Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[K+].[CH2:13]([B-](F)(F)F)[CH3:14].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1)[CH3:14]
Reactant: CC[B-](F)(F)F
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cccc(C(F)(F)F)n1
Temperature: 100 °C

Procedure:
2-Chloro-6-trifluoromethylpyridine (451 mg, 2.5 mmol), ethyltrifluoroborate potassium salt (374 mg, 2.75 mmol), palladium acetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1, 10 mL). After flushing the vessel under a stream of nitrogen gas for 5 minutes, the reaction tube was sealed and then heated at 100° C. for 18 hours. On cooling, the mixture was partitioned between DCM (15 mL) and water (15 mL). The separated aqueous phase was extracted with DCM (2×15 mL) and the combined organic phases were passed through a phase separator and concentrated in vacuo, affording a yellow oil which was used without further purification (460 mg, crude)
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:17][OH:18].C(O)C>O>[I:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:17][OH:18])[NH2:7])=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc(I)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc(I)cc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A mixture of 4-iodobenzonitrile (7.69 g), anhydrous sodium carbonate (6.25 g), hydroxylamine hydrochloride (8.74 g), in water (60 ml) and sufficient ethanol to maintain a clear solution, was heated at 90°-100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and evaporated until a precipitate formed. The solid was collected by filtration, washed with water and recrystallised from acetonitrile to give 4-iodobenzamidoxime (5.97 g), m.p. 155°-161° C.; microanalysis, found: C, 31.4; H, 2.7; N, 10.2%; C7H7IN2 O 0.2H2O requires: C, 31.6; H, 2.81; R, 10.5%; NMR: 5.82(2H,s), 7.46(2H,d), 7.73(2H,d), 9.69(1H,s); m/z 263(M+H).
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[CH:3]=[C:4](Br)Br.[Li][CH2:17]CCC.CI>C1COCC1>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]#[C:4][CH3:17]
Reactant: [Li]CCCC
Reactant: COc1ccc(C(C)(C)C=C(Br)Br)cc1
Solvent: CI
Solvent: C1CCOC1
Product: CC#CC(C)(C)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a stirred solution of Compound 53 (335 mg, 1.00 mmol) in THF (10 ml) was added n-BuLi (1.69M in hexane, 1.19 ml, 2.01 mmol) at -78° C. under N2, then warmed up to 0° C., and stirred for 1.5 h. MeI (213 mg, 1.50 mmol) was added, and stirred for 1.5 h at 0° C. The mixture was quenched by the addition of NH4Cl aq., and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. This was purified by SiO2 chromatography to give Compound 54 (162 mg, 86%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:27]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:28][CH:29]=[CH:30][C:31]=1B(O)O)(=[O:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccnc(C(C)(C)O)n2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3ccnc(C(C)(C)O)n3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 264b (170 mg, 0.50 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (200 mg, 0.50 mmol), Pd(dppf)Cl2 (40 mg, 0.050 mmol), K3PO4 (212 mg, 1.0 mmol), water (0.5 mL), and tetrahydrofuran (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 264c as brown solid (200 mg, 54%). MS-ESI: [M+H]+ 612.3
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.N1C=CC=CC=1.ClCCl.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1)(=[O:32])[CH3:31]
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(C)=O)c23)cc1
Temperature: 4 °C
Reaction time: 96 h
Yield: 43.7 %

Procedure:
To a stirred solution of 4-amino-5-(4-methoxyphenoxy)quinazoline (1.0 g, 3.7 mmol) in 30 ml of dichloromethane pyridine (0.3 g, 3.7 mmol) and acetic anhydride (0.38 g, 3.7 mmol) were added at room temperature and stirring continued for 4 days. After evaporation under reduced pressure, 30 ml of 2-propanol was added and after cooling to 4° C. the solid was collected by filtration, washed, recrystallized from ethanol, filtrated again and dried at 50° C. in vacuo. to give 4-acetamido-5-(4-methoxyphenoxy)quinazoline (0.5 g, 45.4%, m.p. 174-175° C.).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.CCN(C(C)C)C(C)C.[F:23][C:24]([F:37])([F:36])[CH2:25][N:26]1[CH:35]2[CH:30]([CH2:31][CH2:32][CH2:33][CH2:34]2)[NH:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[NH:2]1[CH:3]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([N:29]3[CH:30]4[CH:35]([CH2:34][CH2:33][CH2:32][CH2:31]4)[N:26]([CH2:25][C:24]([F:36])([F:37])[F:23])[CH2:27][CH2:28]3)=[O:13])[CH:7]=2)[CH:5]=[N:1]1
Reactant: FC(F)(F)CN1CCNC2CCCCC21
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1CCN(CC(F)(F)F)C2CCCCC21
Reaction time: 24 h
Yield: 12.2 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.080 g, 0.41 mmol) was suspended in acetonitrile (2 mL) then DIPEA (0.158 mL, 0.90 mmol) and 1-(2,2,2-trifluoro-ethyl)-decahydro-quinoxaline (0.119 g, 0.54 mmol) were added followed by HATU (0.192 g, 0.50 mmol). The resulting mixture was stirred for about 24 hours and then further amounts of DIPEA (79 μL) and HATU (0.192 g) were added and stirring continued over the weekend. The mixture was evaporated and the residue was taken up in sodium hydroxide (1N) and stirred for 30 minutes. HCl (1 N, 2.5 mL) was added and the solution extracted with ethyl acetate (×3). The organics were dried over sodium sulfate, filtered and evaporated. The material was purified by HPLC, eluting with 5%-95% acetonitrile in water (0.1% formic acid) and the fractions containing the desired product were combined and freeze-dried to give the title compound as a white solid (0.020 g). LCMS m/z 399.17 [M+H]+ R.T.=10.05 min (Analytical Method 2).
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[CH:33]([CH:35]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36](OCC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:36]=[C:35]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:33](=[O:34])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CCOC(=O)C(C=O)Cc1ccccc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1ccccc1
Temperature: 160 °C
Yield: 39.8 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (120 mg, 0.236 mmol), ethyl 2-formyl-3-phenylpropanoate (122 mg, 0.591 mmol) and K2CO3 (98 mg, 0.709 mmol) in DMA (5 mL) was heated with a microwave reactor at 160° C. for 1 hour. Purification via MDAP then afforded the title compound as an off-white solid (47 mg, 39.7% yield). LCMS: rt=4.08 min, [M+H+]=501.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CC(C)=O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[O:14])[C:5]([O:12][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(C=O)c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1c(C=O)cc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.6 %

Procedure:
A solution of methyl 5-chloro-3-formyl-2-hydroxybenzoate (6.4 g, 30 mmol) in acetone (50 mL) was added with potassium carbonate (7.4 g, 54 mmol), the mixture was successively added with sodium iodide (0.60 g, 3.0 mmol) and methyl bromoacetate (6.9 g, 45 mmol), and the mixture was stirred at room temperature for 10 hours, and then refluxed for 5 hours by heating. The reaction mixture was cooled to room temperature, and then added with acetone, and the mixture was filtered through Celite. The solvent was evaporated from the filtrate under reduced pressure, the solid formed was suspended in hexane/ethyl acetate (9:1), thereby washed, and then collected by filtration to obtain the objective substance. The filtrate was concentrated under reduced pressure, and the residue was subjected to by silica gel column chromatography (eluted with hexane/ethyl acetate (9:1→1:1)) to further obtain the objective substance. Two portions of the objective substance were combined to obtain 6.5 g (75%) of methyl 5-chloro-3-formyl-2-(2-methoxy-2-oxoethoxy)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].[C:12]([NH:20][C:21]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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(OCC)(=O)C.C1(C)C=CC=CC=1>[C:12]([NH:20][C:21]1[CH:33]=[C:32]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Cl)cc2Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
91 mg of 2,4-dichlorophenol was added to 2.1 mL of toluene suspension containing 22 mg of 60% sodium hydride at room temperature, and the resulting mixture was heated to reflux under nitrogen atmosphere for 15 minutes. After the reaction mixture was cooled to room temperature, 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, 4.7 mg of 2-(di-tert-butylphosphine)-2′,4′,6′-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, 61 mg of 2,4-dichlorophenol, 15 mg of 60% sodium hydride, 4.7 mg of 2-(di-tert-butylphosphino)-2′, 4′,6′-triisopropylbiphenyl and 6.8 mg of tris(dibenzylideneacetone)dipalladium(0) were added and the resulting mixture was heated to reflux under nitrogen atmosphere for 10 hours. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated, sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane; ethyl acetate=20:1] to obtain tert-butyl 2-(benzamido)-4-(2,4-dichlorophenoxy)benzoate.
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]=[C:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13].C>CC(C)=O.CN(C)C1C=CN=CC=1>[C:1]([S:8][CH2:10][CH:11]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:12]([OH:14])=[O:13])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCC(=O)O)C(=O)O
Reactant: OC(=S)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CCC(CSC(=O)c1ccccc1)C(=O)O
Temperature: 60 °C

Procedure:
To a cooled solution (5° C.) of thiobenzoic acid (5.5 g, 39.8 mmol) in acetone (75 mL), was added 2-methyleneglutaric acid (5.25 g, 36.4 mmol) with stirring. To the resulting solution, 4-dimethylaminopyridine (0.5 g, 4.1 mmol) was added and the solution was stirred for 5 hours at 5° C. The temperature was slowly raised to 60° C. and refluxed for 20 hours. The resulting solution was treated with activated charcoal (1 g) and filtered. The clear solution was evaporated to a thick liquid and cold distilled water (100 ml) was added with rapid stirring. The white precipitate formed was filtered and suspsended in a saturated aqueous solution of NaHCO3. After stirring for 15 minutes, the suspension was filtered and the clear filtrate extracted with three portions of EtOAc. The aqueous fraction was then acidified with 18% HCl. The white precipitate formed was collected by filtration, washed with cold distilled water, and dried at 50° C. The crude product was crystallized from aqueous ethanol to yield white shiny crystals, representing a yield of 7.71 g (75%) of the captioned product (mp 144° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5](OC)[C:6]2[C:7](=[N:9][O:10][N+:11]=2[O-:12])[N:8]=1.[CH2:15]([N:17]([CH2:20][CH2:21][NH2:22])[CH2:18][CH3:19])[CH3:16]>CO>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH2:21][NH:22][C:5]1[C:6]2[C:7](=[N:9][O:10][N+:11]=2[O-:12])[N:8]=[C:3]([O:2][CH3:1])[N:4]=1)[CH3:16]
Reactant: CCN(CC)CCN
Reactant: COc1nc(OC)c2c(no[n+]2[O-])n1
Solvent: CO
Product: CCN(CC)CCNc1nc(OC)nc2no[n+]([O-])c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g (15 mmol) of 5,7-dimethoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide (J. Chem. Soc. Perkin Trans. 1, 1976, 1327), 1.75 g (15 mmol) of diethylaminoethylamine and 120 ml of methanol is stirred at room temperature for 2 hours and then concentrated in a rotary evaporator. The residue is dissolved hot in isopropanol, and the solution is filtered and treated with the same amount of hot petroleum ether. Overnight, 2.5 g (59%) of 7-(2-diethylaminoethylamino)-5-methoxy-[1,2,5]oxadiazolo[3,4-d]pyrimidine-1-oxide crystallise out.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.Br[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].[Cl-].[NH4+].O1CCCC1>[Zn]>[CH3:18][C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)([CH3:19])[CH:16]=[CH2:15]
Reactant: CC(C)=CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.62 h

Procedure:
To a suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (2.40 g, 0.0130 mol), 4-bromo-2-methyl-2-butene (3.00 mL, 0.0260 mol) in 15.0 mL sat'd. ammonium chloride and tetrahydrofuran (3.00 mL, 0.0370 mol) was added zinc (1.70 g, 0.0260 mol) at rt. Soon after stirring was started, gas and heat were released. After 30 to 45 min., the resulting light grey mixture was filtered through celite. The filtration was extracted with EtOAc. The organic layers were combined, washed with brine, dried (NaSO4) and concentrated in-vacuo. The residue was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product. LCMS (M+Na) 278.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:22][OH:23])[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:24]1([S:30]([O-:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[OH:23][CH2:22][C:4]1[C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=[C:2]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH:3]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3c(CO)cc(S(=O)(=O)c4ccccc4)cc3c2C1
Yield: 44 %

Procedure:
The product of step E and sodium benzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 1:1 hexane/ethyl acetate) provided tert-butyl 6-(hydroxymethyl)-8-(phenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (33 mg, 44%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.99-7.93 (m, 2H), 7.88 (d, J=1.6 Hz, 1H), 7.58-7.46 (m, 3H), 4.99 (d, J=6.0 Hz, 2H), 4.56 (s, 2H), 3.82 (s, 2H), 2.87 (s, 2H), 2.13 (t, J=6.0 Hz, 1H), 1.51 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:10]#[N:11])[N:3]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(C#N)n1
Temperature: 110 °C

Procedure:
2-Chloro-4,6-dimethylpyrimidine (3.3 g, 0.023 mol) was combined with zinc cyanide (2.7 g, 0.023 mol, 1 eq.) and tetrakis(triphenylphosphine)palladium (0) (2.7 g, 0.0023 mol, 0.1 eq.) in DMF (20 ml), and the slurry was heated at 110° C. under nitrogen for 0.5 h. The mixture was cooled to room temperature, diluted with EtOAc (70 ml) and washed twice with 2N ammonium hydroxide (50 ml). The EtOAc solution was washed with brine (20 ml) and concentrated in vacuum to provide the crude mixture. The crude was then purified by column chromatography (30% EtOAc/hexane) to afford 4,6-dimethylpyrimidine-2-carbonitrile. Yield: 0.8 g (26%). 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 6H), 7.21 (s, 1H). LCMS: (ES+) m/z=133.6 (M)+
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:11])=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14].O>CCCCCC>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][CH3:10])=[C:6]([CH3:11])[N:5]=1
Reactant: CCc1cc(C#N)c(=O)[nH]c1C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: CCc1cc(C#N)c(Cl)nc1C
Yield: 61.2 %

Procedure:
3-Cyano-5-ethyl-6-methyl-2-(1H)-pyridinone (22.9 g, 0.141 mol) and phosphorus pentachloride (33.1 g, 0.159 mol) were intimately mixed and heated at 110°-120° C. for one hour. The liquified solids were poured onto crushed ice and water and the semi-solid was extracted into chloroform. This extract was washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. This amber oil was dissolved in hexane and the insoluble material was removed when filtered through a pad of charcoal. Removal of the solvent gave a light yellow oil which solidified (17.7 g). Trituration of this solid with cold hexane yielded 15.6 g (61%) of pure product, m.p. 63°-64° C.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:1][C:2]([CH3:33])([CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])[CH2:13]1)[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)OC(C)(C)C)C3)c(C)o2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CCC(C)(C)C(=O)O)C3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
300 mg of tert-butyl 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyrate are dissolved in 20 ml of dichloromethane, and 10 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 1 hour. 200 ml of toluene are added and the solvents are then concentrated under reduced pressure. The residue is purified by RP-HPLC. This gives 180 mg of 2,2-dimethyl-4-[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexyl]butyric acid as an oil. C24H33NO4 (399.53), MS(ESI): 400 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH3:28].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:3]2[C:4](=[O:26])[C:5]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]2[CH3:1])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), (4-ethoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.47 g, 91%).