Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9](O)[CH2:8]2)[CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@H:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([N:18]3[C:17](=[O:19])[C:16]4=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]4[C:14]3=[O:24])[CH2:8]2)[CH:2]=1
Reactant: O[C@H]1CCC[C@@H](c2cccnc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CCC[C@H](c2cccnc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of cis-3-(3-pyridyl)cyclohexanol (5.00 g, 28.2 mmol) in THF (100 mL) was cooled to 4° C. and treated with phthalimide (4.56 g, 31.0 mmol), Diisopropylazodicarboxylate (6.10 mL, 31.0 mmol) and triphenylphosphine (8.13 g, 31.0 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and washed with H2O and brine. The organic layers was dried over Na2SO4. After concentration under reduced pressure, the residue was purified by column chromatography (Hexane/EtOAc=4/1) to yield trans-N-[3-(3-pyridyl)cyclohexyl]phthalimide (5.18 g, 60%) as colorless powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][C:43](O)=[O:44])[CH:37]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:43](=[O:44])[CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: O=C(O)Cc1cccnc1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(=O)Cc4cccnc4)CC3)cc2C2=CCCCC2)n1

Procedure:
The title compound was prepared from 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (as prepared in Example 14, step (b)), according to the procedure in Example 29 using pyridin-3-yl-acetic acid. 1H-NMR (400 MHz, CD3OD): δ 8.80 (m, 2H), 8.54 (d, 1H), 8.10 (d, 1H), 8.06 (t, 1H), 7.98 (s, 1H), 7.18 (dd, 1H), 7.08 (d, 1H), 5.78 (m, 1H), 4.68 (m, 1H), 4.20 (m, 1H), 4.18 (s, 2H), 3.36 (m, 1H), 2.84 (m, 2H), 2.28 (m, 4H), 2.06-1.70 (m, 7H), 1.62 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C29H30N6O2, 495.2 (M+H). found 495.2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4](O)=O.ClCCCl.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[F:1][C:2]1[CH:10]=[C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH:17]=[CH2:18])[CH2:13][CH2:12]2)[CH:8]=[C:7]([F:19])[C:3]=1[C:4]#[N:28]
Reactant: c1ccncc1
Reactant: C=C[C@H]1CC[C@H](c2cc(F)c(C(=O)O)c(F)c2)CC1
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: C=C[C@H]1CC[C@H](c2cc(F)c(C#N)c(F)c2)CC1
Temperature: 25 °C

Procedure:
To 20 g of 2,6-difluoro-4-(trans-4-vinylcyclohexyl) benzoic acid were then added 120 ml of 1,2-dichloroethane, 16 g of thionyl chloride and few drops of pyridine. The reaction mixture was then heated under reflux for 6 hours. The reaction mixture was then allowed to cool to room temperature. The solvents and excess thionyl chloride were distilled off under reduced pressure. To the residue was then added 150 ml of dichloromethane. The residue solution was then cooled to a temperature of 10° C. or lower. Ammonia was then introduced into the solution with stirring at a rate such that the liquid temperature was kept at 20° C. or lower. When heat generation was terminated, the solvents were then distilled off under reduced pressure. To the residue was then added 150 ml of N,N-dimethylformamide. The residue solution was then cooled to a temperature of 10° C. or lower. To the solution was then added dropwise 26.5 g of phosphorus oxychloride at a rate such that the liquid temperature was kept at 10° C. or lower. The temperature of the reaction solution was then returned to room temperature. The solution was then poured onto crushed ice. The resulting crystal was then filtered. The crystal thus obtained was washed with water, and then dried under reduced pressure. The crystal was then purified through silica gel column chromatography (solvent: toluene) to obtain 2,6-difluoro-4-(trans-4-vinylcyclohexyl)benzonitrile. The product was then recrystallized from ethanol to obtain 12.1 g of a purified product. The compound thus obtained had a melting point of 39° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[O:32].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccccn1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (300 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (100 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (25 mg) and triethylamine (52 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (220 mg, yield 56%) was obtained as a brown oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 456 (MH+).
Reaction SMILES: OC1C=CC=C2C=1N=CC=C2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([C:31](O)=O)[CH:27]=[CH:26]2.O=O>C1(C)C=CC=CC=1>[S:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=2)[N:29]=1
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Reactant: Nc1ccccc1S
Agent: O=O
Agent: Oc1cccc2cccnc12
Solvent: Cc1ccccc1
Product: Oc1cccc2ccc(-c3nc4ccccc4s3)nc12
Temperature: 40 °C

Procedure:
To introduce a benzo[d]thiazol group into an 8-hydroxyquinoline compound, 2-aminothiophenol (123 mg, 1.1 mmol) and 8-hydroxyquinoline-2-carboxylic acid (189 mg, 2 mmol) were dissolved in dry toluene (30 ml) with blown nitrogen to prevent oxidation which is caused by oxygen in air. The solution was heated to 40° C. and phosphrous trichloride (0.1 ml, 1.1 mmol) was slowly added thereto. Then, the reaction solution was heated at 100° C. for 24 hours and allowed to cool. The reaction mixture was extracted with a 20% aqueous sodium carbonate solution, distilled water and dichloromethane, dried and recrystallized with dichloromethane and hexane to yield 2-(benzo[d]thiazol-2-yl)quinolin-8-ol, the compound of Formula 1 as a light green solid (yield: 75%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=[O:5])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:37]([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>C1COCC1.CN(C=O)C>[CH2:20]([O:19][P:4]([O:3][CH2:1][CH3:2])([CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[C:7]([NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:49])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:9])=[O:5])[CH3:21]
Reactant: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(Cc1ccc(OC)cc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
The product of stage (b) was dissolved in THF (20 ml), cooled to -25° C. and with stirring NMM (1.28 g) and then isobutylchloroformate (1.65 g) successively added. After two minutes, a precooled solution of leucine tert-butyl ester (2.15 g) in DMF (5 ml) was added and the mixture stirred at -15° C. for 2 hr. The temperature was raised to 0° C. and stirring continued for 0.5 hr after the addition of 2 M KHCO3 (14 ml). The product was evaporated in vacuo, the residue suspended in ethyl acetate and succesively washed with 5% citric acid, 10% NaHCO3 and brine, dried (MgSO4) and concentrated to a white solid, m.p. 80°-87° (dec). The structure was confirmed by NMR and the product was used in the next stage without further purification.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23](S(C)(=O)=O)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:37])[N:22]([CH3:36])[C:23]([O:12][CH2:11][CH2:10][CH2:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:18][CH:19]=1
Reactant: Cn1c(S(C)(=O)=O)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(OCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Temperature: 60 °C

Procedure:
Sodium hydride (60% oily suspension, 111 mg, 2.79 mmol) was added to a stirred solution of 3-phenylpropanol (387mg, 2.85 mmol) in tetrahydrofuran (1 ml). After gas evolution ceased, 5-(4-fluorophenyl)-3-methyl-2-methylsulfonyl-6-(4-pyridyl)-4(3H)-pyrimidinone (100 mg, 0.279 mmol) was added and the mixture was heated at 60° C. for 30 min. The reaction mixture was partitioned between dichloromethane and water. The organic solution was washed with brine, dried and evaporated. Column chromatography on silica gel (hexane-ethyl acetate=2:1) provided the title compound. MS (m/z): 416.1 (M+H)+; C25H22FN3O2 requir. 415.5.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[C:25]([CH:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[O:28]1)=[O:26]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[O:28][CH:27]([C:25]([N:24]([CH3:46])[CH3:23])=[O:26])[CH2:36][CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)C(=O)C1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 7 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide. LCMS (M+H)+=528.0/530.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.77 (s, 1H), 7.87 (s, 1H), 7.85 (d, J=9.1 Hz, 1H), 7.06 (s, 1H), 6.95 (d, J=9.1 Hz, 1H), 5.19-5.14 (m, 1H), 3.99 (s, 6H), 3.12 (s, 3H), 2.89 (s, 3H), 2.15-1.95 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].P(Cl)(Cl)([Cl:27])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:27])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1c(Oc2ccc(Cl)cc2)c(Cl)nc2ccc(Br)cc12
Temperature: 120 °C

Procedure:
To a suspension of 6-bromo-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinolin-2(1H)-one (1.08 g, 2.58 mmol, Intermediate 7, step c) in phosphoryl trichloride (7.2 mL, 77.3 mmol) was added diisopropylethylamine (1.33 mL, 7.74 mmol). The resulting mixture was heated at 120° C. for 8 hours. The solution was concentrated in vacuo at room temperature and the resulting residue was cooled to 0° C. with an ice bath. To the cold residue was added ice in small portions to quench excess phosphoryl trichloride. After cessation of bubbling, the solid suspension was diluted with dichloromethane. The organic phase was separated out, dried (MgSO4), filtered and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.[OH-].[Na+]>O>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. The diamine intermediate is air sensitive so care was taken to avoid exposure to air. 500 g (2.56 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added to the reaction mixture over a period of about 30 minutes. The reaction was stirred at 45-55° C. (internal temperature) under N2 until the diamine was completely consumed as determined by HPLC. The typical reaction time was about 2 hours. After the reaction was complete, the reaction was filtered while warm through a pad of Celite. The reaction flask and Celite were then washed with 200 proof EtOH (3×285 mL). The filtrates were combined in a 5000 mL flask, and about 3300 mL of ethanol was removed under vacuum producing an orange oil. Water (530 mL) and then 1M HCL (350 mL) were added to the resulting oil, and the resulting mixture was stirred. The resulting solution was vigorously stirred while 30% NaOH (200 mL) was added over a period of about 20 minutes maintaining the internal temperature at about 25-30° C. while the pH was brought to between 9 and 10. The resulting suspension was stirred for about 4 hours while maintaining the internal temperature at about 20-25° C. The resulting mixture was filtered, and the filter cake was washed with H2O (3×300 mL). The collected solid was dried to a constant weight at 50° C. under vacuum in a vacuum oven providing 345.9 g (90.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder. In an alternative work up procedure, the filtrates were combined and the ethanol was removed under vacuum until at least about 90% had been removed. Water at a neutral pH was then added to the resulting oil, and the solution was cooled to about 0° C. An aqueous 20% NaOH solution was then added slowly with rapid stirring to bring the pH up to 9.2 (read with pH meter). The resulting mixture was then filtered and dried as described above. The alternative work up procedure provided the light tan to light yellow product in yields as high as 97%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(O)c1cc(O)cc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a stirred solution of 3-hydroxy-1-naphthalenecarboxylic acid (6.67 g, 35.4 mmol) and oxalyl chloride (3.86 mL, 44.2 mmol) in DCM (150 mL) was added 3 drops of DMF. The mixture was stirred at room temperature for 3 h., the solvent was removed under reduced pressure and methanol (150 mL) was added. After stirring at reflux for 15 min the solvent was removed under reduced pressure, the residue was purified by column chromatography (10%, 20% and 30% EtOAc/hexane) to give the title compound as a yellow solid (2.5 g, 35%). 1H NMR (DMSO-d6) δ 10.10 (s, 1H), 8.61 (d, 1H), 7.77 (d, 1H), 7.72 (d, 1H), 7.47 (m, 2H), 7.38 (d, 1H), 3.93 (s, 3H); MS m/z 201.1 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][OH:31])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][O:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]2[N:23]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][O:31][S:33]([CH3:32])(=[O:35])=[O:34])=[N:28][CH:29]=3)[O:21][N:20]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(CO)nc3)n2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(COS(C)(=O)=O)nc3)n2)n1
Reaction time: 3 h

Procedure:
To a solution of [5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-methanol (Intermediate 130, 185 mg, 0.44 mmol) in DCM (40 mL) was added methanesulfonyl chloride (48 μL, 0.61 mmol) drop-wise, followed by triethylamine (92 μL, 0.66 mmol). The resulting solution was stirred for 3 h under an inert atmosphere. Incomplete reaction was observed so additional methanesulfonyl chloride (9 μL, 0.10 mmol) and triethylamine (16 μL, 0.11 mmol) were added and stirring was continued for 1 h. The reaction mixture was washed with water (2×50 mL) and the organic phase dried over magnesium sulfate and evaporated to dryness to afford the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate. In a separate flask 2,2,2-trifluoro-ethanol (190 μL, 2.64 mmol) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil, 97 mg, 2.42 mmol) in anhydrous THF (30 mL) at 0 C under nitrogen. The resulting solution was stirred at 0 C for 30 min and then transferred via cannula to a solution of the methanesulfonic acid 5-(3-{4-amino-6-[(2-methoxy-ethyl)-phenyl-amino]-[1,3,5]triazin-2-yl}-[1,2,4]oxadiazol-5-yl)-pyridin-2-ylmethyl ester intermediate (220 mg, 0.44 mmol) in anhydrous THF (30 mL) at 0 C drop wise. The reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with a saturated ammonium chloride aq. solution (5 mL) and extracted with EtOAc (3×50 mL). Combined organics were washed with brine (25 mL), dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method C) to afford the title compound as an off-white solid (21 mg, 10%).
Reaction SMILES: ClC1C=[CH:5][S:4][C:3]=1C(OC)=O.[CH3:11][NH:12][C:13]1[S:14][C:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:17]=1.C(OCC)(=[O:26])C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClC(Cl)C.CCCCCC>[CH3:11][N:12]([C:13]1[S:14][C:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:17]=1)[C:5](=[O:26])[S:4][CH3:3]
Reactant: CCOC(C)=O
Reactant: CNc1nnc(-c2cccnc2)s1
Reactant: COC(=O)c1sccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 75 °C
Reaction time: 72 h
Yield: 83 %

Procedure:
4-Dimethylaminopyridine (81 mg, 0.66 mmol, 1.5 equiv) and methyl chlorothiolformate (50 μL, 0.57 mmol, 1.3 equiv) were sequentially added to a stirred suspension of N-methyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (85 mg, 0.44 mmol, 1.0 equiv) in dichloroethane (3.4 mL) at 23° C. The resulting solution was heated to 75° C. and stirred for 72 h. The cooled reaction mixture was directly subjected to silica gel column chromatography (55% ethyl acetate in hexane spiked with 5% triethylamine) to afford the title compound as an off-white powder (100 mg, 83%): mp 192-194° C.; IR (KBr thin film) 2931 (w), 1727 (w), 1634 (s), 1570 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ 9.13 (d, J=2 Hz, 1H), 8.70 (dd, J=5, 2 Hz, 1H), 8.28 (dt, J=8, 2 Hz, 1H), 7.43 (dd, J=8, 5 Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H); ESIMS m/z 267 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:25][O:26][C:27]1[CH:44]=[CH:43][C:30]([CH2:31][N:32]2[C:36]3=[N:37][CH:38]=[CH:39][C:40](Cl)=[C:35]3[C:34]([CH3:42])=[N:33]2)=[CH:29][CH:28]=1.CC([O-])(C)C.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[N:11]([CH3:23])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:40]1[CH:39]=[CH:38][N:37]=[C:36]2[N:32]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:44][CH:43]=3)[N:33]=[C:34]([CH3:42])[C:35]=12
Reactant: Cn1c(Nc2ccc(F)cc2)ncc(-c2ccc(O)c(F)c2)c1=O
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(Nc6ccc(F)cc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a mixture of 5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)-3-methylpyrimidin-4(3H)-one (25.2 mg, 0.077 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (20 mg, 0.070 mmol) dissolved in DMF (0.5 mL), added KOtBu (0.077 ml, 0.077 mmol) 1M solution in THF, and potassium carbonate (10.6 mg, 0.077 mmol). The mixture was stirred at 110° C. overnight. Cooled to room temperature and partitioned between EtOAc (15 mL) and water (20 mL). The organic layer was dried with brine, Na2SO4, and evaporated to afford 27 mg of crude product. Purified by silica gel column chromatography (Biotage 12M) eluting with 5% MeOH/EtOAc to afford desired product as white solid (4.6 mg, 11%). LRMS (APCI pos) m/e 581.2 (M+1).