Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:8]=2)[N:3]=1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Brc1ccccc1
Reactant: Cc1cc(N2CCC(N)C2)c2cc(Oc3ccccc3)ccc2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: O
Product: Cc1cc(N2CCC(Nc3ccccc3)C2)c2cc(Oc3ccccc3)ccc2n1

Procedure:
1-(2-Methyl-6-phenoxyquinolin-4-yl)pyrrolidin-3-ylamine (0.107 g; see Example 43 below), bromobenzene (0.058 g), 2-dicyclohexylphosphino-2′-dimethylaminobiphenyl (0.023 g), tris-(dibenzylideneacetone)dipalladium (0.03 g), sodium tert-butoxide (0.044 g) and toluene (3 mL) were heated in a microwave at 150° C. for 20 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated to give a brown oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave, after trituration with ether, the title compound as a white solid.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:9]([F:10])=[C:8]([F:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].C(OCC)(=O)C.Cl>CN(C)C=O.O>[F:11][C:8]1[C:9]([F:10])=[C:4]2[C:5]([C:12]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=3[C:14](=[O:16])[O:15]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1-c1ccc(F)c(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1oc2c(F)c(F)ccc2c2ccc([N+](=O)[O-])cc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
60% Sodium hydride (2.82 g, 70.5 mmol) was suspended in anhydrous N,N-dimethylformamide (60 mL), then under ice cooling, an anhydrous N,N-dimethylformamide solution (40 mL) of 2-(2,3,4-trifluorophenyl)-5-nitrobenzoic acid (Reference Compound No. 1-2-(2), 6.97 g, 23.5 mmol) was added dropwise thereto, and then the reaction mixture was stirred under nitrogen atmosphere at 80° C. for 24 hours. After cooling down, ethyl acetate (400 mL), water (400 mL) and 1N aqueous HCl solution (80 mL) were added, and then separated. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Chloroform was added to the obtained solid, and then filtered to give the titled reference compound (3.85 g) as a brown solid. (Yield 59%)
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl>C(O)C1C=CC=CC=1.O.CCO.CCO.CCO.CCO.[Ti]>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH2:18][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: [Ti]
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 3 h
Yield: 143.5 %

Procedure:
A solution of 1.62 9 of tetraethyl orthotitanate in 71 ml of benzyl alcohol was treated with 4.52 g of methyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate and stirred at 115°-120° under argon for 3 hours. The reaction mixture was then cooled, stirred with 71 ml of 1N hydrochloric acid for 1 hour, diluted with 350 ml of water and extracted several times with methylene chloride. The organic phases were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue was stirred in 710ml of diethyl ether for 1 hour, suction filtered and the material obtained was dried in a vacuum. There was obtained 4.02g of benzyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 229°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.[Li+].[Cl-].[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([Sn](CCCC)(CCCC)CCCC)[N:44]=3)=[CH:40][CH:41]=2)[CH:36]=[N:35]1>O1CCOCC1.CCOC(C)=O.[Cu]I.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>[C:26]([O:25][C@@H:19]([C:9]1[C:8]([CH3:30])=[CH:7][C:5]2[N:6]=[C:2]([C:45]3[CH:46]=[CH:47][CH:48]=[C:43]([C:39]4[CH:38]=[C:37]5[C:42](=[CH:41][CH:40]=4)[N:34]([CH3:33])[N:35]=[CH:36]5)[N:44]=3)[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc3c(cnn3C)c2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 100 °C

Procedure:
In a 10 mL reaction vial, (S)-ethyl 2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.0938 mmol) was dissolved in dry dioxane (1.5 mL) under argon atmosphere. The solution was bubbled with argon for 5 min. Then LiCl (11 mg, 0.256 mmol), CuI (5 mg, 0.026 mmol) and Pd(PPh3)4 (10 mg, 0.0085 mmol) were added sequentially. A solution of 1-methyl-5-(6-(tributylstannyl)pyridin-2-yl)-1H-indazole (43 mg, 0.0853 mmol) in 1.4-dioxane (1.5 mL) was then added drop-wise. The resulting reaction mixture was then sealed and heated in oil bath at 100° C. for 3 h. The resulting reaction mixture was diluted with EtOAc (5 mL), filtered and the filtrate was concentrated and purified on silica gel column with 0-40% EtOAc/Hex to afford the title product. LCMS-ESI+: calc'd for: C30H29F3N4O6S2: 663.2, 664.2 (M+H+); Found: 663.1, 664.3 (M+H+).
Reaction SMILES: I[Si](C)(C)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:22][CH2:21][CH2:20][C@H:19]3[N:14]2[C:15](=[O:23])[CH2:16][CH2:17][CH2:18]3)=[CH:9][CH:8]=1.CN(C)CCN(C)C.[I:32]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:22][CH2:21][CH2:20][C@H:19]3[N:14]2[C:15](=[O:23])[CH:16]([I:32])[CH2:17][CH2:18]3)=[CH:9][CH:8]=1
Reactant: II
Reactant: O=C1CCC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Agent: CN(C)CCN(C)C
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C(I)CC[C@H]2CCC[C@@H](c3ccc(Cl)cc3)N12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Iodotrimethylsilane (0.74 mL) was added to a solution of (6S,9aR)-6-(4-chlorophenyl)octahydroquinolizin-4-one (877 mg) and N,N,N′,N′-tetramethylethylenediamine (1.76 mL) in methylene chloride (25 mL) in a nitrogen atmosphere at 0° C., and the reaction solution was stirred at 0° C. for 30 minutes. Iodine (1.26 g) was added to the reaction solution at 0° C., and the reaction solution was stirred at 0° C. for one hour. A sodium thiosulfate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one. A mixture of (6S,9aR)-6-(4-chlorophenyl)-3-iodooctahydroquinolizin-4-one with triethyl phosphite (10 mL) was stirred at 120° C. for two hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure to obtain diethyl [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate. Lithium hydroxide monohydrate (422 mg) was added to a mixed solution of diethyl [(6S,9aR)-6-(4-chlorophenyl)-4-oxooctahydroquinolizin-3-yl]phosphonate and 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (869 mg) in tetrahydrofuran (21 mL) and ethanol (7 mL) at room temperature, and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) and then by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 1.07 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11]1[C:12](=O)[C:13](=[O:18])[C:14]=1[O:15]CC)[CH3:9]>C(O)C>[CH2:8]([O:10][C:11]1[C:14](=[O:15])[C:13](=[O:18])[C:12]=1[NH:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1)[CH3:9]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cnccn1
Solvent: CCO
Product: CCOc1c(Nc2cnccn2)c(=O)c1=O

Procedure:
A solution of aminopyrazine and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol was processed as described in Example 1A to provide the title compound. MS (DCI/NH3) m/z 220 (M+H)+.
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([C:24](=O)[CH2:25][O:26][CH3:27])=[CH:19][C:18]=1[CH3:29])/[C:5]([O:7][CH3:8])=[O:6].Cl.[CH3:31][O:32][NH2:33]>CO>[CH3:1][O:2]/[CH:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20](/[C:24](=[N:33]/[O:32][CH3:31])/[CH2:25][O:26][CH3:27])=[CH:19][C:18]=1[CH3:29])/[C:5]([O:7][CH3:8])=[O:6]
Reactant: CON
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)COC)cc1C
Agent: Cl
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(/C(COC)=N/OC)cc1C
Yield: 46.8 %

Procedure:
In 30 mL of methanol, 0.2 g (0.50 mmol) of (E)-methyl 3-methoxy-2-(2-((4-(2-methoxyacetyl)-2,5-dimethylphenoxy)methyl)phenyl)acrylate obtained in Step 2 was reacted with 0.21 g (5 eq) of methoxyamine hydrochloride at room temperature for 15 hours with stirring. After completion of the reaction, the solvent was removed in a vacuum, and the residue was stirred in water (30 mL) and extracted twice with 30 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Purification by silica gel chromatography afforded 0.1 g of (E)-methyl 3-methoxy-2-(2-((4-((Z)-2-methoxy-1-(methoxyimino)ethyl)2,5-dimethylphenoxy)methyl)phenyl)acrylate as a white solid (yield: 50%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[C:7]4[CH:17]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: Clc1ccc2onc(C3CCNCC3)c2c1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(Cl)cc34)CC2)CC1

Procedure:
The title compound, MS: m/e=462.3 (M+H+), was prepared in accordance with the general method of example 1, intermediate E from a mixture of 5-chloro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (Example 1, Intermediate C).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[CH:7]1([C:10]2[CH:11]=[C:12]([CH3:31])[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=4)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[CH:11]=[C:12]([CH3:31])[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([C:24]4[CH:29]=[CH:28][C:27]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[CH:26][CH:25]=4)=[O:23])[CH2:18][CH2:17]3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2)CC1
Yield: 60.9 %

Procedure:
Using pyrrolidin-2-one (94 mg) and [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 117 and by the reaction and treatment in the same manner as in Example 1, the title compound (246 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1.C(CC(C)(C)C)(C)C.CCCCCC>C1(C)C=CC=CC=1.C(O)(=O)C.C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]([NH2:10])=[S:24])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1c(F)c(F)c(F)c(F)c1F
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: CC(C)CC(C)(C)C
Product: NC(=S)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C

Procedure:
To a solution of pentafluorobenzamide (5.00 g, 23.69 mmol) in toluene (60 mL) was added Lawesson's reagent (5.70 g, 14.20 mmol) and the flask fitted with a drying tube. The reaction was refluxed overnight, cooled to room temperature, and isooctane (200 mL) was added causing a precipitate to form. The suspension was filtered (gravity) and the filtrate concentrated yielding an orange oil which solidified. Flash chromatography of this oil (1:1 hexane:methylene chloride with 2% acetic acid) yielded crude pentafluorothiobenzamide as a white solid (mp 92°-93° C.) which was used without any further purification.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1([C:12](=O)[CH2:13][N:14]([C:22]2[N:23]=[C:24]3[CH:30]=[CH:29][N:28]([S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:25]3=[N:26][CH:27]=2)C(=O)OC(C)(C)C)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([C:12]2[N:23]3[C:24]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=5)(=[O:33])=[O:32])[C:25]=4[N:26]=[CH:27][C:22]3=[N:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CCCCC4)C(=O)OC(C)(C)C)cnc32)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CCCCC4)n23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated H2SO4 (4 mL) was added to tert-butyl 2-cyclohexyl-2-oxoethyl-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (0.07 g, 0.14 mmol) and the reaction mixture was stirred for about 30 min at ambient temperature. The reaction mixture was poured onto ice-cold water (75 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and concentrated to yield 8-cyclohexyl-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine as a yellow oil that was used in Example #9, Step C without further purification (0.051 g, 95%): LC/MS (Table 2, Method a) Rt=2.79 min; MS m/z: 395 (M+H)+.
Reaction SMILES: C1(S([N:10]2[C:14]3=[CH:15][N:16]=[CH:17][C:18]([C:19]4[N:27]=[C:26]5[C:22]([N:23]=[C:24]([CH2:29][N:30]6[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]6)[N:25]5[CH3:28])=[C:21]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)[N:20]=4)=[C:13]3[CH:12]=[C:11]2[CH3:46])(=O)=O)C=CC=CC=1>O1CCOCC1.[OH-].[Na+]>[CH3:28][N:25]1[C:24]([CH2:29][N:30]2[CH2:31][CH2:32][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:34][CH2:35]2)=[N:23][C:22]2[C:26]1=[N:27][C:19]([C:18]1[CH:17]=[N:16][CH:15]=[C:14]3[NH:10][C:11]([CH3:46])=[CH:12][C:13]=13)=[N:20][C:21]=2[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1
Reactant: Cc1cc2c(-c3nc(N4CCOCC4)c4nc(CN5CCC(C(C)(C)O)CC5)n(C)c4n3)cncc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc2c(-c3nc(N4CCOCC4)c4nc(CN5CCC(C(C)(C)O)CC5)n(C)c4n3)cncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.1 %

Procedure:
A 50 mL round-bottomed flask, under nitrogen, fitted with a condenser/inert gas bubbler (via a Claisen head), was charged with a solution of 2-{1-[2-(1-benzenesulfonyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol (0.41 g, 0.64 mmol) in dioxane (8 mL), IMS (8 mL) and NaOH 12.5M (0.8 mL). The resulting mixture was stirred at room temperature for 2 h. The solution was concentrated in vacuo, the residue was dissolved in DCM and a fine solid was removed by filtration through a Celite pad. The solution was purified by flash chromatography (Si—PCC; 25 g SiO2 column, 0% to 20% MeOH in DCM). The residue was then purified further by preparative HPLC [(C18 column) gradient: (acetonitrile/20 mM triethylamine) 30% to 98% in (water/20 mM triethylamine) over 20 min (flow rate 18 ml/min)]. The product was freeze-dried overnight yielding 165 as a white powder (0.136 g, 43%). LCMS (method E): RT=4.89 min, [M+H]+ 505.24. 1H NMR (CDCl3, 400 MHz) δ 9.28 (s, 1 H), 8.70 (s, 1 H), 8.30 (s, 1 H), 4.40 (m, 4 H), 3.96 (s, 3 H), 3.89 (m, 4 H), 3.74 (s, 2 H), 2.96 (m, 2 H), 2.58 (s, 3 H), 2.10 (m, 2 H), 1.75 (m, 2 H), 1.40-1.28 (m, 3 H), 1.18 (s, 6 H)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[BrH:9].[NH+]1C=CC=CC=1>C(O)(=O)C>[Br:9][C:5]1[O:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: Br
Reactant: O=C(O)c1ccoc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: O=C(O)c1coc(Br)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
Furan-3-carboxylic acid (1 g, 8.93 mmol) is added to a solution of pyridinium hydrobromide perbromide (3.02 g, 9.46 mmol) in acetic acid (5 mL). The reaction mixture is stirred at 50° C. for 5 hours, then at room temperature overnight. After removing the solvent in vacuo, water is added and a precipitate is formed. The solid is collected by filtration and dried to yield the title compound (0.364 g, 21%). HPLC (254 nm): Rt 2.65 min (88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:18]([OH:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[N:13][C:14]=1[CH2:15][CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[CH3:31][O:32][CH2:33]OCOC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([C:18]([O:27][CH2:31][O:32][CH3:33])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:20])[F:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCOC
Reactant: CCCc1nc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
2-(5-(Benzyloxy)-6-propylpyridin-2-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (537 mg, 1.37 mmol) was dissolved in N,N′-dimethylformamide (2.5 mL) and added with sodium hydride (purity 50%) (79 mg, 1.64 mmol) and methoxymethyl ether chloride (113 μL, 1.50 mmol) under ice-cold conditions The resultant mixture was stirred under ice-cold conditions for 1.5 hours and then further stirred at room temperature for 45 minutes. After completion of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 3-(benzyloxy)-6-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylpyridine (407 mg, yield 68%) was obtained as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[N:10]1([C:8]([C:7]2[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=2)=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 115.8 %

Procedure:
To a solution of 1.28 g of 1-(4-nitrobenzoyl)pyrrolidine obtained in stage a) below in 50 mL of methanol are added, under argon, 4.26 g of ammonium formate and 9 mg of 10% palladium-on-charcoal. The reaction mixture is stirred at room temperature for 5 hours and then filtered through Celite and concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 1.28 g of 4-(pyrrolidin-1-ylcarbonyl)aniline, the characteristics of which are as follows:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1>O>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:23][O:24][CH2:25][CH2:26][Br:27])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1)=[O:3]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: CCOC(=O)C(=NOCCBr)c1csc(NC=O)n1
Temperature: 50 °C
Yield: 61.6 %

Procedure:
A mixture of acetic anhydride (15.9 g.) and formic acid (7.15 g.) was stirred at 50° C. for an hour. After cooling, ethyl 2-(2-aminothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 25 g.) was added to the solution and stirred at room temperature for an hour. The resultant solution was poured into water and extracted with ethyl acetate twice. The extracts were washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate (three times) and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the solution in vacuo, the oily residue was triturated with a mixture of diisopropyl ether and diethyl ether. The precipitates were collected by filtration to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn icomer, 16.75 g.), mp. 95° to 98° C.