Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:38]=[CH:37][C:18]([CH2:19][C:20]2[NH:21][C:22]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[NH:21][C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)=[CH:37][CH:38]=1
Reactant: COC(=O)CCc1[nH]c(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cc2nc(-c3ccccc3)c(CCC(=O)O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-1H-imidazol-5-yl]propionate (250 mg), lithium hydroxide hydrate (62.0 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 1 hr. 1N Hydrochloric acid (1.5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-1H-imidazol-5-yl]propionic acid (132 mg, yield 54%) as colorless crystals. The crystals were recrystallized from acetone. melting point: 193–196° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=O)([CH3:8])[CH3:7].[NH2:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CC(C)=O.CN(C)C=O>[CH:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([NH:23][CH:24]1[C:42](=[O:43])[N:26]2[C:27]([C:39]([OH:41])=[O:40])=[C:28]([CH2:31][S:32][C:33]3[N:37]([CH3:38])[N:36]=[N:35][N:34]=3)[CH2:29][S:30][C@H:25]12)=[O:14])([CH3:7])[CH3:8]
Reactant: CC(C)ON=C(C(=O)O)c1csc(NC=O)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
Phosphorus oxychloride (0.92 g) was added dropwise over 3 minutes at -5° to -10° C. to a solution of dimethylformamide (0.44 g) in ethyl acetate (2 ml). Ethyl acetate (20 ml) was added thereto and after 10 minutes, 2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.29 g) was added thereto at -5° to -10° C. The mixture was stirred for 10 minutes to give a clear solution. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.64 g) was dissolved under stirring in a solution of sodium bicarbonate (1.68 g) in water (30 ml), and then acetone (20 ml) was added thereto. To the solution was added dropwise with stirring the ethyl acetate solution obtained above at 0° to 5° C. and at pH 6.5 to 7.5. After stirring for 20 minutes at the same temperature, the aqueous layer was separated and acetone was distilled off. The remaining aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid under ice-cooling and stirring. Precipitates were collected by filtration, washed with water and dried to give 7-[2-isopropoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.7 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2].C(N(CC)CC)C.[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH:30]([CH2:34][NH2:35])[CH2:29]1.[NH4+].[OH-]>C1COCC1.CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:35][CH2:34][CH:30]4[CH2:31][CH2:32][CH2:33][CH:28]([OH:27])[CH2:29]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc([N+](=O)[O-])ccc3nc21
Reactant: NCC1CCCC(O)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCn1ncc2c(NCC3CCCC(O)C3)c3cc([N+](=O)[O-])ccc3nc21
Temperature: 110 °C
Yield: 10.5 %

Procedure:
A mixture of 1-ethyl-6-nitro-4-chloro-1H-pyrazolo[3,4-b]quinoline (2.7 g, 17.8 mmol), triethylamine (3 mL, 0.02 mol), DMSO (15 mL) and 3-hydroxycyclohexylmethylamine (4.97 g, 18 mmol) was heated at 110° C. overnight. The reaction mixture was poured into ice-water (200 mL)/NH4OH (10 mL) and the solid which formed was collected by filtration. The filtrate was then extracted with CH2Cl2 (2×100 mL). The solid was stirred and sonicated with CH2Cl2 (2×200 mL) and any solids which did not go into solution were collected by filtration. All of the above CH2Cl2 filtrates and extracts were combined, washed with water and evaporated. The residue was slurried with ethyl acetate (10-15 mL)/ether (20 mL) and a red colored solid was collected by filtration and washed with ether. The solid was purified by column chromatography (2×) on silica gel (note that the solid was preloaded onto 50-100 g of silica gel) eluting with 40% THF/cyclohexane and each of the diastereomers which was isolated was dissolved in hot THF, filtered and the solvent was evaporated. Each of the residues was slurried with ethanol (5 mL), filtered and dried to afford 0.69 g of 1-ethyl-6-nitro-N-(3-hydroxycyclohexylmethyl)-1 H-pyrazolo[3,4-b]quinolin-4-amine (the RS,SR diastereomer which is labelled as Example 36(a)), m.p. 236°-238° C. and 2.23 g of 1-ethyl-6-nitro-N-(3-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (the RR,SS diastereomer which is labelled as Example 36(b)), m.p. 247°-248° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](OCC)=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[N:3]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(C(F)(F)F)ncc1CO
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
To a mixture of ethyl 4-methyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (122.4 mg) in toluene (5.1 mL) was added diisobutylaluminum hydride (1.0 mol/L in hexane, 1.150 mL) at 0° C. The mixture was stirred at 0° C. under nitrogen atmosphere for 2.5 h, and then at room temperature for 2 h. To the mixture was added diisobutylaluminum hydride (1.0 mol/L in hexane, 0.58 mL) again at 0° C. and the mixture was stirred at 0° C. for 2 h. To the mixture was added sodium sulfate decahydrate (556 mg), and the mixture was stirred at room temperature overnight. The mixture was filtered through on the pad of Celite®. The filtrate was concentrated in vacuo to give the title compound (97.6 mg).
Reaction SMILES: II.[CH3:3][O:4][C:5](=[O:17])[C@H:6]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][I:8].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.BrC1CCCC=1>CN(C=O)C.[Zn].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(Cl)Cl>[CH3:3][O:4][C:5](=[O:17])[CH:6]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:7][I:8]
Reactant: COC(=O)[C@@H](CI)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: BrC1=CCCC1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(CI)NC(=O)OC(C)(C)C
Yield: 27.5 %

Procedure:
To a three necked flask charged with zinc dust (2.23 g, 34.1 mmol) under an N2 atmosphere DMF (13 mL) was added. The suspension was efficiently stirred and I2 (0.20 g, 0.80 mmol) was added. ((S)-2-[(tert-Butoxycarbonyl)amino]-3-iodopropionic acid methyl ester (4.50 g, 13.7 mmol) was added in one portion, and immediately after more I2 (0.20 g, 0.80 mmol) and the stirring was continued for 2 h. Negishi coupling was then effected by addition in direct sequence of: Pd2 dba3 (315 mg, 0.34 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (279 mg, 0.68 mmol), and 1-bromocyclopentene (2.32 g, 15.8 mmol) in DMF (4 mL). The reaction was stirred over night. DCM (25 mL) was added and the mixture was filtered, the solids were washed with further DCM, water (30 mL) was added and the phases were separated. The aqueous phase was extracted with DCM (2×20 mL) and the combined organic phases were washed with H2O (20 mL), dried MgSO4, filtered and evaporated. The residue was purified by gradient silica gel chromatography (4-16% EtOAc in iso-hexane) which gave the title compound 1.24 g (30%). GC-MS EI m/z 213 (w), 196 (w), 152, 88, 57, 41.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: CC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC1Cc2cccc(-c3ccccc3)c2C1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2.5 g (13.8 mmol) of 7-chloro-2-methyl-1-indanone (1), 2.11 g (17.3 mmol) of phenylboronic acid and 3.66 g (34.6 mmol) of sodium carbonate were placed in 40 ml of o-xylene/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 1.55 mg (0.0069 mmol) of palladium acetate and 7.3 mg (0.027 mmol) of triphenylphosphine, the reaction mixture was stirred for 8 hours at 100° C. After 2, 4 and 6 hours, the same amount of palladium acetate and triphenylphosphine were added again each time. After addition of 40 ml of water, the phases were separated, the aqueous phase was extracted 3 times with 40 ml each time of ether, the combined organic phases were washed with 40 ml of water and 40 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.9 g of (15) as solid. The 1H-NMR indicated a conversion of about 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14](I)[CH:15]=[C:10]3[C:9]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.[C:28]([OH:34])(=[O:33])[CH2:29][CH2:30][C:31]#[CH:32].C(N(CC)CC)C>[Cu]I.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:23][C:11]3=[N:12][C:13]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([C:32]#[C:31][CH2:30][CH2:29][C:28]([OH:34])=[O:33])[CH:15]=[C:10]3[C:9]=2[C:24](=[O:25])[NH:26][CH3:27])=[CH:4][CH:3]=1
Reactant: C#CCCC(=O)O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(I)cc12
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C#CCCC(=O)O)cc12
Temperature: 80 °C

Procedure:
A mixture of 2-(4-fluorophenyl)-5-iodo-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (52 mg), pent-4-ynoic acid (51 mg), triethylamine (0.43 ml), copper(I) iodide (0.79 mg), Pd(PPh3)Cl2 (5.8 mg) and THF (1.4 ml) was bubbled with nitrogen. Heated at 80° C. for 16 h. Cooled to rt and purified by preparative HPLC. (M+H)+=474.1; Retention time=1.22 min, Method A.
Reaction SMILES: [CH3:1][C:2]1[O:8][C:7]([CH3:9])=[CH:6][C:4](=[O:5])[CH:3]=1>CCO>[CH3:9][CH:7]1[CH2:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[O:8]1
Reactant: Cc1cc(=O)cc(C)o1
Solvent: CCO
Product: CC1CC(=O)CC(C)O1
Reaction time: 3 h

Procedure:
A solution of 2,6-dimethyl-γ-pyrone (17 g, Aldrich) in 300 mL of EtOH 95% was hydrogenated for 3 days under 70 psi. After filtration over celite, the solvent was evaporated and replaced by CH2Cl2. The solution was then treated with celite (30 g) and PCC (48.5 g). The suspension was stirred for 3 hr. and the reaction was diluted with Et2O (300 mL) and then filtered over a pad celite. The filtrate was evaporated to dryness and the residual solution was then chromatographed using hexane/Et2O (1:1) to give the title compound.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])=[O:32])=[CH:26][CH:25]=1)[NH:5][C:6]([C:8]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[OH-].[Na+]>C(O)C>[Cl:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:40])[C:33]=1[C:31]([NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C@@H:4]([C:3]([OH:41])=[O:2])[NH:5][C:6]([C:8]2([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])=[CH:29][CH:28]=1)=[O:32]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)C(=O)O)CCCCC2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a suspension of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(4-methoxyphenylmethyl)cyclohexyl]carbonyl]-L-phenylalanine methyl ester (0.15 g, 0.25 mmol) in ethanol (2 mL) was added aqueous 1.0 N sodium hydroxide (1.5 mL, 3 mmol) at room temperature. The mixture was heated to 50° C. and the resulting clear solution was stirred overnight The mixture was concentrated, the residue was diluted with 5 mL of water and extracted with 25 mL of ether to remove any neutral impurities. The aqueous layer was acidified with 1 N HCl and the precipitated white solid was collected by filtration and washed with water (20 mL) and hexane (20 mL). After air-drying, 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(4-methoxyphenylmethyl)cyclohexyl]carbonyl]-L-phenylalanine (0.12 g, 82%) was obtained as a white solid, mp 136-140° C. HR MS: Obs mass, 583.1763. Calcd mass, 583.1766 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=C1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc2c(c1)CC(N1CCCC1)C2
Reaction time: 8 h

Procedure:
To a solution of 1H-inden-2(3H)-one (6 g, 45.4 mmol) in 100 mL of methanol were added pyrrolidine (7.51 ml, 91 mmol), sodium cyanoborohydride (5.71 g, 91 mmol), and acetic acid (5.20 ml, 91 mmol). The reaction mixture was stirred overnight then concentrated. The crude residue was dissolved in 400 mL of ethyl acetate and washed with aqueous sodium bicarbonate (2×400 mL) and saturated aqueous brine (1×200 mL), dried over magnesium sulfate, filtered and concentrated. Recrystallization in ethyl acetate/hexane afforded the title compound. MS (ESI) m/z 188 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)[CH:3]=1.[CH3:15][Mg]Br.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:13]([OH:14])[CH3:15])[S:11][CH:12]=2)[CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc(-c2cc(Cl)ccn2)cs1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cc(Cl)ccn2)cs1
Reaction time: 3 h

Procedure:
To a solution of 4-(4-chloro-pyridin-2-yl)-thiophene-2-carbaldehyde (160 mg, 0.72 mmol) in THF (3 mL) was added methylmagnesium bromide (3 M, 1 mL) at −78° C. and the resulting mixture was stirred at the temperature for 3 hours. Water was added and THF was removed. The water solution was extracted with EtOAc and organic layer was concentrated. The resulting residue was purified by silica gel column to yield 1-[4-(4-chloro-pyridin-2-yl)-thiophen-2-yl]-ethanol
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][C:14]=2[O:13]1>C1COCC1>[CH2:12]1[O:22][C:21]2[CH:20]=[CH:19][C:16]([CH2:17][C:4]([CH2:17][C:16]3[CH:19]=[CH:20][C:21]4[O:22][CH2:12][O:13][C:14]=4[CH:15]=3)([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6])=[CH:15][C:14]=2[O:13]1
Reactant: COC(=O)CC(=O)OC
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc2c(c1)OCO2)(Cc1ccc2c(c1)OCO2)C(=O)OC
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
A suspension of 6.6 g (0.165 mol) of NaH.oil (60%) in 200 mL THF was cooled in ice and treated dropwise with 10 g (0.075 mol) of dimethyl malonate. After stirring for 0.5 hour, the solution was treated with a solution of 27.3 g (0.16 mol) of 3,4-methylenedioxybenzyl chloride (50% in CH2Cl2). After stirring at room temperature overnight, the solution was heated at reflux overnight. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in EtOAc and washed with 1N HCl, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure gave the crude product. Recrystallization from EtOAc/hexane gave 20.58 g (68.6% yield) of the product as a solid. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]3[CH:13]=[CH:14][C:15]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[N:18]=4)=[CH:16][C:9]=23)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:33][O:34][C:35]1[N:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37](B(O)O)[N:36]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)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].C1C=CC=CC=1>[CH3:33][O:34][C:35]1[N:40]=[C:39]([C:2]2[CH:3]=[C:4]([C:8]3[O:12][N:11]=[C:10]4[CH:13]=[CH:14][C:15]([C:17]5[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[N:18]=5)=[CH:16][C:9]=34)[CH:5]=[CH:6][CH:7]=2)[C:38]([O:41][CH3:42])=[CH:37][N:36]=1
Reactant: COc1ncc(OC)c(B(O)O)n1
Reactant: CC(=O)Nc1nccc(-c2ccc3noc(-c4cccc(Br)c4)c3c2)n1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ncc(OC)c(-c2cccc(-c3onc4ccc(-c5ccnc(NC(C)=O)n5)cc34)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.8 %

Procedure:
A flask was charged with N-{4-[3-(3-bromophenyl)-benzo[c]isoxazol-5-yl]-pyrimidin-2-yl}-acetamide (100 mg, 0.272 mmol), cesium carbonate (97.7 mg, 0.328 mmol), and 2,5-dimethoxypyrimidine-6-boronic acid (55.0 mg, 0.3 mmol). The flask was evacuated and back-filled with nitrogen 5-7 times before adding 5 mL of degassed p-dioxane and 1 mL of degassed DMF. To this stirring solution/suspension was added, 125 μL of a 10% w/v benzene solution of tri-tertbutylphosphine followed by the addition of Pd2(dba)3 (25 mg, 0.0272 mmol) slurred in 1 mL of degassed DMF. The reaction was stirred under nitrogen atmosphere, at 80° C. Reaction was followed by HPLC and deemed to be complete in 4 hours. The reaction mixture was suction filtered hot through a pad of diatomaceous earth and washed the precipitate with DMF and acetonitrile. The filtrate was reduced to an oil under reduced pressure and the crude material purified via HPLC utilizing acetonitrile/water/TFA as the eluent. The material was isolated as a bright yellow powder (15 mg, 13% yield). 1H NMR (500 MHz DMSO-d6) δ 8.93 (s, 1H) 8.6 (s, 1H), 8.31 (s, 1H), 8.29 (d, 1H), 8.25 (d, 1H), 8.07 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H), 7.77 (m, 1H), 4.02 (2 close sing, 6H) in ppm. LC-MS (ES+) m/e=469 (M+H)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([OH:17])=[C:11]3[CH:10]=[N:9]2)[CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:61][N:62](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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]>[OH:17][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[N:8]([C:6]3[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=3[CH3:18])[C:61]#[N:62])[N:9]=[CH:10][C:11]=12
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)cc1-n1ncc2c(O)ncnc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)cc1-n1ncc2c(O)ncnc21
Temperature: 160 °C
Yield: 89 %

Procedure:
1-(5-Bromo-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate AM4) (1.38 g, 4.52 mmol), and zinc cyanide (0.478 g, 4.07 mmol) were dissolved in DMF (15 mL) and sealed into a microwave tube. The reaction mixture was evacuated and back flushed with nitrogen several times. 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.262 g, 0.45 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.207 g, 0.23 mmol) were added. The reaction was heated to 160° C. for 10 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (100 mL) and water (50 mL) and then filtered. Solid was taken up in hot methanol, filtered and dried under vacuum to afford the product (0.99 g, 89%) which was used without further purification. 1H NMR (400 MHz, DMSO) 2.19 (3H, s), 7.67 (1H, d), 7.92-7.96 (2H, m), 8.10 (1H, s), 8.35 (1H, s), 12.38 (1H, s); m/z (ES−) (M−H)−=250; HPLC tR=1.23 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[F:32])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: OB(O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4F)cc3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (300 mg, 0.614 mmol) (see Ex. 2, part B), 2-fluorophenylboronic acid (0.921 mmol), potassium fluoride (88.6 mg, 1.84 mmol), palladium acetate (1.3 mg, 0.14 μmol), and 2-(dicyclohexylphosphino)biphenyl (4.3 mg, 12.3 μmol) were combined under N2, to which anhydrous THF (1.23 mL) was added. The yellow mixture was heated at reflux for 12 h. After cooling to room temperature, the mixture was partitioned between Et2O (20 mL) and 1M NaOH (10 mL). The layers were separated, and the aqueous phase was back-extracted with Et2O (10 mL). Combined organic phases were dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (25 g SiO2, 1:4 ethyl acetate:hexanes) to yield the desired product as an oil. Rf=0.48 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ8.01 (d, J=8.0 Hz, 2H), 7.60 (d, J=8 Hz, 2H), 7.47-7.42 (m, 1H), 7.34-7.28 (m, 1H), 7.22-7.11 (m, 2H), 6.81-6.73 (m, 4H), 4.20 (q, J=6.8 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 1.50 (s, 6H), 1.24 (t, J=6.8 Hz, 3H); MS (EI) 504.2 (M+H)+.