Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C(C)=C)[CH2:21][CH2:22]C>CN1C(=O)CCC1.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:21]([C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1)([CH3:22])=[CH2:20]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN1CCCC1=O
Product: C=C(C)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 90 °C

Procedure:
To a solution of 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.700 g, 1.90 mmol) (Example 2b) in NMP (5 mL) is added tris(dibenzylideneacetone)dipalladium (0.196 g, 0.19 mmol) and trifuryl-2-yl-phospane (0.066 g, 0.285 mmol). Tributylisopropenyltin (1.25 g, 3.80 mmol) is added to the reaction mixture and it is heated to 90° C. for 24 h. The mixture is then allowed to cooled to room temperature, washed with water and extracted with ethyl acetate. The organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichloromethane-methanol, 19:1) to give 4-(5-isopropenyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; (ESI) m/z 283.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.21 (s, 3 H), 1.50 (s, 3 H), 2.24 (br. s, 3 H), 5.31 (br. s, 1 H), 5.56 (br. s, 1 H), 5.73 (s, 1 H), 7.02 (br. s, 1 H), 7.28 (br. s, 1 H), 7.51 (d, J=7.8 Hz, 1 H), 7.69 (td, J=7.8, 1.0 Hz, 1 H), 7.81 (td, J=7.6, 1.3 Hz, 1 H), 8.25 (d, J=7.8 Hz, 1 H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(Cl)c2c1
Yield: 77 %

Procedure:
A solution of ethyl 4-hydroxy-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate (1 g, 2.33 mmol, 1.00 equiv) in POCl3 (10 mL) was heated to reflux for 4 h in an oil bath. The resulting mixture was concentrated under vacuum, then diluted with 30 mL of ethyl acetate, and washed with 1×50 mL of sodium bicarbonate (aq.). The organic layer was concentrated under vacuum and purified by column chromatography (ethyl acetate/petroleum ether (1:10)) yielding 0.8 g (77%) of ethyl 4-chloro-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate as a yellow solid.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.O1CCCC1>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C=CC(=O)OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1cnc2ccccc21
Yield: 91.5 %

Procedure:
A solution of 10.0 g (84 mmol) of benzimidazole, 22.7 ml (250 mmol) of methyl acrylate and 3 drops of DBU in 50 ml of tetrahydrofuran was heated at reflux for 2 days. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 3% methanol in chloroform to provide 15.7 g (92%) of the desired compound (Rf 0.58, 10% methanol in chloroform).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.CC(C)([O-])C.[Na+]>C1COCC1.CCOC(C)=O.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:2]3[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)=[O:6])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Reactant: CSc1ncc2c(n1)CCNC2
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Yield: 79.6 %

Procedure:
A mixture of 3-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (379 mg, 1.10 mmol), 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (200 mg, 1.10 mmol), RuPhos (15.4 mg, 0.033 mmol), Cl—RuPhos-Pd precatalyst (24 mg, 0.033 mmol), and sodium-t-butoxide (148 mg, 1.54 mmol) in anhydrous THF (30 ml) was heated at 80° C. under nitrogen for 21 hours. Upon cooling, the reaction mixture was diluted with EtOAc and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) to obtain a yellow, crystalline solid (389 mg, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][NH2:24].[OH:25][CH2:26][CH2:27][CH:28]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][CH2:22][O:23][N:24]=[CH:28][CH2:27][CH2:26][OH:25]
Reactant: O=CCCO
Reactant: CSc1ccc(/C=C2/C(C)=C(CCON)c3cc(F)ccc32)cc1
Product: CSc1ccc(/C=C2/C(C)=C(CCON=CCCO)c3cc(F)ccc32)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylthiophenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-hydroxypropanal by the method of Example 1.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22].C(N(CC)CC)C>C(OCC)C>[CH3:10][O:11][CH:12]([O:23][CH3:24])[CH2:13][N:14]([C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(CNc1c(C)cccc1C)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(CN(C(=O)c1ccccc1)c1c(C)cccc1C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
2.81 g (0.02 mol) of benzoyl chloride were added in drops in 20 minutes and at a temperature of 0°-5° C. to a solution of N-(2',2'-dimethoxy-ethyl)-2,6-dimethyl aniline (4.45 g; 0.02 mol) in ethyl ether (20 ml) containing triethylamine (2.76 ml; 0.02 mol). The reaction mixture was stirred at room temperature for 15 minutes. The resulting salt was filtered and the solution was washed with 8 ml of an aqueous solution of hydrochloric acid at 5% and then with water up to neutral pH. The organic phase was anhydrified with anhydrous NaSO4 and the solvent was evaporated, so obtaining 5.2 g of a white solid which, recrystallized from petroleum ether (25 ml) provided 4.5 g of product (purity=91% by GLC) with a yield of 65.5% (white solid, melting point=58°-59° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:13][C:14]([O-:16])=[O:15].[Na+].O.Cl>CS(C)=O>[C:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15])#[N:11]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Yield: 66 %

Procedure:
A mixture of 18.6 g (0.10 mol) of 3,4-dichlorophenylacetonitrile and 12 g (1.03 mol) of dry sodium chloroacetate is reacted for 5 hours at room temperature in 150 ml of dry dimethyl sulfoxide, in the presence of 0.5 g (1.05 mol) of sodium tert-butylate. After the reaction, the reaction mixture is poured into 1 liter of iced water and acidified to pH<3 with hydrochloric acid. The cyanoacid is extracted with ethyl acetate, which is washed to pH>3, dried over magnesium sulfate and concentrated to dryness. The residue is solidified in 1,2-dichloroethane to give 16.1 g of the expected compound (III), which is characterized by proton NMR.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1.[Cu][C:26]#[N:27].CN(C=O)C>Cl.[Fe](Cl)(Cl)Cl>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:26]#[N:27])[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: N#C[Cu]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2Br)n1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2C#N)n1
Temperature: 160 °C
Reaction time: 4 h

Procedure:
A round-bottomed flask equipped with a nitrogen inlet and a reflux condenser was charged with 1-(2-(4-(3-bromothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazol-idine-2,4-dione (50 mg, 0.12 mmol), copper (I) cyanide (33 mg, 0.36 mmol), and dry DMF (2 mL). The reaction mixture was heated to reflux (bath temperature 160° C.). After 4 h, the reaction vessel was removed from the oil bath and allowed to cool to approximately 70° C. and poured into a stirring suspension of iron (III) chloride (0.28 g, 1.70 mmol) in 1.7 N aqueous HCl (5.0 mL). The combined mixture was maintained at 60-70° C. for 30 min at which time the mixture was allowed to cool to ambient temperature and extracted with three 15 mL portions of dichloromethane. The combined extracts were washed with two 40 mL portions of 6 N aqueous HCl, saturated aqueous NaHCO3, and H2O, then dried over Na2SO4 and concentrated. Chromatographic purification by preparative TLC, eluting with 8% MeOH/dichloromethane, and subsequent crystallization from EtOAc afforded the product as a white solid. MS (M+H)+ 357.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCCCNCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added (N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57 mmol), DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.117 g (53%) of a colourless oil.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:33](N1C2C(=CC(C(=O)C)=CC=2)C(C)(C)CC1=O)CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:29])[CH:18]=[CH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[C:10]([CH3:31])([CH3:30])[CH2:9][C:8]1=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:33]
Reactant: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Yield: 51 %

Procedure:
Following a procedure similar to that used for the preparation of Compound 8a but using N-heptyl-6-acetyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (Intermediate 6b) as the starting material afforded the title compound as a light yellow solid (51% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(CC)CC)C.[CH:29]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:33]([CH:29]2[CH2:32][CH2:31][CH2:30]2)=[O:34])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)C2CCC2)s1
Temperature: 65 °C

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in 1.5 ml acetonitrile (1.5 mL). Triethylamine (19 μl, 0.18 mmol) was added followed by the cyclobutanecarbonyl chloride (0.11 mmol). The reaction was heated at 65° C. overnight. The reaction mixture was cooled down and passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess carbonyl chloride eluting with additional acetonitrile. The resulting solution was dried and purified by reverse phase HPLC. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.75 (1H), 1.88 (1H), 2.10 (4H), 2.26 (3H), 3.15 (1H), 7.44 (1H), 7.63 (1H), 7.68 (1H), 7.90 (1H); MS (ESI) m/z 403.0 (M+H)+.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]([F:36])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)=[O:18].Cl>CCOCC.C1COCC1>[F:36][C:16]([F:15])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)([C:5]1[S:4][CH:3]=[N:7][CH:6]=1)[OH:18]
Reactant: C[Si](C)(C)c1nccs1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1cncs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 2-trimethylsilanyl-thiazole (157 mg, 1.00 mmol) in dry ether (2 mL) was added n-BuLi (440 μL, 2.5 M in hexanes, 1.10 mmol). After 30 minutes, a solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.50 mmol) in dry ether (2 mL) was added. After 1 hour, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers was washed with 10 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 202 mg of the crude product. To a solution of crude product (100 mg) in THF (2 mL) was added 2 M HCl (1 mL) and the mixture was stirred overnight. The mixture was then quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The mixture was purified over SiO2 using ethyl acetate-hexanes (0-100% gradient) to afford 38.4 mg (39% over two steps) of the title compound. MS m/z 394.26 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(O)=[O:2].ClC(OCC)=O.[NH3:17]>O1CCOCC1.C(N(CCCC)CCCC)CCC>[C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:2])[NH2:17]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCCCN(CCCC)CCCC
Product: Cc1cnc(C(N)=O)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0°-5° C. After ten minutes, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 hours at room temperature, then dioxan was distilled off, and the residue was taken up in saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 204°- 206° C. This amide (7 g) in glacial acetic acid (30 ml) and 35% hydrogen peroxide (20 ml.) was heated with stirring at 70° C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine 4-oxide (5.5 g), m.p. 206°-208° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.CO[C:12](=[O:32])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:14]=1[C:28]([O:30]C)=O.Cl.[NH2:34][CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37].O>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]2[C:14]=1[C:28](=[O:30])[N:34]([CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37])[C:12]2=[O:32])([CH3:25])([CH3:26])[CH3:27]
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C

Procedure:
Diisopropylethylamine (3.20 g, 25 mmol) was added to a stirred suspension of methyl-3-[(t-butoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (8.00 g, 25 mmol) and aminoglutarimide hydrochloride (4.07 g, 25 mmol) in DMF (60 ml). The mixture was heated to 120° C. for 24 hours and then cooled to room temperature. The mixture was poured into cold water (300 ml) and extracted with ethyl acetate (4×100 ml each). The combined ethyl acetate extracts were washed with water (2×50 ml), brine (50 ml) and dried. Solvent was removed in vacuo and the product purified by flash chromatography (dichloromethane/ethyl acetate 8 to 2) to yield 4.66 g of recovered starting material and 3.31 g (82%) of the product as a white solid: mp 180-182° C.; 1H NMR (CDCl3) δ 8.51 (s, 1H), 7.81-7.67 (m, 3H), 5.54 (b, 1H), 5.03-4.96 (dd, J=5.2 and 11.2 Hz, 1H), 4.66 (d, J=6.3 Hz, 2H), 2.95-2.74 (m, 3H), 2.18-2.14 (m, 1H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 170.99, 168.08, 167.95, 167.07, 155.86, 139.17, 135.00, 134.61, 132.15, 128.22, 122.82, 79.81, 49.21, 40.53, 31.33, 28.32, 22.58; Anal. Calcd for C19H21N3O6: C, 58.91; H, 5.46; N, 10.85. Found: C, 59.08; H, 5.51; N, 10.69.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[C:31]1([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:3]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ncnc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 45.1 %

Procedure:
A solution of 3-iodo-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 1.99 mmol) in dimethylformamide (20 mL) was treated with phenylboronic acid (0.485 g, 3.8 mmol), tetrakis(triphenylphosphine)palladium (0.138 g, 0.119 mmol), and a solution of sodium carbonate (0.506 g, 4.78 mmol) in water (10 mL). The reaction mixture was stirred at 80° C. for 18.5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (15 mL) was added. The precipitate was filtered and was washed with water. The crude solid was triturated with diethyl ether (30 mL). The resulting solid was dried over night on the lyophilizer to give 0.407 g (45%) of 3-phenyl-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 7.9416 (s, 1H), 7.6190-7.6011 (m, 2H), 7.5369-7.4493 (m, 3H), 7.3995-7.2248 (m, 15H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt =11.813 min (97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.CS(O[CH2:35][CH:36]1[CH2:39][C:38]([F:41])([F:40])[CH2:37]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:40][C:38]1([F:41])[CH2:39][CH:36]([CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:7]4[N:6]=[CH:5][C:4]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])=[CH:3][C:2]=4[F:1])[O:9][C:10]=3[CH:16]=2)[CH2:37]1
Reactant: C[C@@H](COc1cnc(-c2nc3ccc(O)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCC1CC(F)(F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cnc(-c2nc3ccc(OCC4CC(F)(F)C4)cc3o2)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
A mixture of tert-butyl [(1S)-2-{[5-fluoro-6-(6-hydroxy-1,3-benzoxazol-2-yl)pyridin-3-yl]oxy}-1-methylethyl]carbamate (770 mg), (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg), potassium carbonate (317 mg), and DMF (10 mL) was stirred at 60° C. for 2 hr. Then additional (3,3-difluorocyclobutyl)methyl methanesulfonate (459 mg) and potassium carbonate (317 mg) were added, and the mixture was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg) as a white solid.