Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([F:33])[F:32])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>C(O)C.O1CCCC1>[F:33][CH:31]([F:32])[C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: FC(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1[nH]nc(CCc2cccc(C(F)F)c2)cc1O
Yield: 32 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-(difluoromethyl)phenyl)ethynyl]pyridazine (Intermediate 22) except that the reaction was carried out in a mixture of ethanol and tetrahydrofuran (1:1). The crude material was purified by reverse phase chromatography (25 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give a pale orange solid (yield=32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][C:26](=[O:35])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])=[CH:33][CH:32]=1
Reactant: NCC(=O)Cc1ccc(Cl)cc1
Reactant: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc12
Agent: Cl
Product: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(Cl)cc3)nc12

Procedure:
Adapted from the procedure of example 5 using the product of example 9 and 1-amino-3-(4-chloro-phenyl)-propan-2-one hydrochloride.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14]O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:20])=O>>[Cl:20][CH2:14][C:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)=[N:10][O:11][CH:12]=1
Reactant: OCc1conc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc(-c2nocc2CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A mixture of 3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.00 g) and thionyl chloride (10.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-3-(4-trifluoromethylphenyl)isoxazole (6.16 g, yield 95%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 84–85° C.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6].CI.Cl.[N+](=[CH2:24])=[N-]>O1CCCC1>[O:3]=[C:4]([C:8]([CH3:24])([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: CC(C(=O)C(=O)O)c1ccc(C(=O)O)cc1
Reactant: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C(=O)C(=O)O)c1ccc(C(=O)O)cc1
Yield: 34 %

Procedure:
A 2N aqueous solution (30 ml) of sodium hydroxide and 50 ml of tetrahydrofuran were added to 2.22 g (10 mmoles) of 2-oxo-3-(p-carboxyphenyl)butanoic acid, and the mixture was stirred until a completely uniform solution formed. Then, 1.5 ml (24 mmoles) of methyl iodide was added, and the mixture reacted at room temperature for 24 hours. The reaction mixture was acidified with 1N hydrochloric acid, and extracted with ether. The ether layer was dried. The drying reagent was separated by filtration, and the solvent was evaporated. The NMR spectral analysis of the resulting oily product led to the determination that the desired 2-oxo-3-methyl-3-phenylbutanoic acid formed in a yield of 80 %. This product was converted to a methyl ester by using diazomethane, and isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:10). Then a 1N aqueous solution of sodium hydroxide was added and the ester was hydrolyzed. The hydrolyzate was acidified with 1N hydrochloric acid and extracted with ether. After drying, the solvent was evaporated to give 0.80 g (3.4 mmoles) of 2-oxo-3-methyl-3-(p-carboxyphenyl)butanoic acid as a white solid in a yield of 34 %.
Reaction SMILES: [CH2:1]([C:7]1[CH:40]=[CH:39][C:10]([C:11]([C:13]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([C:25](=O)[C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=3)=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>[Pd].O1CCCC1>[CH2:1]([C:7]1[CH:40]=[CH:39][C:10]([CH2:11][C:13]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=3)=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCC)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 5.26 grams of 2,5-bis(4-hexylbenzoyl)terephthalic acid, 100 mL of tetrahydrofuran, and 0.53 grams of 5% palladium on carbon (as a catalyst) was heated at 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The resulting mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give 2,5-bis(4-hexylbenzyl)terephthalic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])C3C=CC=C(CC(=O)C)C=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:54]([O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72])[CH2:55][NH:56][C:57]([CH3:69])([CH3:68])[CH2:58][C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=2)C(O)=O)=[C:47]2[C:52]=1[NH:51][C:50](=[O:53])[CH:49]=[CH:48]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43]1[CH:44]=[CH:45][C:46]([C@@H:54]([O:70][Si:71]([C:74]([CH3:76])([CH3:77])[CH3:75])([CH3:72])[CH3:73])[CH2:55][NH:56][C:57]([CH3:69])([CH3:68])[CH2:58][C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][CH:67]=2)[C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:33][CH3:34])=[O:32])=[C:47]2[C:52]=1[NH:51][C:50](=[O:53])[CH:49]=[CH:48]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using Intermediate 50 in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C51H68N7O5Si+ 886.5. found m/z=886.5 (M+H)+.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([N:34]5[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH2:35]5)=[O:33])=[CH:28][CH:27]=4)=[CH:21][C:20]=3[Cl:44])[C:14]2=[O:45])[CH2:9][CH2:8]1)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[Cl:44][C:20]1[CH:21]=[C:22]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:41])[F:42])[CH2:36][CH2:35]3)=[O:33])=[CH:30][CH:31]=2)[CH:23]=[C:24]([Cl:25])[C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][CH:13]([N:10]2[CH2:11][CH2:12][CH:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:45]
Reactant: CC(C)(C)[Si](OC1CCN(C2CCN(Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(CN3CCC(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reaction time: 4 h
Yield: 43.6 %

Procedure:
Treat a mixture of 3-[4-(tert-butyl-diphenyl-silanyloxy)-piperidin-1-yl]-1-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.25 g, 0.299 mmol) in THF (10 mL) and water (5 mL) with trifluoroacetic acid (5 mL), heat to reflux, and stir for 4 hours under N2. Cool the reaction and basify with 5N NaOH. Dilute the mixture with ethyl acetate and wash with water. Dry the organic layer (Na2SO4) and remove the solvent in vacuo to afford crude product. Purify with a 5 to 10% methanol in CH2Cl2 gradient to afford 0.078 g (44%) of the titled product. Rf=0.34 (9/1 CH2Cl2/methanol). ES MS (m/z): 598 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1>C(Cl)Cl>[CH2:25]([O:24][C:22]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1)=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
8.84 g (32.0 mmol) of t-butyl 4-(4-aminophenyl)-piperidine-1-carboxylate were dissolved in 150ml of methylene chloride and treated with 3.82 g (35.2 mmol) of ethyl chloroformate in the presence of 2.78 g (35.2 mmol) of pyridine. The reaction mixture was stirred at room temperature for 16 hours. Thereafter, it was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The residue (11.3 g) was chromatographed on 95 g of silica gel 60 with ether/n-hexane (4:6). After recrystallization from ether/n-hexane there were obtained 6.15 g of t-butyl 4-(4-ethoxycarbonylamino-phenyl)-piperidine-1-carboxylate. M.p.: 126°-128°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:20]=[CH:19][C:12]2[C:13](=O)[O:14]C(=O)[NH:16][C:11]=2[CH:10]=1.O>C(O)(=O)C>[C:2]1([NH:1][C:13](=[O:14])[C:12]2[C:11](=[CH:10][C:9]([F:8])=[CH:20][CH:19]=2)[NH2:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(F)ccc1C(=O)Nc1ccccc1

Procedure:
A solution of aniline (1.77 g) in acetic acid (50 ml) was added to a solution of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (1 g) in acetic acid (100 ml) and the mixture heated at 100° for 20 minutes. It was then poured into water and the precipitate collected, dried and recrystallised from toluene to give N1 -phenyl-4-fluoroanthranilamide, m.p. 120°-122°. (Compound 4).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:22]([O:26][C:27]([N:29]1[CH2:47][CH2:46][N:32]2[C:33](=[O:45])[C:34]3[C:39]([C@@H:31]2[CH2:30]1)=[CH:38][C:37](Br)=[CH:36][C:35]=3[C:41]([F:44])([F:43])[F:42])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=[NH:61])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C([O-])(=O)C.[Na+].Cl.NO>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:22]([O:26][C:27]([N:29]1[CH2:47][CH2:46][N:32]2[C:33](=[O:45])[C:34]3[C:39]([C@@H:31]2[CH2:30]1)=[CH:38][C:37]([NH2:61])=[CH:36][C:35]=3[C:41]([F:44])([F:43])[F:42])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(N)cc3C(F)(F)F)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
A solution of tris(dibenzylideneacetone)dipalladium(0) (14 mg, 15 μmol) and 2-(di-tert-butylphosphino)biphenyl (14.0 mg, 46 μmol) in anhydrous toluene (5.5 mL) was degassed with argon for 15 min at room temperature, then N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (110 mg, 0.25 mmol) was added. Upon further degassing, benzophenone imine (0.14 mg, 0.75 mmol) and sodium tert-butoxide (73 mg, 0.75 mmol) were added. The mixture was degassed a final time and then subjected to microwave conditions (150 W, 150° C.) for 1 h. Upon cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth and the pad was washed with EtOAc (100 mL). The filtrate was concentrated in vacuo and the residue was dissolved in MeOH (10 mL) and cooled to 0° C. To this solution was added sodium acetate (95 mg, 1.4 mmol) and hydroxylamine hydrochloride (150 mg, 1.8 mmol). The reaction was warmed to room temperature and stirred for 1.5 h. Additional amounts of sodium acetate (95 mg, 1.4 mmol) and hydroxylamine hydrochloride (150 mg, 1.8 mmol) were added at 0° C. and the reaction was stirred at room temperature for an additional 2.5 h. The solution was concentrated in vacuo and the residue was partitioned between CH2Cl2 (50 mL) and 1 N NaOH (50 mL). The aqueous phase was extracted with CH2Cl2 (4×75 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5–33% EtOAc/hexanes) to provide the product (47 mg) in 50% yield. MS (APCI) 372 (M+H).
Reaction SMILES: [Cl-].[CH3:2][Zn+].Br[C:5]1[C:6]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:7]2[CH:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:8]2=[N:9][CH:10]=1.[NH4+].[Cl-]>C1COCC1.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>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([CH3:2])[C:6]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]4)=[C:7]3[CH:13]=[N:12]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cnc32)cc1
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2ncc3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C)cnc32)cc1
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Methylzinc (II) chloride (2M solution in THF, 1244 μL, 2.488 mmol) was added to a solution of tert-butyl 4-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (500 mg, 0.995 mmol) and Pd(PPh3)4 (86.25 mg, 0.07464 mmol) in THF (5 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 75° C. for 1.5 hours and allowed to cool to room temperature. The mixture was poured into a saturated aqueous NH4Cl solution (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40S+) eluting with 2% MeOH/CH2Cl2 to provide tert-butyl 4-(1-(4-methoxybenzyl)-5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (470 mg, 0.806 mmol, 81.0% yield) as a solid. LCMS (APCI+) m/z 438.2 (M+H)+.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:28]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=O)[CH3:29].C(=O)(O)[O-].[Na+]>CCOCC>[CH2:28]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]=[CH2:2])[CH3:29]
Reactant: CCSc1ccccc1C=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOCC
Product: C=Cc1ccccc1SCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask under dry nitrogen. To the mixture was added in one portion at 0° C. potassium tert-butoxide (0.47 g, 4.19 mmol) and it was stirred for 10 min at room temperature. 2-(ethylsulfanyl)benzenecarbaldehyde (2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred until complete disappearance of the reactants (22 hr) at room temperature (followed by TLC). The mixture was added to 50 mL of saturated sodium bicarbonate solution, followed by extraction with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using petroleum ether 60-80 as eluent. Yield: 0.37 g, 81%, colorless oil. 1H NMR (200 MHz, CDCl3): δ 1.29 (t, J=7.3, 3H), 2.89 (q, J=7.3, 2H), 5.34 (dd, J1=10.9, J2=1.2, 1H), 5.69 (dd, J1=17.4, J2=1.2, 1H), 7.19-7.54 (m, 5H) ppm.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[O:16])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=[O:16]
Reactant: CN1CCC(COCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1CCC(CO)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
3-[(Benzyloxy)methyl]-1-methylpyrrolidin-2-one (4.14 g, 18.88 mmol) was dissolved in methanol (20 ml), followed by addition of 10% hydrous palladium carbon (1.04 g) and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. Palladium carbon was filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol: 10/1) to give the title compound (1.55 g, 64%) as a colorless oily matter.
Reaction SMILES: C([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]([O:25][CH3:26])[CH:13]([N:27]2[CH:35]=[N:34][C:33]3[C:32](=[O:36])[NH:31][C:30]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])=[N:29][C:28]2=3)[O:12]1)([O:6]CC)=[O:5])C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>CN(C=O)C>[C:38]([NH:37][C:30]1[NH:31][C:32](=[O:36])[C:33]2[N:34]=[CH:35][N:27]([CH:13]3[O:12][CH:11]([CH:10]=[CH:9][P:4]([OH:5])([OH:6])=[O:3])[CH:15]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:14]3[O:25][CH3:26])[C:28]=2[N:29]=1)(=[O:42])[CH:39]([CH3:40])[CH3:41]
Reactant: CCOP(=O)(C=CC1OC(n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C(OC)C1OC(=O)c1ccccc1)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COC1C(OC(=O)c2ccccc2)C(C=CP(=O)(O)O)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 14.4 %

Procedure:
Compound 16.7 (460 mg, 0.763 mmol) was dissolved in 8 mL anhydrous DMF, treated with 2,6-lutidine (0.443 mL, 3.81 mmol) and TMSBr (1.5 mL, 11.4 mmol). The mixture was stirred at 80° C. for 4 h and quenched with MeOH. The mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC to yield product 16.8 (60 mg, 14.4% yield).
Reaction SMILES: COC([CH:5]1[C:14]2[N:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)=O.[OH-].[Na+]>>[CH3:15][C:11]1[CH:12]=[N:13][C:14]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: COC(=O)C1CCCc2cc(C)cnc21
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(c1)CCCC2
Reaction time: 4 h

Procedure:
A solution of 15% n-butyl lithium in hexane (51 ml. ca. 0.12 m) was added portionwise to a solution of 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.1 m) in ether (100 ml.) and the mixture allowed to stand at room temperature for 1 hour and then added dropwise to a cooled, stirred solution of methylchloroformate (9.45 g., 0.1 m) in ether (100 ml.). The mixture was stirred at 50° C for 1 hour. The reaction mixture was diluted with water (20 ml.) and then treated with 2N HCl until acidic. The ethereal solution was separted and washed with 2N HCl (2 × 25 ml.). The combined aqueus washings were extracted with ether and the ethereal extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.) and the combined extracts dried and evaporated to give a pale yellow oil (16 g) which on GLC examination (3% SE30) showed a mixture of unreacted tetrahydroquinoline (45%), the title compound (23%) and the 8,8-dicarboxylic ester (20%). The mixture was treated with 10% sodium hydroxide (75 ml.). and heated at reflux with stirring for 4 hours, cooled and extracted with ether (3 × 50 ml.). The combined ethereal extracts were dried, evaporated and distilled to give unreacted 3-methyl-5,6,7,8-tetrahydroquinoline (7 g.) b.p. 116°/18 mm Hg. The basic solution was adjusted to pH 8.5-9.0 with concentrated HCl and evaporated to dryness and the residue treated with methanol previously saturated with dry HCl (50 ml.) and allowed to stand at room temperature for 5 hours. The solvent was removed and the residue dissolved in water (20 ml.) and extracted with ether (2 × 50 ml.). The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 25 ml.) and the combined extracts dried and evaporated to give the title compound (3 gm.).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][CH:6]=[N:5][C:4]=1[CH2:8][CH3:9].[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[CH2:8]([C:4]1[N:5]=[CH:6][S:7][C:3]=1[CH2:2][S:17][C:15]1[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=1)[CH3:9]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCc1ncsc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ncsc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.1 %

Procedure:
A mixture of 5-(bromomethyl)-4-ethyl-1,3-thiazole (7.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (700 mg, 4.9 mmol), and triethylamine (3.0 mL, 21.5 mmol) in absolute ethanol (70 mL) was stirred at room temperature overnight. The mixture was evaporated, and the residue was treated with 50% diethyl ether/acetone (100 mL). The solid material was removed by filtration. The filtrate was recovered and evaporated. The crude product was purified by flash chromatography (0-10% MeOH/CH2Cl2). The column was repeated 4 times, affording the title compound (132 mg, 10% yield); 1H NMR (500 MHz, DMSO-d6): δ 1.19 (t, 2H, J=7.5 Hz), 2.801 (m, 2H, J=7.5 Hz), 4.55 (s, 2H), 6.05 (s, 1H), 8.85 (s, 1H); M+268.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>ClCCl>[CH3:21][N:22]([CH:24]=[N:18][C:16]([C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[N:10][C:11]=12)=[O:17])[CH3:23]
Reactant: NC(=O)c1cnn2c(-c3ccccc3)ccnc12
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=NC(=O)c1cnn2c(-c3ccccc3)ccnc12

Procedure:
A mixture of 600 mg of 7-phenylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 7), 5.0 ml of N,N-dimethylformamide dimethyl acetal and 25.0 ml of dichloromethane are heated on a steam bath for 2 hours with complete solution taking place. The solution is evaporated in vacuo to give a solid. The solid is then recrystallized from acetone to give 58 mg of the desired product as yellow needles, mp 198°-201.5° C.