Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH:21]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])=[CH2:22].C(N(C(C)C)CC)(C)C.C1(C)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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][CH:8]=[C:7]2[CH:22]=[CH:21][N:23]2[C:24](=[O:33])[C:25]3[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:28])=[CH:12][CH:13]=1
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(C=CN3C(=O)c4ccccc4C3=O)c2c1
Temperature: 25 °C
Yield: 80 %

Procedure:
In a reactor, 2 g of the compound obtained in Step A, 2 eq. of N-vinylphthalimide, 1.25 eq. of diisopropylethylamine and 0.05 eq. of palladium tetrakis(triphenylphosphine) are introduced into toluene and heated at reflux. The reaction is continued at reflux for 12 hours and then the reaction mixture is cooled to ambient temperature. Ethyl acetate is added, and then washings with water and IN HCl solution are carried out. After evaporating off the solvents, the residue obtained is purified by chromatography on silica gel (eluant:dichloromethane/heptane 1/1, and then dichloromethane) to yield the title product in a yield of 80% and with a chemical purity of more than 95%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C@@H:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[C:29](=[O:31])[NH2:30])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:6][CH:5]=1.[CH2:33]([NH2:35])[CH3:34]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3](=[O:2])[NH:35][CH2:33][CH3:34])=[CH:9][CH:8]=2)[C@H:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[C:29]([NH2:30])=[O:31])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CCN
Reactant: COC(=O)c1ccc(CN([C@@H]2CCCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCNC(=O)c1ccc(CN([C@H]2CCCCC[C@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
cis-4-[[(2-Carbamoyl-cycloheptyl)-(4-chlorobenzenesulfonyl)-amino]-methyl]-benzoic acid methyl ester (50 mg, 0.10 mmol) and ethylamine (1.0 M in MeOH, 6 mL) were heated with stirring at 60° C. for 16 h. The solution was concentrated to dryness and the product purified by silica-gel column chromatography (20%–90% EtOAc/Hexanes) to afford 9.0 mg (18% yield) of the titled compound: 1 H NMR (DMSO-d6) δ 7.89 (m, 1 H), 7.80 (d, 2 H, J=8.0 Hz), 7.72 (d, 2 H, J=8.0 Hz), 7.64 (d, 2 H, J=8.0 Hz), 7.36 (d, 2 H, J=8.0 Hz), 7.32 (s br, 1 ), 6.67 (s br, 1 H), 4.58 (AB2,2 H,Δv=16,Jab=108 Hz), 3.97 (m, 1 H), 2.76 (m, 1 H), 2.26 (m, 2 H), 1.72 (m, 2 H), 1.35 (m, 8 H), 1.12 (t, 3 H, J=8.0 Hz); MS m/e 492.29 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]3[CH:15]=[C:16]([C@@:21]4([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@H:24]([OH:29])[C@@H:23]([CH2:30][OH:31])[O:22]4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:35]([Si:38]([CH3:40])([CH3:39])[O:31][CH2:30][C@H:23]1[O:22][C@:21]([C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([CH2:13][C:11]3[S:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH:15]=2)([O:32][CH3:33])[C@H:26]([OH:27])[C@@H:25]([OH:28])[C@@H:24]1[OH:29])([CH3:37])([CH3:36])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 16 h
Yield: 89.4 %

Procedure:
(2S,3R,4S,5S,6R)-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 9d (1.8 g, 3.8 mmol) was dissolved in 20 mL pyridine, followed by addition of 4-dimethylamino pyridine (93 mg, 0.76 mmol) and TBSCl (686 mg, 4.55 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, dissolved in 30 mL ethyl acetate and was partitioned after 30 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extracts were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system A to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tertbutyl(dimethyl)silyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 9e (2.0 g, orange solid), yield: 89.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH3:11])[C:3]=1[O:12][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc([N+](=O)[O-])cc(C)c1OCCN1CCCC1

Procedure:
1-[2-(2,6-dimethyl-4-nitrophenoxy)ethyl]pyrrolidine was prepared in a manner analogous to the alkylation described in Example 1, from 2,6-dimethyl-4-nitrophenol (1.0 g, 5.98 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.52 g, 8.97 mmol) and caesium carbonate (5.83 g, 17.94 mmol) to give the desired product as a brown oil. 6H (CDCl3) 7.89 (2H, s), 3.96 (2H, t, J 6.1 Hz), 2.93 (2H, t, J 6.1 Hz), 2.65 (4H, m), 2.35 (6H, s) and 1.83 (4H, m). MS (ES+) 265 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH2:25]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:25])[CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: C=O
Reactant: O=C(O)c1cn(CCF)c2nc(N3CCNCC3)c(F)cc2c1=O
Solvent: O=CO
Product: CN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1
Temperature: 110 °C

Procedure:
A mixture of 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid (3.0 g), 37% formalin (4 ml) and formic acid (9 ml) is heated at 110° C. for 16 hours with stirring. The reaction mixture is concentrated to dryness under reduced pressure. The residue is dissolved in 10% aqueous ammonia, treated with active charcoal, and filtered. The filtrate is adjusted to pH 8-8.5 with 10% hydrochloric acid. The precipitate is collected by filtration, and recrystallized from acetonitrile to give 2.67 g of 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 1), m.p. 224°-226° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl.[CH3:50][CH:51]([CH3:67])[CH2:52][CH:53]([NH2:66])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[N:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:66][CH:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[N:60]2[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]2)[CH2:52][CH:51]([CH3:67])[CH3:50])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(CC(C)C)c2ccccc2N2CCCCC2)cc1OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3 g (11.9 mmols) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid, 3.7 g (14.3 mmols) of triphenylphosphine, 3.3 ml (23.8 mmols) of triethylamine and 1.15 ml (11.9 mmols) of carbon tetrachloride were added successively to a solution of 2.9 g (11.9 mmols) of 3-methyl-1-(2-piperidino-phenyl)-1-butylamin in 29 ml of acetonitrile. The mixture was then stirred for 15 hours at room temperature, the solvent was removed in vacuo, and the residue was taken up in a mixture of ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silaca gel (toluene/acetone=10/1).
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[C:5]1([S:11][C:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[NH:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[C:5]1([S:11][C:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]([CH2:2][CH2:3][CH3:4])[C:13]=2[C:21]([NH2:23])=[O:22])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: CCCn1c(C(N)=O)c(Sc2ccccc2)c2ncccc21
Yield: 30.8 %

Procedure:
Add 1-bromopropane (19 mg, 0.154 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amide (Ia-1, 31.5 mg, 0.12 mmol), Cs2CO3 (60 mg, 0.185 mmol) in pyridine (0.5 ml). Heat the reaction at 80° C. in a sealed vessel for 1 hr. Cool the mixture and extract into ethyl acetate from water. Separate the organic phase and evaporate. Purify the residue (33 mg) by flash chromatography (SiO2, 2 gm, elute with heptane:DCM then MeOH 0-4% in DCM) to provide title compound (11.5 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=311) are consistent for the title compound structure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19]Br)=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:43]([NH2:46])[CH:44]=[CH2:45]>ClCCl>[C:1]([O:5][C:6](=[O:42])[NH:7][C:8](=[N:23][C:24](=[O:41])[CH2:25][C:26]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH:39]=[CH2:40])=[CH:33][CH:32]=1)=[N:27][O:28][CH2:29][CH3:30])[CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([NH:17][C:18](=[O:21])[CH2:19][NH:46][CH2:43][CH:44]=[CH2:45])=[C:12]([Cl:22])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCOc1ccc(C(CC(=O)N=C(Cc2cc(Cl)c(NC(=O)CBr)c(Cl)c2)NC(=O)OC(C)(C)C)=NOCC)cc1
Reactant: C=CCN
Solvent: ClCCl
Product: C=CCNCC(=O)Nc1c(Cl)cc(CC(=NC(=O)CC(=NOCC)c2ccc(OCC=C)cc2)NC(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl-1-(3-(4-(allyloxy)phenyl)-3-(ethoxyimino)-propanoylimino)-2-(4-(2-bromoacetamido)-3,5-dichlorophenyl)ethylcarbamate (100 mg) in dichloromethane (0.30 mL) at room temperature was added allylamine (32 μL), and the resulting solution was stirred at room temperature for 2 h. The solvents were removed in vacuo to give the title compound as a white solid, which was used in Step H without purification. retention time: 2.07 min (method A). MS (ESI) (M+H)+ 675.20.
Reaction SMILES: [SH:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:3]=1[C:4](=O)[CH:5]=[CH:6][CH:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1.C(N(CC)CC)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].O>ClCCl>[CH3:19][O:18][C:14]1[C:3]2[C:4]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:28]([C:29]([O:31][CH3:32])=[O:30])[S:1][C:2]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CBr
Reactant: COc1cccc(S)c1C(=O)C=CC1C=CC=CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc2cccc(OC)c2c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2′-mercapto-6′-methoxydihydrochalcone (1.2 g) and triethylamine (0.92 mL) in dichloromethane (10 mL) was added methyl bromoacetate (0.46 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (15 mL). To the solution was added sodium methoxide (28% methanol solution, 1.7 mL), and the mixture was stirred at room temperature overnight. The crystals precipitated from the reaction mixture were collected by filtration and dried under reduced pressure to give the title compound (1.09 g).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.Cl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3c(=O)[nH]2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Product: O=c1[nH]c(-c2ccc(O)cc2)cc2ccc(O)cc12
Temperature: 140 °C
Yield: 79 %

Procedure:
The compound 7-methoxy-3-(4-methoxyphenyl)isoquinoline-1(2H)-one (300 mg, 1 mmol), benzyltriethylammonium chloride (1.68 g, 7 mmol) and 37% hydrochloric acid (20 mL) are introduced into a sealed tube. The medium is heated for 20 hours at 140° C. then the mixture is evaporated to dryness under reduced pressure. After the addition of water (20 mL) to the residue obtained, a precipitate is formed. It is filtered and dried under in order to produce the expected 7-hydroxy-3-(4-hydroxyphenyl)isoquinoline-1(2H)-one 57 (200 mg, 74%) in the form of a brown solid.
Reaction SMILES: F[C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:12][C@H:13]1[O:18][C@@H:17]([CH3:19])[CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:19][C@@H:17]1[CH2:16][N:15]([C:2]2[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=2)[CH2:14][C@H:13]([CH3:12])[O:18]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(O)c1ncc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2cc(F)cnc2C(=O)O)C[C@H](C)O1
Yield: 102.2 %

Procedure:
A solution of 3,5-difluoropicolinic acid (20.5 g, 128.86 mmol), cis-2,6-dimethylmorpholine (63.5 ml, 515.43 mmol) and DIEA (45.0 ml, 257.72 mmol) in THF (200 ml) was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and extracted 3 times with aqueous Na2CO3. The aqueous layer was acidified with 1N HCl to bring pH to about 3 and was then saturated with NaCl before being extracted 10 times with EtOAc. The EtOAc layers were dried (MgSO4) and solvent was removed to give 33.5 g of product as a solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:3])=O.N1C2C(=CC=CC=2)C(=O)NC1=O.BrCCC1C=C(C=CC=1)C(OC)=O.[N:49]1([C:55]2[N:60]=[CH:59][CH:58]=[CH:57][N:56]=2)[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[N:56]1[CH:57]=[CH:58][CH:59]=[N:60][C:55]=1[N:49]1[CH2:54][CH2:53][N:52]([C:1]([C:4]2[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=2)[CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[NH:11][C:10]2=[O:20])=[O:3])[CH2:51][CH2:50]1
Reactant: O=C(O)c1cccc(CCn2c(=O)[nH]c(=O)c3ccccc32)c1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: COC(=O)c1cccc(CCBr)c1
Agent: O=c1[nH]c(=O)c2ccccc2[nH]1
Product: O=C(c1cccc(CCn2c(=O)[nH]c(=O)c3ccccc32)c1)N1CCN(c2ncccn2)CC1

Procedure:
The compound was prepared from 1-(3-carboxyphenethyl)quinazoline-2,4(1H,3H)-dione (prepared from quinazoline-2,4(1H,3H)-dione and methyl 3-(2-bromoethyl)benzoate using a procedure similar to those used for Examples 1 and 2) and 2-(piperazin-1-yl)pyrimidine using a procedure similar to those described for the synthesis of compound of Example 3. 1H NMR (DMSO-d6): 11.54 (s, 1H), 8.37 (d, J=4.8 Hz, 2H), 7.78 (dd, J=7.8 and 1.5 Hz, 1H), 7.73 (t, J=6.9 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.35-7.22 (m, 5H), 6.66 (t, J=4.7 Hz, 1H), 4.28 (t, J=7.5 Hz, 2H), 3.80-3.20 (m, 8H), 2.95 (t, J=7.4 Hz, 1H). MS: m/z 457.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[O-:30][N+:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a dichloromethane solution (0.1 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added 3-chloroperoxybenzoic acid (1 eq.). The resulting colorless solution was stirred at RT for 13 h. The reaction was then quenched with sat. aq. NaHSO3 and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(COc2cnc(Cl)n(C)c2=O)cc1
Reactant: OB(O)c1cccc(O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2cnc(-c3cccc(O)c3)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 14.1 %

Procedure:
To a solution of 2 g (7.12 mmol) 2-chloro-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one in 20 ml TI-IF was added 521 mg (0.712 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 1.33 g (9.62 mmol) 3-hydroxyphenylboronic acid, and 11.4 ml (11.4 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 30 min in the microwave, then diluted with 10 ml water, extracted with 100 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (50 g silica gel, 0-100% EtOAc:hexane) gave 340 mg (14% yield) of 2-(3-hydroxyphenyl)-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one. LCMS [M+H]+=339.0.
Reaction SMILES: Br.Br.[CH3:3][N:4]([CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:5].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[CH3:5][N:4]([CH2:6][C:7]1([C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1)[CH3:3]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CC1NCCc2cc(O)ccc21
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)CC1(C(=O)Cc2ccc(Cl)c(Cl)c2)NCCc2cc(O)ccc21

Procedure:
Prepared as Ex. No. 5, from 5 g (13.58 mmoles) of 1-dimethylaminomethyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 3.7 g (18.13 mmoles) of 3,4-dichlorophenylacetic acid, 5 ml (35.57 mmoles) of triethylamine and 5.6 g (27.32 mmoles) of dicyclohexylcarbodiimide in 125 ml of dry chloroform.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([NH2:16])[C:14]([CH3:18])([CH3:17])[O:13][N:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1.[CH2:19]([C:21]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20].O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([NH:16][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:21]=3[CH2:19][CH3:20])[C:14]([CH3:18])([CH3:17])[O:13][N:12]=2)[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: Cc1cc(C)cc(C2=NOC(C)(C)N2N)c1
Reactant: CCc1c(OC)cccc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1c(OC)cccc1C(=O)NN1C(c2cc(C)cc(C)c2)=NOC1(C)C
Temperature: 25 °C
Reaction time: 30 h
Yield: 39.6 %

Procedure:
A 5% aqueous solution of NaOH (4 mL) was added to a solution of 3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[ 1 ,2,4]oxadiazol-4-ylamine (90 mg) in 6 mL of toluene. 2-Ethyl-3-methoxybenzoyl chloride (140 mg) was then added to the mixture. The reaction was stirred at room temperature for 30 hours. Water and CHCl3 were added. The organic phase was separated, dried over MgSO4, and the solvent was removed in vacuo. The residue was triturated with 100 mL of 10% ether in hexane by magnetic stirring of the mixture in a vessel for 1 hour. Filtration and air-drying of the resultant solid provided 62 mg (40% yield) of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-2-ethyl-3-methoxy-benzamide. 1H-NMR (300 MHz, CDCl3)δ(ppm): 7.42 (s, 2H), 7.11 (s, 1H), 7.11 (t, 1H), 6.9 (d, 1H), 6.67 (d, 1H), 3.81 (s, 3H), 2.55 (q, 2H), 2.34 (s, 6H), 1.7 (br s, 6H), 1.05 (t, 3H), Rf=0.5 (1:1 ethyl acetate:hexane). The filtrate contained an additional quantity of the intended product.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:21][NH:20][CH2:19][CH2:18]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:21][N:20]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1cc2c(c(OC)c1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(c(OC)c1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 61.8 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (0.34 g), 1,2,3,4-tetrahydro-6,7,8-trimethoxyisoquinoline [0.33 g; J. Chem. Soc. D, (20), 1296-1297 (1970)] and potassium carbonate (0.5 g) in DMF (20 ml) was heated at 50° for 12 h. The mixture was then filtered and the filtrate evaporated. The residue was taken up in water, extracted with dichloromethane, dried, evaporated and purified by column chromatography eluting with dichloromethane/methanol (99:1) to give the title compound (0.34 g) as a red solid, MP: 110°. NMR includes signals at d 3.55 (2H,s,N--CH2Ar), 3.70 (6H,s,OCH3), 3.75 (3H,s,OCH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[N+:18]([O-])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.O>CC(O)=O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:18])=[C:12]([F:17])[CH:13]=[C:14]([F:16])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)cc(F)cc1Nc1cc(F)cc(F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(3,5-difluorophenyl)-3,5-difluoro-2-nitroaniline (1 g, 3.49 mmol) in AcOH (10.5 mL) was added iron powder (585 mg, 10.48 mmol) and the reaction mixture was heated to 100° C. for 1 h. The reaction mixture was cooled to rt and water was added. The organic layer was extracted with EtOAc and was basified by using satd. sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated in vacuo to provide N1-(3,5-difluorophenyl)-3,5-difluoro-benzene-1,2-diamine. The crude product was carried without further purification.