overnight. The resulting mixture was cooled to ambient temperature and poured into a mixture of 0.1 N HCl/EtOAc (15 mL/15 mL). After partition, the organic layer was washed with water, filtered, and concentrated. The residue was purified by preparative TLC using (ethyl acetate-hexane, 1:1) to afford the product as an orange solid (10 mg, 51%). The sample was purified by HPLC to give 3 mg of pure final compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.CO.C([O-])(O)=O.[Na+].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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]([C:15](=[O:17])[CH3:16])=[CH:4][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][CH:7]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1I
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: CO
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(C(=O)N2CCCC2)ccc1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
A mixture of Compound 419c (0.29 g, 0.845 mmol), 4-chlorobenzeneboronic acid (0.159 g, 1.02 mmol)) and Pd(PPh3)4 (97 mg) in toluene (25 mL), MeOH (6 mL) and saturated NaHCO3 (2.5 mL) was stirred under Ar at 70° C. for 16 h. After evaporation of solvent, the residue was dissolved in CHCl3 (30 mL) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography using CHCl3-MeOH (80:1 to 30:1) as the eluent to give an oil (0.266 g, 96%). MS: 328.08 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH3:27])[C:9]([NH:11][C:12]1[C:13]([NH:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[N:14][CH:15]=[CH:16][CH:17]=1)=O)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>CC(O)=O>[F:26][C:21]1[CH:20]=[C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:9]2[CH:8]([NH:7][C:6](=[O:28])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:27])[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of (S)-tert-butyl-1-(2-(3,5-difluorophenylamino)pyridine-3-ylamino)-1-oxopropan-2-ylcarbamate (1.7 g, 4.33 mmol) in AcOH (12 mL) was stirred at 100° C. overnight. After completion of the reaction the mixture was cooled to rt and basified with satd. sodium bicarbonate solution (60 mL). The organic layer was then extracted with EtOAc (150 mL), dried over sodium sulfate an concentrated in vacuo to provide tert-butyl 1-(3-(3,5-Difluorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl)-ethylcarbamate. The crude product was used without further purification.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][N:37]=[C:36]([S:42][CH3:43])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:48][C:47]([F:50])([F:49])[C:45]1[CH:44]=[C:5]([CH:4]=[C:3]([C:2]([F:51])([F:1])[F:52])[CH:46]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[C:39]([O:40][CH3:41])=[CH:38][N:37]=[C:36]([S:42]([CH3:43])=[O:61])[N:35]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(SC)ncc2OC)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2nc(S(C)=O)ncc2OC)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(5-methoxy-2-methylsulfanyl-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (162 mg) is dissolved in chloroform (5 ml) and thereto is added m-chloroperbenzoic acid (70%) (63 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added saturated aqueous sodium thiosulfate solution and chloroform, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:0→19:1) to give ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2-methanesulfinyl-5-methoxy-pyrimidin-4-yl)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (143 mg). MS (m/z): 780 [M+H]+
Reaction SMILES: C(O[CH:5](OC(C)C)[N:6]([CH3:8])[CH3:7])(C)C.[Br:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([CH3:23])=[CH:16][C:15]=1[F:24]>CN(C)C=O>[Br:13][C:14]1[C:15]([F:24])=[CH:16][C:17]([CH:23]=[CH:5][N:6]([CH3:7])[CH3:8])=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: CC(C)OC(OC(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 122.5 °C

Procedure:
A mixture of N,N-dimethyl formamide diisopropyl acetal (1.7 ml, 8.13 mmol) and 1-Bromo-2-fluoro-4-methyl-5-nitro-benzene (1.538 g, 6.57 mmoles) in dry dimethylformamide (10 ml) was heated at 120-125° C. for 1.5 hours. The resulting dark red solution was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give [2-(4-Bromo-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-amine as a dark red solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:19])([F:18])[CH2:9]OS(C(F)(F)F)(=O)=O.[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[CH3:28]>CC#N>[Br:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][CH2:9][C:8]([F:19])([F:18])[F:7])=[CH:23][C:22]=1[CH3:28]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(NCC(F)(F)F)ccc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
Potassium carbonate (2.50 g, 18.1 mmol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.36 ml, 16.4 mmol) were added to a solution of 4-bromo-3-methylaniline (1.68 g, 9.03 mmol) in MeCN (39.0 ml) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate) to give (4-bromo-3-methyl-phenyl)-(2,2,2-trifluoro-ethyl)-amine (2.20 g, 91%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][C:40]([CH:43]2[CH2:45][CH2:44]2)=[N:41][CH:42]=1>>[CH:43]1([C:40]2[N:41]=[CH:42][C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:38][N:39]=2)[CH2:45][CH2:44]1
Reactant: Brc1cnc(C2CC2)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cnc(C3CC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 5-bromo-2-cyclopropyl-pyrimidine (for preparation see WO 2006004532) following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]#[N:7])C.[NH2:8][CH:9]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:11][C:10]1([CH3:18])[CH3:17]>C(O)C>[C:6]([NH:5][CH:4]=[N:8][CH:9]1[C:16]2[CH:15]=[CH:14][S:13][C:12]=2[CH2:11][C:10]1([CH3:18])[CH3:17])#[N:7]
Reactant: CC1(C)Cc2sccc2C1N
Reactant: CCOC=NC#N
Solvent: CCO
Product: CC1(C)Cc2sccc2C1N=CNC#N
Reaction time: 2 h
Yield: 55.9 %

Procedure:
2.7 g of N-cyanoimidoformic acid ethyl ester are added dropwise to a solution of 3.0 g of 4-amino-5,6-dihydro-5,5-dimethyl-4H-cyclopenta-[b]thiophene in 1.0 ml of ethanol. The exothermic reaction is complete after 2 hours. The reaction mixture is concentrated by evaporation. The crystalline residue is recrystallised from ether, yielding 2.2 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-formamidine having a melting point of 118°-119° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].Cl[C:19]1[N:20]=[N:21][C:22]([Cl:34])=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>CN(C=O)C.O>[Cl:34][C:22]1[N:21]=[N:20][C:19]([O:15][CH:13]2[CH2:12][N:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH2:14]2)=[C:24]([N:25]2[CH2:30][CH2:29][CH:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH:23]=1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: CC(=O)C1CCN(c2cc(Cl)nnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1CCN(c2cc(Cl)nnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2, step 1; 0.78 g, 3.8 mmol) in DMF (20 mL) at room temperature was added sodium hydride (60% wt in mineral oil) (0.18 g, 7.6 mmol). The mixture was stirred at room temperature for 10 min and then 1-(1-(3,6-dichloropyridazin-4-yl)piperidin-4-yl)ethanone (1.0 g, 3.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (5% to 30% EtOAc in hexanes) to give the title product (1.1 g, 2.6 mmol, 70% yield) as white solid. ESI-MS (M+1): 438 calc. for C24H25ClN4O2 437.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(N(CC)CC)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Reactant: NCc1ccccc1O
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1CNc1ncnc2c1ncn2C1CCCO1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 2-hydroxybenzylamine, and 5 ml of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane) (1:1) (v:v): single spot; HPLC: purity >98%. 1H NMR (400 MHZ, DMSO): 2.22sep (1H); 2.44m (1H); 3.82q (1H, J=7.3 Hz); 4.15q (1H, J=7.3 Hz); 4.69bs (2H); 6.26m (1H); 6.73t (1H, J=7.5 Hz); 6.82d (1H, J=7.9 Hz); 7.06t (1H, J=7.8 Hz); 7.17d (1H, J=7.3 Hz); 8.05bs (1H); 8.22s (1H); 8.23s (1H); 9.82bs (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([OH:5])=O.C([Li])CCC.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27])C(Cl)=O>O1CCCC1.CCCCCC.Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[O:5]
Reactant: CCOC(=O)CC(=O)O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(C(=O)OC)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl hydrogen malonate (4.38 g, 33.2 mmol) in dry tetrahydrofuran (100 ml) cooled under an atmosphere of nitrogen to -60° C. with efficient stirring was added a solution of n-butyllithium in hexane (2.5M, 26.5 ml) rapidly dropwise, allowing the temperature to rise to -10° C. during the addition. After stirring the resulting suspension for 15 min at -10° C. it was recooled to -70° C. and a solution of 3-methoxy-4-methoxycarbonylbenzoyl chloride (4.46 g, 19.5 mmol) in dry tetrahydrofuran (30 ml) added dropwise. After addition, the reaction mixture was allowed to warm to room temperature and after 1 h diluted with cold aqueous hydrochloric acid (2M, 35 ml) and ice. The mixture was extracted with diethyl ether (200 ml) and the extract washed twice with a saturated solution of sodium bicarbonate, water and a saturated solution of sodium chloride. The organic layer was dried over magnesium sulphate, filtered and evaporated. The residue was purified on flash silica eluting with dichloromethane to give ethyl 3-methoxy-4-methoxycarbonylbenzoylacetate as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl.[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]([C:32]([O:34][CH3:35])=[O:33])[NH:27][CH2:26][CH2:25]2.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(O)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]([C:32]([O:34][CH3:35])=[O:33])[N:27]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH2:26][CH2:25]2
Reactant: COC(=O)C1NCCc2cc(O)ccc21
Reactant: COc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1

Procedure:
4-(4-Methoxyphenoxy)benzenesulfonyl chloride is reacted with methyl 6-hydroxytetra-hydroisoquinoline-1-carboxylate hydrochloride in analogy to the method described in 3B to give the desired sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)[N:11]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)[N:11]=1)=[O:29]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 90.1 %

Procedure:
Using ethyl 6-(3-aminophenoxy)imidazo[1,2-b]pyridazine-2-carboxylate (350 mg, 1.17 mmol), 3-(trifluoromethyl)benzoic acid (342 mg, 1.80 mmol), 1-hydroxybenzotriazole (243 mg, 1.80 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg, 1.80 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (496 mg, 90%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33](OC)=[O:34])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][CH2:33][OH:34])(=[O:30])=[O:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CCO)no2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of (R)-methyl 2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)acetate INT-14 (0.025 g, 0.05 mmol) in THF (25 mL) was added sodium borohydride (0.05 g, 0.12 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.02 mL, 0.05 mmol) was added. After 1 h, the reaction was cooled and concentrated and purified by preparative HPLC to give 16.0 mg (66%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-hydroxyethanesulfonamide 37. LCMS-ESI (m/z) calculated for C24H26N4O5S: 482.6; found 505.1 [M+Na]+, tR=3.46 min. 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J=5.4, 2.4 Hz, 1H), 8.35-8.25 (m, 1H), 7.95 (dt, J=7.7, 3.9 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.43-7.32 (m, 1H), 7.12 (t, J=7.5 Hz, 1H), 4.80 (m, 3H), 4.12 (t, J=5.2 Hz, 2H), 3.46-3.28 (m, 2H), 3.17 (dt, J=18.0, 5.9 Hz, 1H), 3.02 (dt, J=18.1, 6.8 Hz, MX 2.68 (s, 1H), 2.12 (m, 1H), 2.07-1.82 (m, 3H), 1.47 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.82, 169.22, 162.81, 137.73, 136.90, 134.12, 133.89, 132.15, 130.28, 126.46, 126.33, 116.65, 115.22, 113.57, 103.93, 72.78, 57.32, 56.17, 52.54, 30.60, 28.06, 21.72, 19.04. Chiral HPLC: (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)-2-hydroxyethane sulfonamide 37 was eluted with 15% water/MeOH, (Chiral Method 2): 99.82% ee, tR=22.23 min.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([O:42][C:43]([F:46])([F:45])[F:44])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][C:39]([O:42][C:43]([F:45])([F:44])[F:46])=[CH:40][CH:41]=4)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 89 %

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-(trifluoromethoxy)benzenesulfonamide (20 mg, 0.031 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 16 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)-4-(trifluoromethoxy)benzenesulfonamide (percentage yield: 89%), was obtained.