Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([C:11](I)=[CH:12][N:13]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:11]2[N:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]3=[N:13][CH:12]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccn2c(I)cnc12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)c1cccn2c(-c3ccc(F)cc3)cnc12
Reaction time: 16 h

Procedure:
To a degassed (with Argon gas) solution of 3-iodo-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (2.2 g, 7.3 mmol) and 4-fluorophenyl boronic acid (1.48 g, 9.44 mmol) in a 1:1 mixture of ethanol-benzene (100 mL) is added an aqueous solution of 2 M sodium carbonate (9 mL, 18 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.42 g, 0.36 mmol) and the reaction mixture is warmed at reflux. After 16 hours, the reaction mixture is filtered through filter agent washing with EtOAc. The filtrate is diluted with water and the organic layer is separated. The pH of the aqueous layer is adjusted to 4-5 with 6 N aqueous HCl. The solid is collected by filtration and triturated with Et2O to afford the title compound. Mp: >400° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[N:9][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([C:33]#[C:34][Si](C)(C)C)[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:23])=[O:22])[CH2:17][CH2:16]3)=[O:14])=[N:11][CH:12]=2)=[CH:3][CH:2]=1.[OH-].[K+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([S:21]([C:24]4[S:28][C:27]5[CH:29]=[C:30]([C:33]#[CH:34])[CH:31]=[CH:32][C:26]=5[CH:25]=4)(=[O:22])=[O:23])[CH2:19][CH2:20]3)=[O:14])=[N:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C#Cc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ncc(-c5ccncc5)cn4)CC3)sc2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2cc(S(=O)(=O)N3CCN(C(=O)c4ncc(-c5ccncc5)cn4)CC3)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
In a mixed solvent of tetrahydrofuran (5 ml) and methanol (7 ml) was dissolved 1-[[5-(4-pyridyl)pyrimidin-2-yl]carbonyl]-4-[(6-trimethylsilylethynylbenzo[b]thien-2-yl)sulfonyl]piperazine (167 mg), followed by the addition of potassium hydroxide (34 mg). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was made weakly acidic with a saturated aqueous solution of ammonium chloride, and then made weakly alkaline with a saturated aqueous solution of sodium bicarbonate. After concentration under reduced pressure, the concentrate was extracted (4 times) with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=1:0→24:1). The resulting amorphous was dissolved in methylene chloride, followed by the dropwise addition to hexane to precipitate the resulting mixture as powder. The title compound (112 mg) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH3:19])[CH2:15][C:16](O)=O)=[O:13])[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24]([NH2:30])[C:25]([NH2:29])=[CH:26][C:27]=1[Cl:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]([CH2:15][C:16]3[NH:29][C:25]4[CH:26]=[C:27]([Cl:28])[C:22]([Cl:21])=[CH:23][C:24]=4[N:30]=3)[CH3:19])=[O:13])[C:6]=2[CH:20]=1
Reactant: CN(CC(=O)O)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)C(=O)Cn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a mixture of N-[(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)acetyl]-N-methylglycine (90 mg), 4,5-dichlorobenzene-1,2-diamine (53 mg), and DMF (3 mL) were added TEA (95 μL), HOBt (43 mg), and WSC.HCl (60 mg), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, a saturated aqueous NaHCO3 solution, and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. To the residue was added acetic acid (3 mL), followed by heating and stirring at 110° C. for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The resulting solid was collected by filtration and then washed with MeOH to obtain 2-(5-chloro-2-oxo-1,3-benzothiazol-3(2H)-yl)-N-[(5,6-dichloro-1H-benzimidazol-2-yl)methyl]-N-methylacetamide (54 mg).
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[OH:18]C1C=C(C=C(O)C=1)C=O.OC1C=C(C=C(O)C=1)C=C.C(OC1C=CC(I)=CC=1)(=O)C>>[C:1]1([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[CH:12]1[C:11](/[CH:10]=[CH:9]/[C:1]2[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=2)=[CH:17][C:16]([OH:18])=[C:14]([OH:15])[CH:13]=1
Reactant: O=Cc1cc(O)cc(O)c1
Agent: C=Cc1cc(O)cc(O)c1
Agent: CC(=O)Oc1ccc(I)cc1
Agent: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Product: Oc1cc(O)cc(/C=C/c2ccc(O)c(O)c2)c1

Procedure:
Processes for the preparation of resveratrol have been disclosed, inter alia, in WO 01/60774 and Tetrahedron Letters 43 (2002) 597-598. The latter reference describes a process wherein resveratrol is prepared by a multistep reaction sequence starting with 3,5-dihydroxybenzaldehyde and involving a Heck reaction of 3,5-dihydroxystyrene with 4-acetoxy-iodobenzene in a yield of 70%. The process of the present invention utilizes a more readily available starting material and proceeds in less steps and superior yield, thus providing a technically more attractive approach to resveratrol and piceatannol and derivatives, such as esters, thereof.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[NH:24])[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH3:23])[CH:16]=1)([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[CH2:31][CH:32]=O.CC(O)C>O.C(OCC)(=O)C>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5]=1[N:13]1[CH:32]=[CH:31][N:24]=[C:14]1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH3:23])[CH:16]=1)([CH3:12])[CH3:11]
Reactant: COc1cc(C)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C)cc(-c2nccn2-c2c(C(C)C)cccc2C(C)C)c1

Procedure:
To a 250 mL round bottom flask was mixed N-(2,6-diisopropylphenyl)-3-methoxy-5-methylbenzimidamide (5.83 g, 17.97 mmol), sodium bicarbonate (3.02 g, 35.9 mmol), 2-chloroacetaldehyde (50%, 4.56 ml, 35.9 mmol), and 80 mL of 2-propanol. The reaction mixture was heated to reflux for 3 hours under nitrogen. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, evaporated leaving a brown oil. The oil was purified by column chromatography eluting with 20% ethyl acetate/hexane (5.78 g, 92%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[CH:15]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:30]([OH:33])[C:31]#[CH:32]>N1CCCC1.C(Cl)Cl.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>[N:24]1([C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:14]3[CH:15]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([C:32]#[C:31][CH2:30][OH:33])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=[N:13]3)=[CH:21][CH:20]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(Br)ccc34)nn2)cc1)N1CCOCC1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(C#CCO)ccc34)nn2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
A mixture of {4-[4-(6-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), propargyl alcohol (39 μl; 0.66 mmol; 2.0 eq.) and Pd(PPh3)4 (19 mg, 0.02 mmol, 0.05 eq.) in pyrrolidine (1.5 mL) was heated O/N at 80° C. in a sealed tube. The reaction mixture was then diluted with DCM and washed with a saturated solution of NH4Cl (three times) and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (40 mg, 28%). 1H NMR (300 MHz, DMSO-d6-d6): 13.50 (brs, 1H), 9.42 (s, 1H), 8.34 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.70-7.67 (m, 3H), 7.28 (dd, J=8.5 Hz, 1.0 Hz, 1H), 5.40 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.64 (m, 6H), 3.47 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([N:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:15][N:13]([CH3:14])[C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=[CH:10][C:11]=1[NH:16][C:28](=[O:29])[CH:27]([N:19]1[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[N:22]=[C:18]1[CH3:17])[CH3:31]
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Reactant: CN(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A mixture of crude 2-(4-fluorophenyl)-N3,N3-dimethyl-pyrazole-3,4-diamine (from step b, 0.042 g, 0.18 mmol), 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.060 g, 0.27 mmol), HATU (0.10 g, 0.27 mmol), and 100 μL of Et3N in 1 mL of CH2Cl2 was stirred at room temperature. After 30 minutes, the reaction mixture was diluted with 10 mL of aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) afforded the title compound as a colorless solid (0.019 g, 0.045 mmol, 25% for 3 steps). 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.53-7.43 (m, 2H), 7.27 (s, 1H), 7.17-7.08 (m, 2H), 6.91 (s, 1H), 4.90 (q, J=7.2 Hz, 1H), 2.53 (s, 6H), 2.45 (s, 3H), 1.85 (d, J=7.2 Hz, 3H). MS: (ES) m/z calculated for C19H20F4N6O1 [M+H]+ 424.2, found 424.1.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1.N>CO.[Pd]>[C:14]([C:10]1[CH:9]=[C:8]2[C:13]([CH:4]([NH2:3])[CH2:5][CH2:6][O:7]2)=[CH:12][CH:11]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CON=C1CCOc2cc(C(C)(C)C)ccc21
Agent: [Pd]
Agent: N
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)OCCC2N
Yield: 104 %

Procedure:
The product of Example 1B (1.53g) was taken into a solution of 20% ammonia in methanol, and hydrogenated for 4 hours at 60 psi at 50° C. in the presence of 1.55 g of 10% palladium on carbon as catalyst. The reaction mixture was filtered to remove catalyst, and the solvent removed under reduced pressure to give 1.40 g of the title compound (93% for two steps). 1H NMR(300 MHz, CDCl3) δ 7.25 (d, 1H, J=6.8 Hz), 6.96 (dd, 1H, J=2.0 and 8.1 Hz), 6.85 (d, 1H, J=2.0 Hz), 4.18-4.32 (m, 2H), 4.04 (t, 1H), 2.11-2.21 (m, 1H), 1.80-1.90 (m, 1H), 1.29 (s, 9H). MS (DCI) m/e 206 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].[N:24]1([CH2:29][CH2:30][CH2:31]O)[CH:28]=[CH:27][N:26]=[N:25]1>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][C:6]3[C:5]4[C:10](=[CH:11][C:2]([O:1][CH2:31][CH2:30][CH2:29][N:24]5[CH:28]=[CH:27][N:26]=[N:25]5)=[C:3]([O:22][CH3:23])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1O
Reactant: OCCCn1ccnn1
Product: COc1cc2c(Nc3ccc4[nH]ccc4c3)ncnc2cc1OCCCn1ccnn1
Yield: 42.1 %

Procedure:
Using an analogous procedure to that described in Example 205, 7-hydroxy-4-(indol-5-ylamino)-6-methoxyquinazoline (98 mg, 0.32 mmol), (prepared as described for the starting material in Example 201), was reacted with 3-(1,2,3-triazol-1-yl)propan-1-ol (61 mg, 0.48 mmol) to give 4-(indol-5-ylamino)-6-methoxy-7-(3-(1,2,3-triazol-1-yl)propoxy)quinazoline (56 mg, 42%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:25]([O:24][C:22]([C:20]1[N:21]=[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[NH:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1c[nH]c(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(C2CCNCC2)n1
Yield: 99.6 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(4-ethoxycarbonylimidazol-2-yl)piperidine (0.82 g) in ethanol (20 mL) was hydrogenated over 10% palladium on carbon (0.10 g) at a hydrogen pressure of 3.45 bar for 1 hour. The mixture was filtered through diatomaceous earth and the filter cake was washed with ethanol. The filtrate was evaporated to leave the piperidine derivative as a white foam (0.510 g); NMR: 7.65 (s, 1), 4.18 (q, 2, J=7.1), 2.99 (broad d, 2, J=12.2 H), 2.75 (m, 1), 2.55 (m, 2), 1.80 (broad d, 2, J=12.6), 1.57 (m, 2), 1.25 (t, 3, J=7.1); MS: m/z=252(M+1+28).
Reaction SMILES: Cl.[NH2:2][OH:3].CC([O-])=O.[Na+].[C:9]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[CH:14][C:13]=1[OH:20])(=O)[CH3:10].CCO>O>[Br:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([CH2:9][CH:10]=[N:2][OH:3])=[C:13]([OH:20])[CH:14]=1
Reactant: CC(=O)c1cc(C)c(Br)cc1O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(CC=NO)c(O)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of hydroxylamine hydrochloride (400 mg, 5.8 mmol) in 1 ml water was added to a solution of NaOAc in 1 ml water. To the resulting solution was added 1-acetyl-4-bromo-2-hydroxy-5-methylbenzene (101) (1.14 g, 5 mmol) followed by addition of 15 ml EtOH. The reaction mixture was stirred at 80° C. for 1 h. After concentrated to half of it's volume, the reaction mixture was poured in to 60 ml ice-water. Precipitate formed was filtered, washed with water and dried to give 1.19 g (yield: 97.5%, purity>95%) 5-bromo-2-((hydroxyimino)ethyl)-4-methylphenol (102) as white solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:22](=O)[CH3:23])[C:15]([O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[O:16].[NH2:25][C:26]([CH3:31])=[CH:27][C:28](=[O:30])[CH3:29]>C(O)C>[C:28]([C:27]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])=[C:22]([CH3:23])[NH:25][C:26]=1[CH3:31])(=[O:30])[CH3:29]
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CC1
Reactant: CC(=O)C=C(C)N
Solvent: CCO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
648 mg (1.98 mmol) of cyclopropylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 196 mg (1.98 mmol) of 4-aminopent-3-en-2-one in 10 ml of ethanol and heated under reflux under argon for 24 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 327 mg (41% of theory) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][O:5][C:6]=1[CH3:7].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:50]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1)#[CH:51]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][C:6]1[O:5][N:4]=[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]=1[C:51]#[C:50][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1
Reactant: Cc1onc(-c2ccccc2)c1I
Reactant: C#Cc1ccccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccccn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
A mixture of 4-iodo-5-methyl-3-phenylisoxazole (285 mg, 1.00 mmol), palladium(II) acetate (7 mg, 0.03 mmol), 1,3-bis(diphenylphosphino)propane (12 mg, 0.03 mmol), triethylamine (348 μL, 2.50 mmol) and 2-ethynylpyridine (131 μL, 1.30 mmol) in N,N-dimethylformamide (2 mL) was evaporated and flushed with argon. Cuprous iodide (4 mg, 0.02 mmol) was added and the reaction mixture was stirred for 3 h at 90° C. before cooling to ambient temperature and separated between aqueous sodium hydroxide (1 M, 30 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and washed with aqueous sodium hydroxide (1 M, 30 mL). The combined organic layers were dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (60 mg, 23%) as a light brown solid. MS: m/e=261.2 [M+H]+.
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][CH:13]=[C:14]([C:16](=[O:18])[NH2:17])[N:15]=2)[CH2:7][CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:40]2[C@H:41]([CH3:64])[C@H:42]3[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]3[C:44]=2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:16]([C:14]1[N:15]=[C:11]([N:8]2[CH2:7][CH2:6][CH:5]([S:4][C:40]3[C@H:41]([CH3:64])[C@@H:42]4[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]4[C:44]=3[C:45]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=3)=[O:46])[CH2:10][CH2:9]2)[S:12][CH:13]=1)(=[O:18])[NH2:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CCN(c2nc(C(N)=O)cs2)CC1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CCN(c4nc(C(N)=O)cs4)CC3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 4-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)piperidine (400 mg, 1.40 mmol) (obtained as described in Reference Example 15) in dimethylformamide (20 ml) was added hydrazine acetate (142 mg, 1.54 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 2 hours. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.25 g, 2.10 mmol) in acetonitrile (37 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.61 ml, 3.50 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (10:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)piperidin4-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate as a pale yellow solid (348 mg, yield 42%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][CH:7]([N:15]=[N+]=[N-])[C@@H:6]1[Cl:18])(=[O:3])[CH3:2].[H][H]>O1CCOCC1.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][CH:7]([NH2:15])[C@@H:6]1[Cl:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(N=[N+]=[N-])[C@H](Cl)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1OC(N)[C@H](Cl)[C@@H]1OC(C)=O
Yield: 99 %

Procedure:
Compound (30) obtained in step (2) above (300 mg) was dissolved in dioxane (6 ml). The solution obtained was subjected to a catalytic reduction by blowing hydrogen therein at room temperature in the presence of palladium black as catalyst for 1 hour. The resulting reaction solution was filtered and the filtrate was concentrated to about a half volume and then diluted with dichloroethane (50 ml). The solution as diluted was dried over calcium chloride and concentrated to afford compound (31) as a colorless syrup (270 mg).
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:26][CH2:27][CH2:28]Cl)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Na+].[I-].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(#N)C.O>[C:1]([NH:4][C:5]([CH2:26][CH2:27][CH2:28][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: C1CCNC1
Reactant: CC(=O)NC(CCCCl)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)NC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(CCCN1CCCC1)C(=O)NC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 2-acetamido-N-tert-butyl-2-(3-chloropropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.39 g, 0.9 mmol) in acetonitrile was treated with NaI (10% mol) and pyrolidine (0.75 mL, 9 mmol). The mixture was warmed to 50° C. and stirred overnight. After cooling to room temperature, the reaction was diluted with water, extracted with dichloromethane, dried over MgSO4, and concentrated to give crude 2-acetamido-N-tert-butyl-2-(3-(pyrrolidin-1-yl)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.31 g). This material was used in the next step without further purification. ESI MS found for C25H48BN3O4 m/z [466.6 (M+1)].