Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:31][CH3:32])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(CC)CC2)ncn1
Temperature: 60 °C
Yield: 43 %

Procedure:
To the stirred solution of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.20 g, 0.61 mmol) and potassium carbonate (0.10 g, 0.72 mmol) in DMF (3 ml) was added ethyl bromide (0.07 g, 0.05 ml, 0.61 mmol) at room temperature. The reaction mixture was heated at 60° C. for one hour. The progress of the reaction was monitored by TLC. The reaction mixture was poured onto ice water and extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether (3 ml), filtered and dried under high vacuum to afford 1-ethyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #3A) (0.093 g, 43%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][OH:23]>>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][O:23][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: OCc1cccc(F)c1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1cccc(F)c1F)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][NH:40][CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH:22]([F:43])[CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[C:31]3[CH2:42][CH2:41][N:40]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:39][C:32]3=[N:33][C:34]=2[NH:35][CH:36]([CH3:38])[CH3:37])[CH2:25][CH2:24]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCNC2
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (5.8 mg, 0.054 mmol) was added to a solution of 2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (14.3 mg, 0.027 mmol) and triethylamine (11 μL, 0.080 mmol) in DCM (270 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (14.3 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (dd, J=6.4, 1.9 Hz, 6H), 1.40-1.49 (m, 1H), 1.55-1.77 (m, 2H), 2.01 (d, J=13.1 Hz, 2H), 2.70-2.84 (m, 4H), 2.87-2.94 (m, 6H), 3.40-3.52 (m, 2H), 3.53-3.57 (m, 2H), 4.11 (quin, J=6.4 Hz, 1H) 4.29 (s, 2H) 5.53 (dd, J=46.2, 7.3 Hz, 1H), 6.97-7.09 (m, 2H), 7.47-7.55 (m, 1H); ESI-MS m/z [M+H]+ 491.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=1[CH3:25].[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([NH2:38])=[CH:36][C:35]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1>[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[C:37]([NH:38][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:14]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=4[S:21]([CH3:24])(=[O:23])=[O:22])[C:3]=3[CH3:25])=[CH:36][C:35]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[CH:34][N:33]=2)[CH2:28][CH2:27]1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)quinoline (50.0 mg, 0.13 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(5-methyl-2-(methylsulfonyl)phenyl)-quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.07 (1H, d, J=8.0 Hz), 7.83 (1H, d, J=12.5 Hz), 7.42-7.58 (3H, m), 7.21 (1H, br. s.), 7.05 (1H, ddd, J=13.6, 8.6, 2.6 Hz), 6.53 (1H, br. s.), 3.84-4.04 (4H, m), 3.78 (4H, d, J=4.3 Hz), 3.41 (2H, br. s.), 2.85-3.21 (9H, m), 2.50 (3H, s), 1.93 (3H, s). Mass Spectrum (ESI) m/e=610.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:32]4[CH2:37][CH2:36][CH:35]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:34][CH2:33]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(N2CCOCC2)CC1
Yield: 43 %

Procedure:
4-{1-[5-Chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazin-7-yl}benzoic acid (70 mg) was reacted with 4-piperidin-4-yl-morpholine as in General Procedure 8 to give the title compound as a light yellow foam (43% yield). M.p. (foam), LCMS: m/z=600.14 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.42-1.58 (m, 2H), 1.72-1.94 (m, 2H), 2.35-2.45 (m, 1H), 2.52-2.58 (m, 4H), 2.86-3.03 (m, 2H), 3.47-3.53 (m, 2H), 3.63-3.74 (m, 6H), 3.88-3.96 (m, 1H), 4.58 (s, 2H), 5.12 (s, 1H), 6.59 (d, J=1.3 Hz, 1H), 7.32-7.49 (m, 5H), 7.64 (d, J=8.3 Hz, 1H), 7.74 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH2:1]([O:15][C:16](=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]([OH:30])=[C:23]([OH:31])[CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(OC(=O)C)(=O)C>[C:1]([O:31][C:23]1[CH:22]=[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:32])[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24]=1[O:30][C:24](=[O:30])[CH3:23])(=[O:15])[CH3:2]
Reactant: CCCCCCCCCCCCCCOC(=O)CCCCc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CCCCc1cc(OC(C)=O)c(OC(C)=O)c([N+](=O)[O-])c1

Procedure:
A solution containing 0.1 g of the product obtained in Example 29 in 2 ml of acetic anhydride was refluxed for 20 min. The solvent was evaporated in vacuo and the residue crystallized from petroleum ether (b.p. 40° C.), m.p. 52°-54° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][CH:21]([CH3:24])[CH2:22][OH:23]>>[CH2:22]([O:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1)[CH:21]([CH3:24])[CH3:20]
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: CC(C)CO
Product: COc1ccc2c(OCC(C)C)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-propan-1-ol to give (1-isobutoxy-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 313 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].N1C=CN=C1.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:6]=[O:7]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COCCCOc1cc(C=O)ccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COCCCOc1cc(C=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
In a round bottom flask, 4-hydroxy-3-(3-methoxypropoxy)benzaldehyde (10 g, 47.6 mmol) was introduced. DMF (69 mL) was added. The solution was cooled to 0° C. and imidazole (8.09 g, 118.9 mmol), followed by triisopropylsilyl chloride (10.7 mL, 49.9 mmol) were added. The mixture was stirred for 2 hrs and the solvent was evaporated. A saturated aqueous ammonium chloride was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 12 g (69%) of the desired product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(O)C>[CH2:17]([NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[OH:8])[CH3:18]
Reactant: Nc1cc(CCc2ccccn2)ccc1O
Reactant: CCN=C=O
Solvent: CCO
Product: CCNC(=O)Nc1cc(CCc2ccccn2)ccc1O
Yield: 82.1 %

Procedure:
A solution of 2-[2-(3-amino-4-hydroxyphenyl)ethyl]pyridine (3.2 g) and ethyl isocyanate (1.58 g) in ethanol (80 ml) was stirred at 35° to 40° C. for 2 hours. The reaction mixture was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2-[2-{3-(3-ethylureido)-4-hydroxyphenyl}ethyl]pyridine (3.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:17](=[O:18])[C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][N:14]=[C:9]12)([O-:3])=[O:2]>C(O)(=O)C.Cl.O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]1[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]=[C:9]12)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cnc2c3cccc([N+](=O)[O-])c3ccn2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc2c3cccc([N+](=O)[O-])c3ccn2c1=O
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A suspension of ethyl 8-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (400 mg) in a mixture of acetic acid (20 ml) and 36% hydrochloric acid (4 ml) was heated at 80° C. for 5 hours. The mixture was cooled and diluted with water. The precipitated solid obtained was collected and dried to give 8-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylic acid (320 mg).
Reaction SMILES: [C:1]([C@:5]1([CH3:34])[C@@H:18]2[C@@:9]3([CH2:20][CH2:19][C@:16]4([CH2:17]2)[C@@:11]25[C:27]6[C:22](=[CH:23][CH:24]=[C:25]([OH:29])[C:26]=6[O:28][C@@H:10]32)[CH2:21][C@H:15]4[N:14]([CH2:30][CH:31]2C[CH2:32]2)[CH2:13][CH2:12]5)[O:8][CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].C(N1CC[C@@]23C4C5C[C@@H]1[C@H]2C[C@H]([C@](O)(C(C)(C)C)C)[C@H](O)[C@@H]3OC=4C(O)=C1CCC1=5)C=C.C1(CN2CC[C@@]34C5C6C[C@@H]2[C@H]3C[C@H]([C@](O)(C(C)(C)C)C)[C@H](O)[C@@H]4OC=5C(O)=C2CCC2=6)CC1>>[CH2:30]([N:14]1[CH2:13][CH2:12][C@@:11]23[C:27]4[C:22]5[CH2:21][C@@H:15]1[C@:16]12[CH2:19][CH2:20][C@:9]2([O:8][CH2:7][O:6][C@@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:34])[C@H:18]2[CH2:17]1)[C@@H:10]3[O:28][C:26]=4[C:25]([OH:29])=[CH:24][CH:23]=5)[CH:31]=[CH2:32]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Agent: C=CCN1CC[C@]23c4c5c6c(c(O)c4O[C@H]2[C@@H](O)[C@@H]([C@](C)(O)C(C)(C)C)C[C@@H]3[C@H]1C5)CC6
Agent: CC(C)(C)[C@@](C)(O)[C@H]1C[C@@H]2[C@H]3Cc4c5c(c(O)c6c4[C@@]2(CCN3CC2CC2)[C@@H](O6)[C@H]1O)CC5
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@]24CC[C@]3(C[C@@H]2[C@@](C)(C(C)(C)C)OCO4)[C@H]1C5
Yield: 49 %

Procedure:
The title compound 17 was synthesized similar to the procedure described in Example 1 for preparing compound 3 using compound 16 rather than compound 2. After column chromatography, 1.29 g (49.0% yield) of compound 17 was isolated in a purity of >99% as a-white solid.
Reaction SMILES: CC1C=CC(C)=CC=1.[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)[C:16](Cl)=O)(=[O:11])[CH3:10].[C:26]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=C)=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>CC([O-])=O.CC([O-])=O.[Pd+2].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:34][C:33]2[CH:36]=[CH:37][C:30]([O:29][C:26](=[O:28])[CH3:27])=[CH:31][CH:32]=2)[CH:19]=[C:20]([O:22][C:23](=[O:25])[CH3:24])[CH:21]=1)(=[O:11])[CH3:10]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(=O)Oc1cc(OC(C)=O)cc(C(=O)Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Solvent: Cc1ccc(C)cc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C=Cc2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
A 100 mL round bottom flask was charged with p-xylene (56 mL), Pd(OAc)2 (62.86 mg, 0.28 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (119.53 mg, 0.28 mmol), 3,5-diacetoxybenzoyl chloride (7.19 g, 28 mmol), 4-acetoxystyrene (5.35 mL, 33.6 mmol), and N-methyl morphorline (4.2 mL, 33.6 mmol). The mixture was stirred at 120° C. for 3.5 h at nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography (15% EtOAc/hexane, 25% EtOAc/Hexene, then 35% EtOAc/hexane) and gave resveratrol triacetate (6.95 g, 70.1%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.50 (d, 2H), 7.12-6.94 (m, 6H), 6.82 (t, 1H), 2.31 (s, 9H); 13C NMR (CDCl3, 75 MHz) 169.6, 169.2, 151.5, 150.6, 139.7, 134.7, 129.9, 127.9, 127.4, 122.1, 117.1, 114.6, 21.4; mp=116-118° C.; HRMS (EI+) found 354.1118 M+, calcd 354.1103 for C20H18O6; Anal. Calcd for C20H18O6: C, 67.79, H, 5.12. Found: C, 67.93, H, 5.26.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[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].[C:36](#N)[CH3:37].C[Si](C#C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[C:36]([C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([O:21][C:22]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH3:35])[N:29]=3)=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=1)=[O:6])#[CH:37]
Reactant: CC#N
Reactant: CNc1nccc(-c2cccnc2Oc2cc(Br)cc(C(=O)Nc3cccc(C(F)(F)F)c3)c2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cc(Oc2ncccc2-c2ccnc(NC)n2)cc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 3-Bromo-5-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-N-(3-trifluoromethyl-phenyl)-benzamide (110 mg, 0.20 mmol), acetonitrile (5 mL) and Et3N (1 mL) in a sealed tube was added trimethylsilyl acetylene (0.14 mL, 1.0 mmol) followed by PdCl2(PPh3)2 (14 mg, 0.02 mmol) and CuI (4.0 mg, 0.02 mmol). The tube was sealed and heated at 85° C. for 15 h. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The resulting crude mixture was reconstituted in methanol (5 mL), saturated with solid K2CO3 (˜200 mg) and allowed to stir at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and reconstituted in EtOAc (20 mL). The organic phase was washed successively with water (2×5 mL) and brine (1×5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via RP-HPLC to afford the title compound as an off-white solid. MS m/z=490 [M+1]+, Calc'd for C26H18F3N5O2: 489.45.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[C:10](=O)[CH2:9][CH2:8]3)=[CH:3][CH:2]=1.CC([O-])=O.[Na+].[NH2:20]O.[ClH:22].[BH4-].[Na+]>CO.Cl[Ni]Cl>[ClH:22].[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH:10]([NH2:20])[CH2:9][CH2:8]3)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C23CCC(=O)C2C3)cc1
Reactant: NO
Agent: Cl[Ni]Cl
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: Cc1ccc(C23CCC(N)C2C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-p-tolyl-bicyclo[3.1.0]hexan-2-one (100 mg, 0.54 mmol) and anhydrous NaOAc (87.5 mg, 1.1 mmol) in anhydrous MeOH (10 mL) was added with stirring NH2OH.HCl (69.5 mg, 1 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue, dioxime [IS THIS CORRECT?] was reconstituted in anhydrous MeOH (5 ml) and anhydrous NiCl2 (194 mg, 1.5 mmol) was added with stirring. The reaction mixture was cooled to −30° C. and NaBH4 (567 mg, 15 mmol) was added in small portions. After completion of the addition the mixture was allowed to warm to room temperature and concentrated in vacuo. This was then basified with aqueous solution of NaOH and extracted with CH2Cl2 (3×). Organic phases were concentrated and purified by silica gel chromatography. The oily product was converted to HCl salt (62 mg, 51%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].[F:13]C1C=CC(C(O)=O)=CC=1O>>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:13])[CH:6]=[O:7])[CH3:12]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: CCOc1cc(C=O)ccc1Cl
Product: CCOc1cc(C=O)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate B2, vide infra) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overall yield after purification by flash column chromatography on silica eluting with hexane/ethyl acetate (10:1). 1H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.12 (q, 7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56 (m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH4]+.
Reaction SMILES: [C:1]1(=O)C2C(=CC=CC=2)C(=O)N1.[O:12]=[C:13]([N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH2:14][C@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17].O=C(N1CC2C(=CC=CC=2)C1)C[C@@H](CC1C=CC=CC=1)C(O)=O.O=C(N1CC2C(=CC=CC=2)C1)CC(CC1C=CC=CC=1)C(O)=O>>[CH3:1][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[CH2:34][N:26]([C:13](=[O:12])[CH2:14][C@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17])[CH2:27]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(O)[C@H](CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Agent: O=C(O)C(CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Agent: O=C(O)[C@@H](CC(=O)N1Cc2ccccc2C1)Cc1ccccc1
Product: Cc1ccc2c(c1)CN(C(=O)C[C@H](Cc1ccccc1)C(=O)O)C2

Procedure:
By reproducing this example using as starting material 1H-isoindole-1,3-(2H)-dione, it was possible to prepare γ-oxo-α(S)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid, γ-oxo-α(R)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid and γ-oxo-α(R,S)-(phenylmethyl)-2,3-dihydro-1H-isoindole-2-butanoic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[C:20]([C:22](OC)=[O:23])[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+]>CCOCC>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[O:18][C:19]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCN(C(=O)OCc3ccccc3)CC2)oc1-c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC(c2nc(CO)c(-c3ccc(F)cc3F)o2)CC1

Procedure:
To a 0.5 liter round bottom flask fitted with a condenser, nitrogen inlet, and mechanical stirrer is added 30.25 g, 66.3 mmoles of 4-[5-(2,4-Difluoro-phenyl)-4-methoxycarbonyl-oxazol-2-yl]-piperidine-1-carboxylic acid benzyl ester, and a mixture of methanol and ether (4 mL to 200 mL). Lithium borohydride 2.17 g (0.1 mol) is added in three portions and then the mixture is stirred and heated to reflux for 30 minutes. The reaction is allowed to cool and carefully quenched with 400 mL of 0.5 N hydrochloric acid. The resulting mixture is extracted with 3×200 mL of methylene chloride. The organics are combined, washed with brine, dried over magnesium sulfate and concentrated to a thick residue to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[O:30]([CH3:32])[Na]>CO>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:30][CH3:32])=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: CO[Na]
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Yield: 98 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methane sulfonylamino-benzyl)-acrylamide (40 mg, 0.088 mmol) was reacted with 30% NaOCH3 in CH3OH to give the title compound (39 mg, 98%).
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-:15].[Na+]>CC(C)=O>[CH3:1][Si:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(CCCCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CCCCI)c1ccccc1
Yield: 92.6 %

Procedure:
Following the same procedure as in Example 44 Step A, 5 g (19 mmol) of dimethyl-(4-chlorobutyl)-phenylsilane in 150 ml of acetone are refluxed for 60 hours with 17 g (114 mmol) of sodium iodide to afford 5.6 g (83%) of expected dimethyl-(4-iodobutyl)-phenylsilane.