Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]S(O)(=O)=O.CC1(C)C[O:10][C:9]([C:12]2[C:20]([CH2:21][CH3:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=N1>O1CCOCC1>[CH2:21]([C:20]1[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]=1[C:9]([OH:10])=[O:1])[CH3:22]
Reactant: CCc1cc(OC)cc(C(=O)O)c1C1=NC(C)(C)CO1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CCc1cc(OC)cc(C(=O)O)c1C(=O)O
Temperature: 130 °C

Procedure:
A solution of 6.00 mol/L H2SO4 (aq.) (700 mL) was added to a solution of compound G (65.7 g, 237 mmol) in 1,4-dioxane (700 mL) at room temperature. The mixture was heated at 130° C. (oil bath temperature) and stirred. After 64 h the mixture was concentrated in vacuo, and cooled to 0° C. The precipitate was filtered and rinsed with a small amount of water to give the desired compound H (23.8 g, 106 mmol) as an off-white solid. The filtrate was extracted twice with ethyl acetate and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to give the desired compound H (10.8 g, 48.2 mmol) as an off-white solid. The aqueous phase (after salting with NaCl) was extracted with CHCl3/MeOH (4/1), and the combined organic phases were dried over Na2SO4 and concentrated in vacuo to recover the starting material G (26%). 1H NMR (DMSO-d6 400 MHz): δ 1.14 (3H, t, J=7.6 Hz), 2.60 (2H, q, J=7.6 Hz), 3.80 (3H, s), 7.04 (1H, d, J=2.4 Hz), 7.16 (1H, d, J=2.4 Hz). EIMS (+): 224 [M]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:21]([OH:23])[CH:22]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C1C=CC=CC=1.CC(C)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:21]([OH:23])[CH:22]=2)=[N:12][CH:13]=1
Reactant: C=CC(=O)Cl
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)c(O)c3)ncc2F)c1
Temperature: -30 °C
Reaction time: 0.58 h

Procedure:
In a 50 mL 3-neck RBF equipped with a magnetic stirrer, calcium chloride guard tube and thermo pocket was charged 5-((4-((3-aminophenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(2-methoxyethoxy)phenol (0.17 g in 5 mL DCM) and cooled to −30° C. To the reaction mixture was slowly added acryloyl chloride solution in DCM (0.043 g in 5.0 mL DCM) and reaction mixture was stirred at −30° C. for 30 to 40 minutes. The reaction was monitored on TLC using benzene:acetone (8.5:1.5) as mobile phase. The reaction mixture was poured in water (100 mL) and basified using sodium bicarbonate. The solution was extracted with DCM (25 mL×2) and the combined organic layer was washed with 25 mL brine solution. The organic layer was dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. Crude material was purified by preparative HPLC using 0.1% TFA in ACN and 0.1% TFA in water as mobile phase to give 23 mg of N-(3-((5-fluoro-2-((3-hydroxy-4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide. M+1=439.3. 1H NMR: DMSO-d6 (400 MHz): 3.294 (s, 3H), 3.871-3.902 (t, 2H, J=6.0), 3.970-3.993 (t, 2H, J=4.4), 5.774-5.749 (d, 1H, J=10), 6.246-6.288 (d, 1H, J=16.8), 6.436-6.503 (m, 1H), 6.724-7.753 (d, 1H, J=11.6), 7.099 (s, 2H), 7.252-7.333 (m, 1H), 7.404-7.423 (d, 1H, J=7.6), 7.612-7.592 (d, 1H, J=8), 7.934 (s, 1H), 8.057-8.065 (d, 1H, J=3.2), 8.788 (s, 1H), 8.861 (s, 1H), 9.366 (s, 1H), 10.110 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[I:12]I>CCCCCCC.[Hg]=O>[I:12][C:9]1[S:8][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:11][CH:10]=1
Reactant: II
Reactant: Cc1ccc(-c2cccs2)s1
Agent: O=[Hg]
Solvent: CCCCCCC
Product: Cc1ccc(-c2ccc(I)s2)s1
Reaction time: 20 h

Procedure:
A solution of 12.2 grams (0.068 mole) of 5-methyl(2,2'-bithienyl) in 50 mL of heptane was stirred, and, in alternate portions, 17.8 (0.070 mole) of iodine and 12.4 grams (0.057 mole) of mercury (II) oxide were added. Upon completion of addition the reaction mixture stirred for 20 hours, and then was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to yield 5.2 grams of 5-iodo-5'-methyl(2,2'-bithienyl).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:7]([CH2:13][CH3:14])[C:8](OCC)=[O:9]>>[N:1]1([CH:7]([CH2:13][CH3:14])[CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Br)CC
Reactant: C1CCNC1
Product: CCC(CO)N1CCCC1
Yield: 64 %

Procedure:
The title compound was prepared in 64% yield for 2 steps from pyrrolidine and ethyl 2-bromobutyrate by essentially following the procedure detailed in Example 121, Part A.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:4](=[O:6])[C:3]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:11][C:2]=2[OH:1])[CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)cc1O
Reactant: NC1CC1
Product: COc1ccc(COc2ccc(C(=O)NC3CC3)c(O)c2)cc1

Procedure:
Methyl 2-hydroxy-4-[(4-methoxybenzyl)oxy]benzoate (Percec, V; Tomazos, D. J. Mater. Chem. 1993, 3, 643-650) (530 mg, 1.83 mmol) was dissolved in cyclopropyl amine (3 mL) and left at room temperature for a week. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (040% ethyl acetate in petroleum ether) to give the subtitled compound (407 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>C1(C)C=CC=CC=1.C(O)C.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.O>[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:14]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[C:12]([Cl:16])[CH:13]=1
Reactant: OB(O)c1ccccc1Br
Reactant: Clc1cnc(OCc2ccccc2)c(Br)c1
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: CCO
Solvent: O
Solvent: CCOCC
Product: Clc1cnc(OCc2ccccc2)c(-c2ccccc2Br)c1
Temperature: 70 °C
Yield: 42.7 %

Procedure:
2-(Benzyloxy)-3-bromo-5-chloropyridine (150 mg, 0.5 mmol) and 2-bromophenylboronic acid (100 mg, 0.5 mmol) were dissolved in toluene/ethanol (1:1, 5 ml) under nitrogen. Potassium carbonate (550 mg, 4 mmol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol). The resulting mixture was heated at 70° C. in a Smithcreator® microwave for 10 minutes. After cooling, diethyl ether(10 ml) and water (10 ml) were added, The organic layer was washed with water, dried (MgSO4) and evaporated. The product was purified by flash chromatography (silica gel, 2% ethyl acetate:isohexane) to give the title compound as a clear oil (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:15][C:16]1[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=1.[OH-].[Na+]>O>[Cl:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([S:9][CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[CH:19]=[CH:18][N:17]=3)[NH:6][C:5]=2[CH:10]=1
Reactant: COc1ccnc(CCl)c1C
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccnc(CSc2nc3cc(Cl)c(Cl)cc3[nH]2)c1C

Procedure:
A suspension of 13 g of 5,6-dichloro-2-benzimidazolethiol in 360 ml of alcohol was treated with 13 g of 2-chloromethyl-4-methoxy 3-methylpyridine hydrochloride. A solution of 4 g of sodium hydroxide in 170 ml of water was added dropwise thereto while cooling with ice. The mixture was left to boil at reflux overnight and then concentrated to about 1/3 of its volume in a vacuum. After the addition of 600 ml of water the crystals were filtered off and thereupon washed thoroughly with water and then with ether. There was obtained 5,6-dichloro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]benzimidazole of melting point 254°-256°.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].O>C1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 62.6 %

Procedure:
42 g (0.3 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 200 ml of benzene, and 30.6 g of acetic anhydride was added dropwise thereto at 20° to 40° C. while cooling with water. After completion of the dropwise addition, the mixture was allowed to react at 50° to 60° C. for 3 hours. Thereafter, the reaction product was cooled, and water was added to form a precipitate. The precipitate was collected by filtration, and washed with water and benzene to obtain 34 g of 3-acetylamino-5-t-butylpyrazole. This product was recrystallized from hydrous methanol and found to have a melting point of 194° to 195° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]([CH:8]2[CH2:10][CH2:9]2)[C:6]([F:11])=[CH:5][N:4](C(OC2C=CC=CC=2)=O)[CH:3]=1.[S]>C1C2C(CCCC2)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:11])[C:7]=1[CH:8]1[CH2:9][CH2:10]1
Reactant: O=C(Oc1ccccc1)N1C=C(F)C(C2CC2)C(Br)=C1
Agent: [S]
Solvent: C1CCC2CCCCC2C1
Product: Fc1cncc(Br)c1C1CC1
Temperature: 25 °C

Procedure:
A mixture of the crude phenyl 3-bromo-4-cyclopropyl-5-fluoropyridine-1 (4H)-carboxylate (1.14 g, 0.0034 mol) and sulphur (0.108 g, 0.0034 mol) were heated at reflux in DECALIN (10 mL) for a period of 3 h, then cooled to room temperature. Purification by silica gel chromatography, eluting first with hexanes, then with a 2-5% ethyl acetate-hexane gradient, gave the title compound. MS (M+1): 217.1.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[Li]C(C)(C)C.[Sn:19](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:28]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[C:5]1[N:1]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)[N:2]=[N:3][CH:4]=1)[CH2:29][CH2:30][CH3:31]
Reactant: N#Cc1ccc(-n2ccnn2)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1-c1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
4-[1,2,3]Triazol-1-yl-benzonitrile (0.105 g, 0.6 mmol) and dry THF (6 ml) and a magnetic stirrer were placed in a flask. The flask was flushed with argon and kept under an inert atmosphere and cooled to −78° C. At this temperature, tert-BuLi (0.36 ml, 1.7M, 0.6 mmol) was added dropwise during 1 to 2 minutes. The mixture was stirred at this temperature for 15 minutes and Bu3SnCl (0.19 g, 0.6 mmol) was added during 1 minute, and the mixture was then allowed to slowly reach RT. The crude mixture was directly purified on silica (heptane:EtOAc 4:1) giving 0.12 g (43%) of the title stannane.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][CH3:10])=[S:8])[N:5]=[C:4]([N:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](OC(OCC)OCC)(=O)C>>[CH:12](=[N:11][C:4]1[N:3]=[C:2]2[N:1]=[CH:10][N:9]([CH3:19])[C:7](=[S:8])[N:6]2[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC(=S)n1nc(N=Cc2ccccc2)nc1N
Reactant: CCOC(OCC)OC(C)=O
Product: Cn1cnc2nc(N=Cc3ccccc3)nn2c1=S
Yield: 93 %

Procedure:
The synthesis method of Example 55 was applied. The compound (783 mg) obtained in Example 37 and diethoxymethyl acetate (5 ml) were used as reagents. The mixture was reacted at 90° C. for 1.5 hours to give 757 mg of white powdery crystals (yield 93%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)c1
Yield: 11.9 %

Procedure:
The title compound (0.012 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-methylbenzyl bromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.43 (m, 4H), 7.19 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 5.34 (s, 2H), 3.88 (s, 2H), 3.16-3.13 (m, 2H), 2.88-2.85 (m, 2H), 2.30 (s, 3H), 1.80-1.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[OH-:17].[K+].Cl>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: Cl
Agent: [K+]
Product: O=C(O)c1c[nH]c2cc(Cl)ccc12
Yield: 96 %

Procedure:
A solution of 21.6 g (87.2 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 110 ml of a 4 M aqueous solution of potassium hydroxide was heated at reflux for 2 h. After cooling to 0° C. neutralisation with 36.7 ml of a concentrated aqueous hydrochloric acid solution a white solid precipitated from the solution. The solid was collected by filtration and washed with water. Drying in high vacuo at 80° C. gave 16.4 g (96%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:48]1([CH2:54][CH2:55][O:56][C:57]2[C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[C:60]([NH2:67])=[CH:59][CH:58]=2)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>CN(C)C=O.O>[C:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:67][C:60]1[C:61]2[C:66](=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:57]([O:56][CH2:55][CH2:54][N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)=[CH:58][CH:59]=1)=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Oc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.2 %

Procedure:
To a solution of 3-tert-butoxy-benzoic acid (0.15 g, 0.774 mmol) in dimethylformamide (5 ml) is added HBTU (0.44 g, 1.5 eq) followed by the addition of diisopropylethylamine (0.296 ml, 3.0 eq). The mixture is stirred at room temperature for five minutes. A solution of 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine (0.21 g) in dimethylformamide (2 ml) is then added. This mixture is stirred at room temperature for 15 h, diluted with water and extracted with ethyl acetate. The organic layer is washed with water, dried over Na2SO4 and evaporated. The residue is purified by column chromatography on silica gel (ethyl acetate) to give 3-tert-butoxy-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide (0.146 g). Mp: 50-51° C. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.22 (m, 1H), 7.85 (m, 2H), 7.66 (s, 1H), 7.55 (m, 2H), 7.23 (d, J=7.5 Hz, 1H), 7.03 (d, J=8.1Hz, 1H), 4.31 (t, J=5.1Hz, 2H), 3.61 (t, J=4.2 Hz, 4H), 2.89 (brs, 2H), 2.58 (brs, 4H), 1.35 (s, 9H). MS: 449 (M+1).
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]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]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]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)(=[O:34])=[O:35])[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)C1CCCCC1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)C1CCCCC1
Reaction time: 2 h
Yield: 90 %

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)cyclohexanesulfonamide (20 mg, 0.035 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 15 mg of the target compound, N-(3-(3-(9H-purin-6-yl)pyridin-2-ylamino)-2,4-difluorophenyl)cyclohexanesulfonamide (percentage yield: 90%), was obtained.
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:10]([F:13])([F:12])[F:11])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].O.[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH2:1]([O:5][CH:6]([C:10]([F:11])([F:12])[F:13])[C:7]([O:9][CH2:15][CH3:16])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(C(=O)O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCCCOC(C(=O)OCC)C(F)(F)F
Reaction time: 12 h
Yield: 750.2 %

Procedure:
A mixed solution of (+)-2-butoxy-3,3,3-trifluoropropionic acid (1.2 g) obtained in Example 6, ethanol (40 ml) and p-toluenesulfonic acid monohydrate (0.1 g) was heated with stirring for 12 hours, followed by distilling off the solvent under normal pressure, extracting the residue with ether, neutralizing, washing with water and concentrating to obtain (+)-ethyl 2-butoxy-3,3,3-trifluoropropionate (0.9 g). [α] +24.1 (cl. 06, CHCl3).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:6][C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1.[CH3:23][NH:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:7]2[O:6][C:5]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:3]=2[CH2:2][N:24]([CH3:23])[C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[N:10][CH:11]=1
Reactant: Fc1ccc(-c2nc(CBr)c(Sc3ccc(Cl)cn3)o2)cc1
Reactant: CNc1ccc(C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)Cc2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cc1

Procedure:
A solution of 2-{[4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazol-5-yl]sulfanyl}-5-chloropyridine (intermediate B3.1, 0.03 g, 0.075 mmol), methyl 4-methylaminobenzoate (0.013 g, 0.08 mmol) and K2CO3 (0.03 g, 0.225 mmol) in DMF was heated at 65° C. for 2 hr, filtered and purified by reverse phase HPLC to give methyl 4-[({5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methyl)(methyl)amino]benzoate. 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=2.5 Hz, 1H), 8.03 (m, 2H), 7.72 (d, J=9.2 Hz, 2H), 7.34 (dd, J=8.4, 2.5 Hz, 1H), 7.13 (m, 2H), 6.70 (m, 3H), 4.62 (s, 2H), 3.84 (s, 3H), 3.17 (s, 3H); HRMS exact mass calc for C24H19ClFN3O3S [M+H]+: 484.0892; observed: 484.0890.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O[C:21]([C:23]1[C:24]2[CH2:32][CH2:31][CH2:30][CH2:29][C:25]=2[S:26][C:27]=1[NH2:28])=[O:22])C.[CH2:33]([O:35][C:36](=[O:43])[CH:37]=[C:38](OCC)[CH3:39])[CH3:34].[O-]CC.[Na+]>C1(C)C=CC=CC=1.C(O)C>[OH:22][C:21]1[C:37]([C:36]([O:35][CH2:33][CH3:34])=[O:43])=[C:38]([CH3:39])[N:28]=[C:27]2[S:26][C:25]3[CH2:29][CH2:30][CH2:31][CH2:32][C:24]=3[C:23]=12
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: CCOC(=O)C=C(C)OCC
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1O)CCCC3
Temperature: 40 °C
Yield: 64 %

Procedure:
In a 10 L reaction vessel, pyridinium p-toluenesulfonic acid (39.7 g, 158 mMol) was added to a stirred solution of ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Preparation 1) and ethyl-3-ethoxybut-2-eneoate (Preparation 2) in toluene (6.0 L) at room temperature under argon. The resulting mixture was heated to reflux, and stirred at reflux for 6 hours. The mixture was cooled 40° C. and stirred at 40° C. for 16 hours. The mixture was heated to 50° C. (to dissolve the precipitate) and the solution was run out of the reaction vessel. The reaction vessel was charged with 21% (w/w) sodium ethoxide in ethanol (1.1 L, 3.48 Mol) and ethanol (2.0 L), and the resulting mixture was heated to 50° C. The reaction mixture was then poured back into the reaction vessel over 5 minutes. The resulting mixture was heated to reflux and stirred at reflux for 2 hours. The mixture was cooled to 30° C. and split into 2 approximately equal batches. Each batch was treated with Celite® (approx. 2 L) and concentrated under reduced pressure. The resulting solids were suspended in water (2.0 L, 40° C.) and stirred vigorously until all solids were free flowing. The solids were collected by filtration through a pad of Celite®, and the filter-cake was washed with water (2.5 L, 40° C.). The filtrate was washed with diethylether (2×1.3 L) and then cooled to 15° C. 6 M hydrochloric acid was added carefully until pH 4 was achieved. The resulting precipitate was collected by filtration and the filter-cake was washed with dilute hydrochloric acid (500 mL). The filter-cake was dried in a drying oven, at 50° C. for 2 days. This gave the title compound as a yellow solid (584 g, 64%).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+:18].O>CC(O)C>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O-:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Li+:18]
Reactant: O=P(O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=P([O-])(c1ccccc1)c1ccccc1

Procedure:
To a flask were added 1.0 g diphenylphosphinic acid, 182 mg lithium hydroxide monohydrate, 10 ml of water and 30 ml 2-propanol. The mixture was heated to 70 C under nitrogen until a clear solution was obtained. The mixture was cooled and the solvent was removed under reduced pressure and the product was slurried in a small amount of 2-propanol, filtered and washed with 2-propanol. After drying, a white solid was obtained.