Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH2:16][CH2:17][OH:18].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][O:18][CH2:17][CH2:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[F:8])[CH3:7]
Reactant: OCCc1cc(F)ccc1F
Reactant: CCOC(=O)CI
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COCCc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.2 %

Procedure:
Ethyl iodoacetate (340 □l, 2.9 mmol) was added to an ice cold solution of 2-(2,5-difluoro-phenyl)-ethanol (500 mg, 2.4 mmol), silver trifluoromethanesulfonate (685 mg, 2.7 mmol) and 2,6-di-tert-butylpyridin (820 □l, 3.6 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at ambient temperature for 14 h, diluted with dichloromethane and filtered over speedex. Ice water/0.1 N aqueous HCl 1/1 was added to the filtrate and the filtrate was extracted two times with dichloromethane. The combined extracts were washed with aqueous NaHCO3 solution and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure left a colorless oil which was purified by column chromatography (silica gel, isopropyl acetate/heptane) to give the title compound (320 mg, 1.3 mmol; 54%) as colorless oil. MS: m/e=245.0 [M+H+].
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]2([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]2)/[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([CH:43]=[N:44][C:45]([O:47][Si](C)(C)C)=[CH2:46])[CH:42]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]4([C:31]([O:33][CH3:34])=[O:32])[CH2:30][CH2:29][CH2:28]4)[CH2:46][C:45](=[O:47])[NH:44][CH:43]3[C:41]3[CH:42]=[C:37]([F:36])[CH:38]=[CH:39][C:40]=3[CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CCC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(Oc2ccc(Cl)cc2C2CC(=O)NC(c3cc(F)ccc3C)C23C(=O)Nc2cc(Cl)ccc23)CCC1
Temperature: 60 °C
Yield: 11.5 %

Procedure:
A mixture of E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) and 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (10 mmol) prepared in Example 4 in toluene (10 mL) was heated at 60° C. for 3 h. To the mixture was added TFA (5 mL), and the resultant solution was stirred at room temperature for 20 min, then concentrated in vacuo. The residue was partitioned between ethyl acetate and diluted aqueous NaOH solution. The organic layer was separated, washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (200 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:5][N:6]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>>[N+:12]([CH:15]=[C:16]([S:17][CH3:18])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][N:5]=1)([O-:14])=[O:13]
Reactant: NCCSCc1nnc(N)s1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])NCCSCc1nnc(N)s1

Procedure:
By the procedure of Example 8(i), 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazole (from the dihydrobromide) is reacted with 1-nitro-2,2-bis-methylthioethylene to give 1-nitro-2-methylthio-2-[2-((2-amino-5-(1,3,4)-thiadiazolyl)methylthio)ethylamino]ethylene.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8](CC)(P(O)(O)=O)[C:9]([OH:11])=[O:10])C.[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:27]=1C=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][C:27]=1/[CH:6]=[CH:8]/[C:9]([OH:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(CC)(C(=O)O)P(=O)(O)O
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 2.5 M n-butyl lithium (3.64 mL) in dry tetrahydrofuran (THF) (20 mL) that is cooled to −70° C. under nitrogen is added a solution of diethyl phosphonoacetic acid (0.89 g) in THF (5 mL). After 30 minutes a solution of 2,4-dibenzyloxybenzaldehyde (1.46 g) in THF (5 mL) is slowly added to the cooled solution so as to maintain the temperature. The resulting mixture is stirred at −70° C. for 3 hours and then at 25° C. for 18 hours. The resulting suspension is treated with water, the THF is removed in vacuo,the residue is extracted with ethyl acetate, the extract is dried and evaporated. The residual solid is recrystallized from isopropanol to yield (E)-3-(2,4-dibenzyloxyphenyl)prop-2-enoic acid as colourless crystals (0.6 g), m.p. 153-155° C. H NMR (DMSO) 5.15 (2H,s), 5.21(2H,s), 6.4(1H,d,J=16 Hz), 6.7(1H,d), 6.85(1H,s), 7.3-7.5(10H,m), 7.6(1H,d), 7.8(1H,d,J=16 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CC(O)C.CCCCCC>[Cl:17][CH2:18][C:19]([N:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.4 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine are heated to about 80° C. and treated with 10.75 g of chloroacetylchlonde. The mixture is stirred for 2 hours and diluted with 10 ml of 2-propanol. The solution is cooled to 35-40° C. and seeded. The precipitated suspension is diluted with 30 ml of hexane, cooled to 0-5° C. and stirred for about 1 hour. The crystals are isolated by filtration, washed with a cold solution of 2-propanol/hexane ⅓. After drying, 22.7 g of 2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide are obtained. HPLC purity: 99%. Melting point: 79-80° C. 1H-NMR(DMF-d7, 400 MHz, 393K) δ 2.44(s, 3H, CH3); 4.32 (s, 2H, CH2), 7.35[d, J=8.0 Hz, 2H, HC(3) and HC(5)], 7.43[ddd, J=8.0, 2.0 Hz, JH-F=8.0, 1H, HC(5′)], 7.48[d, J=8.0 Hz, 2H, HC(2) and HC(6)], 7.55[d, J=8.0 Hz, 1H, HC(3′)], 7.60[ddd, J=8.0 Hz, JH-F=5.5, 1H, HC(4′)].
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[NH:9])[CH3:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20].C(OCC)(=O)C>C1C=CC=CC=1>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[C:12]=1[NH:18][C:19]([N:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:2][CH3:3])=[O:20]
Reactant: CCN1CCCC1=N
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride of 1-ethyl-2-iminopyrrolidine (7.43 g.; 0.05 mole) is converted to free base (5.6 g.; 0.05 mole) in benzene in the usual manner. Then 7.35 g. (0.05 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 13/4 hours and then the solvent is evaporated to dryness in vacuo to give an oily residue. Trituration with ethyl acetate and cooling produces a solid product, 1-(2,6-dimethylphenyl)-3-(1-ethyl-2-pyrrolidylidene)urea, m.p. = 120°-122° C. Recrystallization from acetone gives the pure product, m.p. - 121°-123° C.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
H2O2 (70%, 0.66 mL, ca. 13.2 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 197 (363 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 198 (98 mg, 25%) as a red solid: mp (MeOH/EtOAc) 149-151° C.; 1H NMR δ 8.12 (s, 1H, H-5), 7.54 (s, 1H, H-9), 7.27 (br s, 1H, NH), 4.75 (t, J=8.3 Hz, 2H, H-7), 3.58-3.64 (m, 2H, CH2N), 3.43 (t, J=8.2 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2]; 13C NMR δ 159.9, 148.9, 141.6, 135.2, 130.9, 113.1, 97.4, 72.4, 57.5, 45.1 (2), 38.8, 29.7. Anal. calcd for C13H17N5O3.¼H2O: C, 52.8; H, 6.0; N, 23.7. Found: C, 52.8; H, 5.7; N, 23.5%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:11][CH:12]([O:31][CH3:32])[CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:4]=1.[NH:33]1[CH:37]=[CH:36][N:35]=[CH:34]1>C1(C)C=CC=CC=1>[CH2:15]([O:14][CH2:13][CH:12]([O:31][CH3:32])[CH2:11][O:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:8]=[CH:7][CH:6]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCCCCCCCCCOCC(COCc1cccc(CBr)c1)OC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(COCc1cccc(Cn2ccnc2)c1)OC
Temperature: 80 °C
Yield: 86.3 %

Procedure:
a mixture of 2.4 g of 1-(bromomethyl)-3-[[3-(hexadecyloxy)-2-methoxypropoxy]methyl]benzene, 2.54 g of imidazole and 30 ml of toluene was heated at 80° C. under argon in a pressure bottle for 4 hours and then evaporated. The residue was purified by chromatography, giving 2.02 g of the desired product as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: Fc1ccccc1Cc1n[nH]c2nccnc12
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3nccnc32)n1

Procedure:
A solution of 144 mg (0.63 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyrazine from example 14A, 92 mg (0.63 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 18 mg (0.038 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 287 mg (0.88 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with ethyl acetate and a little methanol and filtered with suction. The solid is again stirred with methanol and filtered off with suction once again. The filtrates are then combined and concentrated, and the residue is purified by preparative HPLC. The product fraction obtained is concentrated, again stirred with methanol and filtered off with suction. 13 mg (6% of theory) of the desired product are obtained in this way.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[C@@H:30]([CH3:34])[CH2:29]1)[CH3:27]
Reactant: CCN1CCN[C@@H](C)C1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)c(F)c4C)c3O)nc2)[C@@H](C)C1

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-3-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (t, J=7.20 Hz, 3H) 1.38 (d, J=7.07 Hz, 3H) 2.33 (d, J=2.27 Hz, 3H) 2.68-5.32 (m, 9H) 7.63 (d, J=7.33 Hz, 1H) 7.70-7.80 (m, 1H) 7.94-8.73 (m, 4H) 8.97-10.49 (m, 1H). ESI-MS m/z [M+H]+449.3.
Reaction SMILES: [NH3:1].Cl[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]>>[NH2:1][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N
Product: Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 85 %

Procedure:
A 100 ml stainless steel autoclave was charged with about 50 ml of liquid ammonia. Then 4-chloro-3-nitrobenzenesulfonamide (5.0 g, 21 mmol) was added and the bomb was heated in an oil bath at 100° C. for 3 h. Excess ammonia was allowed to evaporate, and the solid residue was successively washed with water, cold ethanol and ether to give 3.9 g (85%) of the title compound. M.p. 211.5°-213° C. (ethanol); 1H-NMR (DMSO-d6): 6.97 (d,J=9Hz, 1H, H-5), 7.12 (s, 2H, NH2), 7.57 (dd, J6-5 =9 Hz, J6-2 2Hz, H-6), 7.70 (broad s, 2H, NH2), 8.22 (d,J 2Hz, H-2).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (152 mg, 1.0 mmol.) in DMF was added K2CO3 (277 mg, 2.0 mmol.) and iodocyclopentane (295 mg, 1.5 mmol.). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate (30 mL×3), washed with brine, dried over Na2SO4, concentrated to give a residue, which was purified by column chromatography to afford 2-chloro-1-cyclopentyl-1H-benzo[d]imidazole (130 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 7.68˜7.60 (m, 1 H), 7.39˜7.30 (m, 1 H), 7.20˜7.15 (m, 2 H), 5.04˜4.90 (m, 1 H), 2.25˜1.92 (m, 6 H), 1.85˜1.70 (m, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[Cl-].[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:31]CCO)=[CH:26][CH:25]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(NCC)C>C(Cl)Cl>[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH2:30][O:31][CH2:2][CH2:1][N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])=[CH:28][CH:29]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: OCCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: [Cl-]
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)CCOCc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Triethylamine (33 ml, 0.241 mmol) and mthanesulphonyl chloride (19 ml, 0.241 mmol) were added to a solution of 4-anilino-5-bromo-2-[4-(2-hydroxyethoxy)methylanilino]pyrimidine (Example 31; 100 mg, 0.241 mmol) in DCM (5 ml) at 0° C. The solution was warmed to ambient temperature and left to stand for 1 hour. Diethylamine (2 ml) was added, and the mixture was heated at 50° C. for 3 hours. The solvent was removed by evaporation, and the residue was purified by column chromatography, eluting with 0–2% methanol solution in DCM containing 0.5% aqueous ammonia solution, to give the product as a cream solid (38 mg, 34%). NMR (CDCl3): 1.03 (t, 6H), 2.58 (q, 4H), 2.69 (t, 2H), 3.54 (t, 2H), 4.48 (s, 2H), 7.06 (d, 2H), 7.17 (t, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.38 (dd, 2H), 7.49 (d, 2H), 7.58 (d, 2H), 8.15 (s, 1H); MS (MH+): 470.4, 472.4.
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.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].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:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

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. 1-propansulfonyl chloride (6 uL, 0.052 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)propan-1-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.P([N:44]=[N+:45]=[N-:46])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C(N(CC)CC)C>C(O)(C)C>[F:27][C:2]([F:1])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:44]=[N+:45]=[N-:46])=[O:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To (E)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylic acid (C22) (1.72 g, 4.59 mmol) in isopropanol (15.3 mL) was diphenyl phosphorazidate (1.3 mL, 6.03 mmol) and triethylamine (0.96 mL, 6.89 mmol) and stirred at room temperature for 6 hours. The white precipitate for filtered, rinsed with isopropanol, and dried to afford the title compound as a white solid (1.46 g, 78%): mp 106° C. (dec); 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 7.86-7.73 (m, 3H), 7.66 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 6.52 (t, J=14.6 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 401 ([M+H]+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH:32]([OH:35])([CH3:34])[CH3:33].O[C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58]>>[CH3:33][CH:32]([O:35][C:37]1[CH:42]=[CH:41][C:40]2[C:43]3([CH2:59][O:60][C:39]=2[CH:38]=1)[C:51]1[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=1)[N:45]([CH2:52][C@H:53]1[CH2:57][CH2:56][CH2:55][O:54]1)[C:44]3=[O:58])[CH3:34]
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc(O)ccc12
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)Oc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
To a stirred solution of triphenylphosphine (0.23 g, 0.89 mmol) in anhydrous tetrahydronfuran (200 mL) at 0° C. under nitrogen were added diethyl azodicarboxylate (0.14 mL, 0.89 mmol), isopropanol (0.23 mL, 2.97 mmol) and 6-hydroxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1H)-one (0.20 g, 0.59 mmol). The reaction mixture was stirred at ambient temperature for 16 h, and then the reaction was quenched with ammonium chloride solution. The solvent was removed, and the residue was dissolved in ethyl acetate (100 mL), which was washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated to dryness, and the residue was purified by flash chromatograph with 25% ethyl acetate in hexanes to afford 6-(1-methylethoxy)-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.19 g, 85%) as colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.33-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.58 (d, J=8.4 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 6.33 (dd, J=8.4, 2.1 Hz, 1H), 4.93 (d, J=9.0 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.53-4.43 (m, 1H), 4.33-4.23 (m, 1H), 4.00-3.66 (m, 4H), 2.10-1.66 (m, 4H), 1.31 (d, J=6.0 Hz, 6H); MS (ES+) m/z 380.0 (M+1), 402.0 (M+23).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)(C)(C)C.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O>C1COCC1>[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[OH:22].[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:14][CH2:13][C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cc1ccncc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1OC[C@@H]1CCCN1
Reaction time: 0.08 h

Procedure:
(S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (590 mg, 2.94 mmol), 4-methyl-3-pyridinol (320 mg, 2.94 mmol), DEAD (509 uL, 3.23 mmol) and PPh3 (848 mg, 3.23 mmol) in THF (100 mL) were allowed to react as described in Example 2a. Solvent was removed, and the residue was chromatographed with CHCl3 /MeOH (10:1) to provide 1.8 g of the crude mixture. This material was immediately treated with trifluoroacetic acid (2.0 mL) at room temperature for 3 hours, and excess trifluoroacetic acid was removed under reduced pressure. Water (3 mL) and EtOAc (20 mL) were added, and the mixture was stirred for 5 minutes. The organic layer was decanted, and the residue washed with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography on silica gel eluting with CHCl3 /MeOH/NH4OH (10:1:0.02 and 10:1.5:0.1) to provide 52 mg (14% yield from 4-methyl-3-pyridinol) of the title compound. TLC Rf 0.18 (10:1:0.02 CHCl3 /MeOH/NH40H). MS (DCI/NH3) m/e 193 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.16 (s, 1H, ArH), 8.12 (d, J=6.9 Hz, 1H, ArH), 7.07 (d, J=6.9 Hz, 1H, ArH), 4.12-4.00 (m, 2H, OCH2), 3.75-3.63 (m, 1H, NCH), 3.18-3.02 (m, 2H, NCH2), 2.24 (s, 3H, NCH3), 2.08-1.64 (m, 4H, 2CH2).