Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:16]([OH:18])=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])[CH3:3].Cl.[CH2:20]([O:27][C:28](=[O:34])[C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@@H:9]([C:16]([N:30]1[CH2:31][CH2:32][CH2:33][C@H:29]1[C:28]([O:27][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:34])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.7 %

Procedure:
A solution of Boc-D-phenylglycine (15.0 g, 59.7 mmole) and proline benzyl ester hydrochloride (14.43 g, 59.7 mmole) in 60 ml of DMF was cooled to 0° C. and N,N-diisopropylethylamine (10.3 ml, 59.7 mmole) was added followed by 1-hydroxybenzotriazole hydrate (8.1 g, 59.7 mmole) and DCC (12.3 g, 59.7 mmole). The reaction mixture was stirred for 3 days at room temperature after which it was filtered and the filtrate was evaporated to an oil under vacuum. The oil was dissolved in 200 ml of ethyl acetate and 150 ml of water and after shaking the organic layer was separated, washed three times with 100 ml portions of 0.1N HCl, once with 150 ml of water, three times with 100 ml portion of 5% sodium bicarbonate and again with 150 ml of water. The washed organic solution was dried over MgSO4 and then was evaporated under vacuum to provide 24.8 g of Boc-D-Phg-Pro-OBzl as a solid (95% of theory): TLC Rf (A) 0.75; FAB-MS 439 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH:4]=[O:5].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:12]([O:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([CH:4]=[O:5])=[C:6]([CH3:11])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)cc(C)c1C=O
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Treat a solution of 2,6-Dimethyl-4-hydroxybenzaldehyde (4.0 g, 27 mmol) and benzyl bromide (3.3 mL, 28 mmol) in DMF (50 mL) with Potassium carbonate (4.5 g, 32 mmol). Heat the reaction to 60° C. and stir for 1 hr. Cool the reaction and quench with 1N aqueous HCl. Extract the aqueous with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Remove the solvent to afford 6.4 g (100%) of product. 1H NMR (d6-CDCl3) δ 10.46 (s, 1H), 7.31-7.43 (m, 5H), 6.65 (s, 2H), 5.08 (s, 2H), 2.58 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:17])=[CH:9][C:10]=3[F:16])[C:5](=O)[C:4]=2[CH:3]=1.[CH3:19][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[N:7][C:8]([Cl:17])=[CH:9][C:10]=3[F:16])[C:5](=[CH2:19])[C:4]=2[CH:3]=1
Reactant: C[Mg]Cl
Reactant: O=c1c2cc(Br)ccc2oc2c(F)cc(Cl)nc12
Solvent: C1CCOC1
Product: C=C1c2cc(Br)ccc2Oc2c(F)cc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-2-chloro-4-fluoro-10H-chromeno[3,2-b]pyridin-10-one (44 mg, 0.134 mmol) in 10 mL of dry THF was added dropwise methylmagnesium chloride (3M in THF, 0.12 mL, 0.335 mmol) in at −78° C. The reaction was slowly warmed up to 0° C. over 2 hours. The reaction was quenched at 0° C. with saturated NH4Cl (20 mL) and extracted with EtOAc (2×10 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to dryness. The derived tertiary alcohol was taken up in 10 mL of CH2Cl2 treated with 1 mg of PPTS. After stirring for 30 minutes the mixture was cooled to 0° C. and 0.1 g of NaHCO3 was added. The solvent was evaporated to dryness to give crude 8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine which was directly used in the next step. A solution of iodine (7.24 μL, 0.141 mmol) in THF at −25° C. was treated with silver cyanate (20.07 μL, 0.536 mmol). After stirring for 30 minutes, a solution of the derived olefin (8-bromo-2-chloro-4-fluoro-10-methylene-10H-chromeno[3,2-b]pyridine) in THF (10 mL) was added dropwise. The slurry was maintained at −25° C. for 2 h at which point the slurry was filtered through celite. The brown solution was concentrated to dryness, taken up in 10 mL THF, cooled to 0° C. and treated with ammonia (2M in 2-propanol (0.3 mL, 0.536 mmol). The reaction was allowed to slowly warm to rt and stirred overnight. The solvent was evaporated and the residue was purified by flash column (CH2Cl2 to CH2Cl2/EA=2:1 to 1:1 to CH2Cl2/MeOH=100:5) to give 8-bromo-2-chloro-4-fluoro-5′H-spiro[chromeno[3,2-b]pyridine-10,4′-oxazol]-2′-amine as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[ClH:23]>CO>[ClH:1].[ClH:23].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:21][CH3:22]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CO
Product: COc1cc(N2CCNCC2)ccc1Cl
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A 4-L beaker equipped with a mechanical stirrer was charged with tert-butyl 4-(4-chloro-3-methoxyphenyl)piperazine-1-carboxylate (500 g, 1.53 mol, 1 equiv) and MeOH (1.50 L). While stirring at room temperature conc. 37% HCl (500 mL, 4 equiv) was added over 5 min. The internal temperature rose to 40° C., and the solution became thick with precipitate. After 15 min, the mixture was heated to an internal temperature of 60° C. on a hotplate. (Foaming begun at approximately 50° C. as the mixture warms.) After 2 h at 60° C., the solution was cooled to room temperature, and subsequently to 5° C. in a refrigerator. The product was collected by filtration in two batches. Each batch of the red-brown filtrate was washed with EtOAc (2×500 mL) to give a light yellow solid. The two batches were combined to afford the product (391.3 g). The filtrate was concentrated to a volume of 300 mL in vacuo and treated with hot (50° C.) MeOH (500 mL). The mixture was cooled to 5° C. in a refrigerator for 24 h. The resulting precipitate was collected by filtration and washed with EtOAc (2×200 mL) to afford an additional 44.3 g of product (total of 435.6 g, 95% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][NH:11][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:13]([O:15]C)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH2:23]([O:25][C:26](=[O:29])[CH2:27][NH2:28])C.CC(O)=O.[BH3-]C#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[N:28]([CH2:27][C:26]([O:25][CH3:23])=[O:29])[C:13](=[O:15])[C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[NH:11][CH2:10]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCC(CC)(NCC(=O)c1cc(F)cc(F)c1)C(=O)OC
Reactant: CCOC(=O)CN
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CCC1(CC)NC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)OC)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of methyl 2-{[2-(3,5-difluorophenyl)-2-oxoethyl]amino}-2-ethylbutanoate from Step B (475 mg, 1.59 mmol) and glycine ethyl ester hydrochloride (332 mg, 2.38 mmol) in MeOH (5 mL) were added titanium(IV) isopropoxide (1.16 mL, 3.97 mmol) and AcOH (0.273 mL, 4.76 mmol). The resulting mixture was stirred at ambient temperature for 15 min, then NaCNBH3 (150 mg, 2.38 mmol) was added. The stirred reaction mixture was heated at 50° C. for 18 h, then at 70° C. for 24 h, and allowed to cool. The mixture was quenched with saturated aqueous NaHCO3 and then extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the racemic product. The enantiomers were separated by HPLC, using a Chiralcel OD column and eluting with hexane:EtOH—60:40. The first major peak to elute was methyl [(6S)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate and the second major peak to elute was methyl [(6R)-6-(3,5-difluorophenyl)-3,3-diethyl-2-oxopiperazin-1-yl]acetate, the title compound. MS: m/z=341 (M+1).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:11]=[CH2:12])[OH:10])([CH3:3])=[CH2:2].[BH4-].[Na+]>C(Cl)Cl.[OH-].[Na+]>[CH3:3][C:1]1[CH2:2][CH2:12][CH2:11][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: C=CC1(O)CCCCC1C(=C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC1=CCCCCC(=O)CCC1

Procedure:
A mixture of 2-isopropenyl-1-vinylcyclohexan-1-ol (0.166 g, 10-3 mol) and mercuric trifluoroacetate (0.423 g) in methylene chloride (10 cc) is kept at a temperature of the order of 20° C. After a reaction time of 5 minutes, a solution of sodium borohydride (0.010 g) in 3 N sodium hydroxide solution (0.66 cc) is added to the reaction mixture. The reaction mixture is extracted with methylene chloride (3×10 cc). The organic extracts are dried over magnesium sulphate. After filtration and concentration of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), 5-methylcyclodec-5-en-1-one (0.024 g) is obtained, the characteristics of which are as follows: Infra-red spectrum of a liquid film: characteristic bands at 2980 and 1710 cm-1 ;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([Cl:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,5-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.28-1.37 (m, 2 H) 1.71-1.82 (m, 2 H) 2.47-2.53 (m, 3 H) 4.29 (t, 2 H) 6.83 (s, 1 H) 7.73 (s, 1 H) 8.06 (s, 2 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42](Cl)[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl-].C(C1C=CC=C(C(C)C)C=1[N+]1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C=1)(C)C>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]>[NH2:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:11]=4[N:10]=3)=[CH:25][CH:26]=2)[CH:41]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1-n1cc[n+](-c2c(C(C)C)cccc2C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Nc1ccnc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)c1
Temperature: 120 °C

Procedure:
A reaction tube charged with 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (20.0 mg, 0.038 mmol), 4-amino-2-chloropyridine (9.8 mg, 0.076 mmol), Cs2CO3 (24.8 mg, 0.076 mmol), Pd2(dba)3 (1.7 mg, 0.002 mmol), and 1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride (1.6 mg, 0.004 mmol) is purged with nitrogen. Anhydrous 1,4-dioxane (0.5 mL) is added via syringe. The reaction mixture is heated at 120° C. for 3 days, cooled down to room temperature, taken in H2O (5 mL), and extracted by ethyl acetate (3×3 mL). The combined organic phase is concentrated and purified by reverse phase HPLC to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.09 (d, 2H), 8.06 (d, 1H), 7.63 (d, 2H), 7.54 (t, 2H), 7.44 (d, 2H), 7.39 (t, 1H), 7.29 (d, 2H), 7.03 (d, 2H), 6.89 (s, 1H), 6.59 (d, 1H); HPLC-MS calculated for C28H19ClN6O (M+H+) 491.1. Found: 491.1.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](Br)Br)=[CH:13][C:12]=2[F:20])[S:6]1(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].C([OH:25])C>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:25])=[CH:13][C:12]=2[F:20])[S:6]1(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(C(Br)Br)cc2F)S1(=O)=O
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC(C)(C)N1C(=O)CC(c2ccc(C=O)cc2F)S1(=O)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-tert-Butyl-5-[4-(dibromomethyl)-2-fluorophenyl]isothiazolidin-3-one 1,1-dioxide (4.2 g, 9.2 mmol) and silver nitrate (3.12 g, 18.4 mmol) in ethanol (200 mL) and water (50 mL) were heated at reflux for 0.5 h. The solution was cooled to rt, filtered to remove precipitate, and concentrated to remove most of the ethanol. The residue was diluted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and then dried over sodium sulfate. Concentration in vacuo followed by purification by silica gel chromatography (30% ethyl acetate:hexanes) afforded product as a white solid (2.4 g, 83%). 1H NMR (400 MHz, CDCl3): δ 10.0 (d, J=2.0 Hz, 1H), 7.78–7.75 (m,1H), 7.70–7.65 (m, 1H), 7.56–7.52 (m, 1H), 5.13 (dd, J=8.9, 6.6 Hz, 1H), 3.35 (dd, J=17.2, 8.9 Hz, 1H), 3.15 (dd, J=17.2, 6.6 Hz, 1H), 1.66 (s, 9H). LCMS found for C14H17FNNaO4S (M+Na)+: m/z=336.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:6]([C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)[CH:5]=1.[OH-].[Na+]>C1COCC1>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][C:6]=2[C:24]2[N:28]([CH3:29])[C:27]([CH2:30][CH3:31])=[N:26][N:25]=2)(=[O:12])=[O:13])=[CH:15][CH:16]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCc1nnc(-c2cc(C(=O)OC)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nnc(-c2cc(C(=O)O)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A 10 mL scintillation vial was charged with 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid methyl ester (20 mg, 0.044 mmol) and 3 M NaOH (aq)/THF (1:3) (1.5 mL). The reaction was heated to 60° C. and stirred overnight. The following day, the volatiles were removed in vacuo to about 200 μL at which point the solution was purified by preparative TLC to afford 4-(4-tert-butyl-benzenesulfonylamino)-3-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-benzoic acid as a light yellow solid: MS (ES) M+H expect 443.2, found 443.4.
Reaction SMILES: C([O:8][C:9](=[O:43])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[C:14]([CH3:31])[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:12]1=[O:42])C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([N:22]2[C:18]([C:15]3[C:16](=[O:17])[N:11]([CH2:10][C:9]([OH:43])=[O:8])[C:12](=[O:42])[N:13]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=4)[C:14]=3[CH3:31])=[CH:19][CH:20]=[N:21]2)=[CH:24][CH:25]=1)#[N:30]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CC(=O)OCc2ccccc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 111.1 %

Procedure:
To a solution of 2-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid benzyl ester (prepared in Example 6) (50.0 mg) in ethyl acetate (3.0 ml)/methanol (3.0 ml) was added 5% palladium/carbon (9.0 mg) and the resulting mixture was stirred at room temperature under hydrogen atmosphere for six hours. The reaction mixture was degassed and then filtered through Celite (trade mark) and then concentrated under reduced pressure to afford 2-[5-[1-(4-cyanophenyl)-1H-pyrazole-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]acetic acid (47.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:30][CH2:29]4)=[O:27])[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[N:13](COCC[Si](C)(C)C)[N:12]=1.[OH-].[Na+]>Cl(O)(=O)(=O)=O.C(O)(=O)C>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[C:22]([C:26]([N:28]4[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:32][CH2:33]4)=[O:27])[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][N:12]=1
Reactant: COc1cccc(OC)c1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cccc(OC)c1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 56 %

Procedure:
A solution of (3-(3-(2,6-dimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone in 5% of perchloric acid in acetic acid (1 mL) was stirred for 45 minutes at room temperature. Sodium hydroxide solution (2M) was then added to the solution slowly until pH ˜8. Ethyl acetate was then used for extraction and the organic layers were combined and concentrated to dryness, which was then redissolved in methanol (1 mL) and sodium carbonate (2M, 1 mL). The mixture was stirred at room temperature for 15 hours before being diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Mass triggered reverse phase HPLC purification afforded (3-(3-(2,6-dimethoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)(4-(2-(dimethylamino)ethyl)piperazin-1-yl)methanone (22.70 mg, 56% yield for two steps) as white solids. 1H NMR (500 MHz, CD3OD) δ 2.48 (br, 2H), 2.52 (s, 6H), 2.60 (m, 4H), 2.69 (m, 2H), 3.51 (br, 2H), 3.74 (s, 6H), 3.80 (br, 2H), 6.80 (d, J=8.5 Hz, 2H), 7.43 (m, 2H), 7.56 (t, J=8.0 Hz, 1H), 7.69 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 8.09 (d, J=2 Hz, 1H), 8.81 (d, J=2 Hz, 1H). MS: m/z 515.2 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([C:12]([F:15])([F:13])[F:14])=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: C=O
Reactant: CN(N)C(=O)Nc1nnc(C(F)(F)F)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C(F)(F)F)s2)C1=O
Temperature: 35 °C

Procedure:
The 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)semicarbazide prepared in Example 2 was dissolved in methanol (100 ml) in a glass reaction flask equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (12 ml; 37% concentration) was then added to the flask with stirring. The reaction mixture warmed to a temperature of about 35° C. Sufficient aqueous potassium hydroxide was then added to adjust the pH of the reaction medium to from about 7 to 8. A solid precipitate was formed. The precipitate was then recovered by filtration, was recrystallized from an ethyl acetate-heptane mixture and was dried under vacuum to yield the desired product 2-methyl-4-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one having a melting point of 187° to 188° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH2:9][CH3:10])=[CH:5][N:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cnc(Br)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)c1cnc(Br)s1
Temperature: 0 °C
Reaction time: 18 h
Yield: 41.5 %

Procedure:
2-Bromo-thiazole-5-carbaldehyde (1.00 g, 5.21 mmol) was dissolved in THF (10 ml). A solution of ethylmagnesium bromide (3 M in diethylether, 5.00 mL, 15.0 mmol) was added. The mixture was stirred for 18 h. The reaction was poured into sat. ammonium chloride solution/ice (100 mL) and diluted with ethyl acetate (100 ml). The organic phase was separated, washed with sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes provided 1-(2-bromo-thiazol-5-yl)-propan-1-ol (480 mg, 42%). Unreacted 2-Bromo-thiazole-5-carbaldehyde (465 mg, 46%) was also obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28].O1CCOCC1>C(OCC)(=O)C.CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:27][CH3:28])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)[N:3]=1
Reactant: N#Cc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCn1cnc2c(Nc3cccc(C#N)c3)nc(Cl)nc21

Procedure:
1.5 g (3.95 mmol) of 2-chloro-6-(3-cyano-phenyl-amino)-purine, 2.1 g (6.3 mmol) of caesium carbonate and 2.6 ml (31.6 mmol) of iodoethane are stirred in 66 ml of a mixture comprising dioxane:water:DMF in a ratio of 1:2:3 at RT for 19 h. Thereafter, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with water. After drying over sodium sulfate, the residue is chromatographed over silica gel (mobile phase: ethyl acetate:hexane=4:1). After removal of the solvent, 2-chloro-9-ethyl-6-(3-cyano-phenyl-amino)-9H-purine is obtained as a crystalline precipitate. This precipitate is filtered off and dried; m.p. 189° C.; FAB-MS: (M+H)+=299; Rf=0.9 (CH2Cl2:methanol 9:1).