Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C=CCCCC.C(=O)([O-])[O-:10].[Na+].[Na+].[F:15][C:16]([F:42])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40]#[N:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]>CO>[F:42][C:16]([F:15])([O:20][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][N:37]=[C:36]([C:40](=[O:10])[NH2:41])[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:24]=[CH:25][CH:26]=1)[CH:17]([F:19])[F:18]
Reactant: N#Cc1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C=CCCCC
Product: NC(=O)c1cc(-c2ccnc(Nc3cccc(OC(F)(F)C(F)F)c3)n2)ccn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
0.58 ml of hydrogen peroxide (30%), 0.16 ml of 1-hexene, 11 mg of sodium carbonate and 2 ml of methanol are added to 50 mg (0.12 mmol) of N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-cyano-4-pyridyl)-2-pyrimidineamine and the reaction mixture is stirred for 14 h at RT. The product is isolated by filtration, washed with methanol/water (9:1) and dried to give N-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-4-(2-carbamoyl-4-pyridyl)-2-pyrimidineamine; m.p. 224°-225°, FAB-MS: 408 (M+ +H), 290.
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccc(F)cc2)CC1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 18 h

Procedure:
Chlorotrimethylsilane (0.122 ml) and water (9 μl) were added to a solution of the more polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-fluoro-phenyl)-acetamide (310 mg, 0.9 mmol) in ethyl methyl ketone (2 ml). After 18 h it was possible to isolate the hydrochloride as a solid in a yield of 64% (220 mg; 0.6 mmol) (Example 58).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1>[Pd].CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(N)c2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cccc(N)c2)c1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
Into the reaction flask was added tert-butyl {5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbamate (0.50 g, 1.6 mmol), 50 mL of methanol and 10% palladium on carbon (100 mg, 0.094 mmol). The mixture was hydrogenated at 50 psi for 3 h. The reaction mixture was filtered to remove the catalyst and then concentrated under vacuum to give the desired product as an off-white powder (0.50 g, 99%). LCMS for C18H24N3O2 (M+H)+: m/z=314.1.
Reaction SMILES: [CH2:1]([Si:9]([O:14]C)([O:12]C)[O:10]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>C(O)(=O)C>[CH2:1]([Si:9]([OH:14])([OH:10])[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCC[Si](OC)(OC)OC
Solvent: CC(=O)O
Product: C=CCCCCCC[Si](O)(O)O

Procedure:
By changing the reaction condition, 1,3-di(7-octenyl)disiloxane-1,1,3,3-tetraol, a dimer of the octenylsilanetriol, can be synthesized as main product. 0.60 g (yield: 78%) of 1,3-di(7-octenyl)disiloxane-1,1,3,3-tetraol was obtained in the same manner by adding 1 mL of a 3 wt % acetic acid aqueous solution and 1.0 g of 7-octenyltrimethoxysilane and carrying out reaction. The structure of the product was identified by NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:29][CH2:28][CH2:27][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:6]([CH:7]=2)=[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]2=[N:3][C:2]=3[NH2:1])=[CH:19][CH:18]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)cc12

Procedure:
2-(4-(2-(Tert-butyldimethylsilyloxy)ethoxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 139, but using (2-bromoethoxy)(tert-butyl)dimethylsilane.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.Cl.[N:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>>[N:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([N:2]3[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]4[CH2:7][CH:1]3[CH2:6][CH2:5]4)(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Agent: Cl
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(Oc2ccncc2)cc1

Procedure:
Ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 1 (b) is subjected to a reaction similar to the reaction (c) of Example 1 using [4-(4-pyridyloxy)phenyl]sulfonyl chloride hydrochloride in place of 4-methoxybenzenesulfonyl chloride, to give ethyl 2-{[4-(4-pyridyloxy)phenyl]sulfonyl}-2-azabicyclo[2.2.1]heptane-3-carboxylate.
Reaction SMILES: C(O)[C@H]1[O:7][C@H](O[C@@H]([C@H](O)[C@@H](O)CO)[C@H](O)CO)[C@H](O)[C@@H](O)[C@@H]1O.[OH-].[K+].[CH2:26]([O:30][C:31]1[CH:44]=[CH:43][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:36])=[CH:33][CH:32]=1)[CH:27]1[O:29][CH2:28]1.Cl(O)(=O)=O>CS(C)=O.C(O)C.O>[C:35]([C:34]1[CH:43]=[CH:44][C:31]([O:30][CH2:26][CH:27]([CH2:28][OH:7])[OH:29])=[CH:32][CH:33]=1)(=[O:36])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OC[C@@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)[C@@H](O)CO
Reactant: O=C(c1ccccc1)c1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [O-][Cl+2]([O-])O
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(OCC(O)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
Then, 2.921 g of maltitol and 476.0 mg of potassium hydroxide were dissolved in 20 ml of dimethylsulfoxide, and the mixture was stirred under flow of nitrogen for 30 minutes. A solution obtained by dissolving 719 mg of the resultant 4-glycidyloxy benzophenone dissolved in 1 ml of dimethylsulfoxide was dripped to it. Furthermore, heating and agitation was continued for 1 hour under flow of nitrogen, and the reaction system was cooled to the room temperature and neutralize with chloric acid. The reaction system was fractionated according to the column chromatography using the hyperporous polymer (Hiporous resin supplied from Mitsubishi Kasei Kogyo Kabushiki Kaisha) at first as a developing solvent with purified water, and then a mixture of ethyl alcohol and purified water with the mixing ratio of 1:1, and effluent fraction in which the mixing ratio of ethyl alcohol and purified water was 1:1 was condensed to obtained 500 mg of 1-(4-benzoylphenyl) glycerol maltitolether (Yield: 30%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[O:4][NH:3]1.[CH3:17][O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N=C=NCCCN(C)C)C.CO>ClCCl.CN(C)C=O.C(#N)C>[CH3:1][CH:2]1[CH:7]=[C:6]([CH3:8])[CH:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[O:4][N:3]1[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1
Reactant: COc1ccc(C2ONC(C)C=C2C)cc1
Reactant: COc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(=O)N2OC(c3ccc(OC)cc3)C(C)=CC2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.75 ml of a 0.05M solution of 3,5-dimethyl-6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine in dichloromethane, 0.5 ml of a 0.05M solution of 4-methoxybenzoic acid in dimethylformamide, and 0.5 ml of a 0.075M solution of N-ethyl-N′-dimethylaminopropyl-carbodiimide hydrochloroide in acetonitrile was stirred at ambient temperature for 18 h. Methanol (1 ml) was added with stirring and the mixture applied to a methanol washed 500 mg Isolute SCX cartridge (Jones Chromatography). The absorbent was then washed with methanol (2.5 ml) and the combined run through and washing concentrated to dryness using a centrifugal evaporator. The residue was dissolved in ethyl acetate (0.5 ml) and applied to a 100 mg Isolute SI cartridge (Jones Chromatography). Elution with ethyl acetate (2 ml) followed by removal of the solvent by centrifugal evaporation gave 3,5-dimethyl-2-(4-methoxybenzoyl)-6-(4-methoxyphenyl)-3,6-dihydro-2H-1,2-oxazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:27][CH2:26][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Br:23])[C:20]([F:24])=[C:19]([Br:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C

Procedure:
N-[[2-chloro-4-[5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl]methyl]phthalimide (0.75 g) in ethanol (10 mL) was added hydrazine monohydrate (1.07 g). The mixture was heated to reflux for 1 hour and then cooled to room temperature. The resulting mixture was filtered and concentrated under reduced pressure. The residue was dissolved in chloroform (10 mL) and filtered, and the filtrate was washed with water (10 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with methanol-ethyl:acetate (1:9) to afford the title compound as a pale yellow resin (0.51 g).
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.II>CO>[F:23][C:22]([F:24])([F:25])[C:19]1[CH:18]=[CH:17][C:16]([N:15]=[C:3]2[CH:4]=[C:5]3[C:14](=[N:13][C:12]4[C:7]([S:6]3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:1]=[CH:2]2)=[CH:21][CH:20]=1
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: II
Solvent: CO
Product: FC(F)(F)c1ccc(N=c2ccc3nc4ccccc4sc-3c2)cc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
Phenothiazine (2.0 g, 10 mmole) and 4-aminobenzotrifluoride (1.77 g, 11 mmole) were dissolved in methanol (MeOH) (100 mL) with warming to 45° C., treated with a solution of I2 (5.0 g, 19.4 mmole) in MeOH (80 mL) in one portion and allowed to stir for 3 h at 45° C. The reaction mixture was filtered and the collected solid was washed with MeOH (100 mL). The solid was dissolved in CHCl3 (60 mL) containing triethylamine (NEt3) (6 mL) then this solution was diluted with hexane (200 mL) and chilled in an ice bath for 2 h. The purple solid that separated was collected by filtration and redissolved in CHCl3 /NEt3 (10:1, v:v) (50 mL) and chromatographed on silica gel (250 g) using CHCl3 /acetone (96:4, v:v) development. The purple product band was collected and evaporated to dryness in vacuo to afford 4 (0.26 g, 7.3%) with mp=207°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([NH:8][C:4]1[C:3]([N+:9]([O-:11])=[O:10])=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)(=[O:14])[CH3:13]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1nccc(Cl)c1[N+](=O)[O-]

Procedure:
When 10.0 g. of 4-chloro-2-amino-3-nitropyridine, from Example I-5, and 20 ml of acetic anhydride are heated under reflux for 1 hour and then concentrated, there is obtained 2-acetamido-4-chloro-3-nitropyridine, and, this, heated at 300° C. and treated with chlorine gives 2-acetamido-4,5-dichloro-3-nitropyridine. The latter by the procedure of Example I-2 gives 2-amino-4,5-dichloro-3-pyridinol.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCOC(C)=O.CCCCCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]1([C:25]#[C:26][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C(#Cc1ccc2ccccc2n1)c1ccccc1
Reaction time: 0.08 h

Procedure:
After 2-chloroquinoline (29.7 mg, 0.182 mmole) was dissolved in THF (1.5 mL), PdCl2(PPh3)2 (2.6 mg, 0.0037 mmole), and CuI (1.5 mg, 0.0063 mmol) were added thereto and stirred for 5 min under nitrogen atmosphere. To the resulting mixture triethylamine (0.15 mL) and phenylacetylene (0.03 mL, 0.273 mmol) were successively added, followed by stirring at 80° C. for 24 hr after sealing. The completion of the reaction was confirmed by TLC (EtOAc/Hexane=1:10). When the reaction was completed, the reactant was filtered through Celite and extracted with a mixture of EtOAc and H2O, to thereby separate an organic layer. The organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography (EtOAc/Hexane=1:10, R.f: 0.35), to thereby obtain 2-(phenylethynyl)quinoline (24.9 mg, 60%) as a brown solid.
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[C:22]([CH2:28]O)[CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:44]1([CH2:50][CH2:51][CH2:52][NH2:53])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[O:1]([CH2:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[CH2:26][N:53]([CH2:52][CH2:51][CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:28]2)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](OCc1ccc(CO)c(CO)c1)(c1ccccc1)c1ccccc1
Reactant: NCCCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)[Si](OCc1ccc2c(c1)CN(CCCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.867 g (14.429 mM) of [4-(tert-butyldiphenylsiloxymethyl)-2-hydroxymethylphenyl]methanol and 12.6 ml (72.1 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was added a solution of 3.47 g (30.3 mM) of methanesulfonyl chloride in 10 ml of acetonitrile dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. To this reaction mixture was added 2.15 g (15.9 mM) of 3-phenylpropylamine and the mixture was stirred at 80° C. overnight. The solvent was then distilled off under reduced pressure and the residue was diluted with aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CCOCC.O>[C:8]1([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=3)[N:7]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nccc(-c2ccccc2)n1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(O)Cc1ccc(Nc2nccc(-c3ccccc3)n2)cc1
Temperature: 160 °C
Yield: 77 %

Procedure:
A mixture of 2-chloro-4-phenylpyrimidine (0.19 g, 1.0 mmol), 2-(4-aminophenyl)acetic acid (0.38 g, 2.5 mmol), diisopropylethylamine (0.38 mL, 2.0 mmol), THF (3.0 mL) and water (1.0 mL) was placed in a seal tube and heated up to 160° C. in a microwave (Biotage, Model: Initiator) for 10 h. The reaction mixture was diluted with ether and washed with brine. The organic layer was separated, dried (MgSO4), and concentrated to afford 2-(4-(4-phenylpyrimidin-2-ylamino)phenyl)acetic acid in 77% yield. MS (ESI) 306 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:16]2[C@H:12]([O:13]C(C)(C)[O:15]2)[C@@H:11]([CH2:19][O:20]C(C)(C)C)[C:10]1=[CH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C:10](=[CH2:25])[C@H:11]([CH2:19][OH:20])[C@H:12]([OH:13])[C@@H:16]1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1[C@H](COC(C)(C)C)[C@H]2OC(C)(C)O[C@H]2[C@H]1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C1[C@H](CO)[C@H](O)[C@H](O)[C@H]1OCc1ccccc1
Yield: 86.1 %

Procedure:
Compound 4 (450 mg, 1.3 mmol) was dissolved in MeOH and treated with 3 N HCl at refluxed temperature for 3.5 h. After neutralized with solid NaHCO3, the solvent was removed and the residue was purified by vacuum silica gel column chromatography (MeOH:CH2Cl2=1:30 to 1:10) to give triol 5 (280 mg, 85%) as a white solid. mp 122-124° C.; [α]24D −123.05° (c 0.37, MeOH); 1H NMR (500 MHz, CD3OD) δ 7.46-7.30 (m, 5H), 5.34 (dd, J=1.0 and 3.0 Hz, 1H), 5.21 (s, 1H), 4.77 (d, J=12.0 Hz, 1H), 4.62 (d, J=12.5 Hz, 1H), 4.17-4.14 (m, 2H), 3.95-3.93 (m, 1H), 3.82-3.73 (m, 2H), 2.69-2.66 (m, 1H); 13C NMR (125 MHz, CD3OD) δ 148.9, 138.3, 128.0, 127.6, 127.3, 109.1, 80.8, 71.7, 71.0, 70.8, 61.8, 49.6; HR-MS Calcd. for (C14H18O4+H)+251.1283, found 251.1281.
Reaction SMILES: OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrCCCCCCBr.C([O-])([O-])=O.[K+].[K+].[N+]([C:35]1[CH:36]=[C:37]([C:43]#[N:44])[C:38](=[CH:41][CH:42]=1)[C:39]#[N:40])([O-])=O.Cl>O.CS(C)=O>[C:43](#[N:44])[C:37]1[C:38](=[CH:41][CH:42]=[CH:35][CH:36]=1)[C:39]#[N:40]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: BrCCCCCCBr
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1C#N
Temperature: 90 °C

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer and a nitrogen inlet were added bisphenol A (100 g, 0.298 mol), 1,6-dibromohexane (53.4 g, 0.219 mol), powdered anhydrous K2CO3 (150 g, 1.09 mol), and dimethylsulfoxide (DMSO) (1000 mL). The resulting mixture was degassed with nitrogen at ambient temperature and heated at 90° C. under a nitrogen atmosphere for 8-16 hr. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (77.6 g, 0.449 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 hr. The mixture was allowed to cool to ambient temperature and poured into 1000 mL of distilled water. The mixture was made acidic by the addition of 6 M aqueous HCl and the resin was extracted out of the water layer by toluene (200 mL). The toluene extracts were washed 3 times with 500 mL of distilled water and dried using magnesium sulfate. Removal of the toluene resulted in an amber oil, which was dried at 80° C. under vacuum. The 2:1 oligomeric phthalonitrile was isolated as an amber glassy solid (165 g, 95%). 1H-NMR [CDCl3]: λ 7.70 (m, aromatic-HR), 7.31 (m, aromatic-HR), 7.11 (m, aromatic-HR), 7.00 (m, aromatic-HR), 6.80 (m, aromatic-HR), 3.92 (m, aliphatic-HR), 1.78 (m, aliphatic-HR), 1.73 (s, aliphatic-HR), 1.67 (s, aliphatic-HR), 1.61 (s, aliphatic-HR), 1.50 (m, aliphatic-HR).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12](I)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1.[NH2:20][C:21]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=1[C:23]([NH:25][CH3:26])=[O:24]>>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[CH:13]=[C:12]([NH:20][C:21]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:22]=3[C:23]([NH:25][CH3:26])=[O:24])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)=[CH:5][C:4]([CH3:19])=[N:3]1
Reactant: CNC(=O)c1ccc(F)cc1N
Reactant: Cc1cc(Nc2cc(I)c(C(F)(F)F)cn2)n(C)n1
Product: CNC(=O)c1ccc(F)cc1Nc1cc(Nc2cc(C)nn2C)ncc1C(F)(F)F

Procedure:
This compound was prepared from N-(1,3-dimethylpyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine and 2-amino-4-fluoro-N-methylbenzamide. 54 mg, 33%; triturated in tBuOMe; NMR Spectrum: (DMSOd6) 2.08 (s, 3H), 2.76 (d, 3H), 3.55 (s, 3H), 6.04 (s, 1H), 6.76 (s, 1H), 6.95 (ddd, 1H), 7.39 (dd, 1H), 7.79 (dd, 1H), 8.27 (s, 1H), 8.69 (q, 1H), 9.06 (s, 1H), 10.65 (s, 1H); Mass spectrum: MH+ 423.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)=[N:7][C:8]=1[O:9][CH3:10].O[Li].O.Cl>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)n4)c4ncsc4n3)C2)cc1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nc3scnc23)nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
To a stirred solution of methyl 4-(1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoate (350 mg, 0.65 mmol) in 20 mL of methanol and 40 mL of THF was added a solution of LiOH.H2O (274 mg, 6.5 mmol) in one portion at room temperature. Then the solution was stirred at room temperature for 24 hours. The solution was acidified with 1N HCl to pH=4. The solvent was evaporated and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (70 mg, 20.5%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 8.87-8.18 (m, 2H), 8.67 (s, 1H), 8.03-7.96 (m, 5H), 7.44 (d, 1H, J=8.7 Hz), 4.66 (brs, 1H), 4.11 (brs, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.68 (brs, 2H), 2.27 (brs, 1H), 2.08 (brs, 1H). LC-MS: 522 [M+H]+, tR=1.44 min. HPLC: 99.68% at 214 nm, 99.31% at 254 nm, tR=6.98 min.