Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](=[O:38])[N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[NH:39]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:39][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C@@H:17]([CH2:20][C:21]([N:22]2[CH2:23][CH2:24][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:26][CH2:27]2)=[O:38])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2cccnc2[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1c2cccnc2[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a methylene chloride (5 mL) solution of tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl)ethyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ylcarbamate (0.1452 g, 0.229 mmol) was added TFA (1 ml, 12.98 mmol) at room temperature. The reaction was stirred at room temperature for 3 h before removal of the solvent in vacuo. The crude mixture was partitioned between ethyl acetate and water. Sodium bicarbonate (sat) was added and the ethyl acetate layer was separated. The ethyl acetate layer was dried (sodium sulfate), filtered and concentrated. Flash chromatography using methanol in methylene chloride from 0 to 10% gave a product that was still somewhat impure. The product was further purified by prep TLC eluting with 10% methanol in methylene chloride (25.9 mg, 20%): MS(ESI)[M+H+]=533.29; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.47 (1H, td, J=5.3, 3.5 Hz), 8.09 (1H, d, J=5.3 Hz), 7.49-7.58 (1H, m), 7.27-7.34 (1H, m), 7.18 (1H, ddd, J=15.3, 7.4, 4.9 Hz), 6.95-7.10 (4H, m), 4.87 (1H, d, J=13.1 Hz), 4.57-4.76 (1H, m), 4.44 (1H, d, J=13.1 Hz), 4.10-4.33 (2H, m), 3.46-3.67 (1H, m), 3.20-3.40 (2H, m), 2.39-2.79 (3H, m), 1.50-2.33 (9H, m).
Reaction SMILES: [Na].C(O)C.Cl.[CH3:6][CH:7]([CH3:12])[CH2:8][C:9](=[NH:11])[NH2:10].[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>O.C(O)(=O)C>[CH2:8]([C:9]1[N:10]=[C:15]([OH:16])[CH:14]=[C:13]([OH:20])[N:11]=1)[CH:7]([CH3:12])[CH3:6]
Reactant: CC(C)CC(=N)N
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)Cc1nc(O)cc(O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
Sodium (0.75 g, 32.94 mmol) and ethanol (20 mL) were introduced in a flask. Once all the sodium had dissolved, 3-methylbutanimidamide hydrochloride (1.5 g, 10.98 mmol) and diethyl malonate (1.67 mL, 10.98 mmol) were added. It was stirred for 1 hour at room temperature and for 5 hours under reflux. The reaction crude was cooled at room temperature and concentrated to dryness. The solid obtained was dissolved in water and the pH was adjusted to 5 with acetic acid. The precipitate formed was filtered providing 1.5 g of the title compound (yield: 81%).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([F:30])[CH:17]=1.Cl>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][C:18]=1[F:30])#[N:29]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1F
Reactant: CCCC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OCC
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a suspension (200 mL) of 60% sodium hydride (1.8 g) in tetrahydrofuran was added dropwise a solution (50 mL) of ethyl 3-oxohexanoate (10.9 g) in tetrahydrofuran at 0° C. The mixture was stirred at the same temperature for 30 min, 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (10.0 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (12.9 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:19])[CH2:11][NH:12][C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](ON1C(=O)CCC1=O)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>ClCCl>[CH2:23]([O:22][C:20]([N:12]([CH2:11][CH:10]([CH3:19])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](C)NCC(C)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](C)N(CC(C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of methyl N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate (2.5 g, −8.9 mmol) in dichloromethane (50 mL) was added Cbz-OSu (2.25 g, 9.0 mmol). The resulting mixture was stirred at room temperature for 3 days. The solvent was removed on a rotavap, and the crude product was purified by flash chromatography on a Biotage® system (silica, 25-80% ethyl acetate in hexanes) to yield methyl N-[(benzyloxy)carbonyl]-N-{3-[(tert-butoxycarbonyl)amino]-2-methylpropyl}-D-alaninate as colorless viscous oil. MS (M+1−Boc): 309.4
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH:11]=[CH:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1.[CH3:22][C:23]1C=CC(OC2C=CC(C(C=CC(O)=O)=O)=CC=2)=CC=1>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH:11]=[CH:12][C:13]([O:15][CH2:22][CH3:23])=[O:14])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2Cl)cc1
Reactant: Cc1ccc(Oc2ccc(C(=O)C=CC(=O)O)cc2)cc1
Product: CCOC(=O)C=CC(=O)c1ccc(Oc2ccccc2Cl)cc1

Procedure:
The procedure in Example 17(1) was followed, except that 6.05 g of 3-[4-(2-chlorophenoxy)benzoyl]acrylic acid were used in place of 3-[4-(4-methylphenoxy)benzoyl]acrylic acid, to give 5.06 g of ethyl 3-[4-(2-chlorophenoxy)benzoyl]-acrylate in the form of an oil.
Reaction SMILES: O1CCCC1.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl>O>[F:20][C:7]([F:6])([F:19])[C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[CH:16][N:17]([CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1cccc(-c2c[nH]cn2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
To a 250 mL round bottom flask (fitted with rubber septum and nitrogen blanket and stir bar) add Tetrahydrofuran (30 mL; 368.66 mmoles; 30.00 mL; 26.58 g), 4-(3-Trifluoromethyl-phenyl)-1H-imidazole (1.047 g; 1.00 equiv; 4.93 mmoles; 1.05 g) and cool the mixture to 0° C. with stirring on and hold for 5 min. Add sodium hydride (0.138 g; 1.11 equiv; 5.46 mmoles; 138.00 mg) to the flask and stir the reaction for 20 min. Add 2-(trimethylsilyl)ethoxymethyl chloride (1.15 mL; 1.31 equiv; 6.49 mmoles; 1.15 mL; 1.08 g) and allow the reaction to warm to room temperature. Dilute the reaction with water and extract the mixture two times with ethyl acetate and discard the aqueous phase. Dry the material over Na2SO4, filter, and concentrate to dryness. Purify the crude mixture by flash chromatography on silica gel eluting with ethyl acetate/hexane from 10-60% EtOAc. Combine the appropriate fractions and concentrated to give 4-(3-Trifluoromethyl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (1.178 g; 0.70 equiv; 3.44 mmoles; 1.18 g; 69.71% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([CH:8]=[C:9]([N:15]=[N+]=[N-])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>CC1C=CC=CC=1C>[F:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8]2
Reactant: CCOC(=O)C(=Cc1cccc(F)c1C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2c(C)c(F)ccc2[nH]1
Yield: 40.4 %

Procedure:
A solution of ethyl 3-(3-fluoro-2-methylphenyl)-2-azidopropenoate (10.0 g, 40.1 mmol) in o-xylene (100 ml) was slowly added dropwise in o-xylene (500 ml) at a temperature of 110° C. under stirring. The mixture was stirred at 120-122° C. for 5 hours and the solvent was distilled off under reduced pressure. The residue obtained was recrystallized from isopropyl-alcohol (60 ml) to give 3.58 g of ethyl 5-fluoro-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18](=[S:27])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[OH:26])=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[N:6][CH:7]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:26][C:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=2[C:18]([NH:17][C:16]2[C:11]([C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[S:27])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a 0° C. mixture of N-(5-chloropyridin-2-yl)-3-[2-hydroxy-4-methylthiobenzoylamino]pyridine-2-carboxamide (750 mg, 1.8 mmol), 1-t-butoxycarbonyl-4-hydroxymethylpiperidine (387 mg, 1.8 mmol), triphenylphosphine (568 mg, 2.26 mmol) and DMF (9 mL) was added DEAD (0.36 mL, 2.26 mmol), and the mixture was stirred for 18 h. The reaction mixture was concentrated and chromatographed (CH2Cl2; 10% EtOAc/CH2Cl2) to give the desired product as a white solid (950 mg, 86%).
Reaction SMILES: S(=O)(=O)(O)O.C(O/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([O:23][CH3:24])[CH:15]=1)=[O:12])C>>[CH3:24][O:23][C:16]1[CH:15]=[C:14]2[C:19]([CH:9]=[CH:10][C:11](=[O:12])[NH:13]2)=[CH:18][C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: CCO/C=C/C(=O)Nc1ccc([N+](=O)[O-])c(OC)c1
Agent: O=S(=O)(O)O
Product: COc1cc2[nH]c(=O)ccc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.3 %

Procedure:
Concentrated sulfuric acid (1 mL) was added to (E)-3-ethoxy-N-(3-methoxy-4-nitro-phenyl)-acrylamide (225 mg) with cooling and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then poured into ice-water and stirred for 1 hour. The solid which crushed out was collected by filtration and dried under vacuum to give 142 mg of 7-methoxy-6-nitro-1H-quinolin-2-one as a brown solid. MS=221 [M+H]+.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.C[O-].[Na+].[CH3:10][C:11]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[C:17](OC)=O)([CH3:13])[CH3:12].Cl>CO>[CH3:13][C:11]([C:14]1[CH:15]=[C:16]([C:17]2[NH:5][N:4]=[C:1]([NH2:3])[N:2]=2)[CH:21]=[C:22]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]=1[O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])([CH3:10])[CH3:12]
Reactant: N=C(N)NN
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=O)OC)cc1C(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCCOCOc1c(C(C)(C)C)cc(-c2nc(N)n[nH]2)cc1C(C)(C)C
Temperature: 0 °C

Procedure:
A 0° C. slurry of 7.00 g (63.32 mmol) of aminoguanidine hydrochloride in 30 ml of methanol is treated with 3.42 g (63.31 mmol) of sodium methoxide. The mixture is treated dropwise with 5.60 g (15.89 mmol) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzoic acid, methyl ester in 20 ml of methanol over 30 minutes under a nitrogen atmosphere. The reaction is warmed at reflux for 40 hours and poured onto 400 ml of ice water. The aqueous mixture is neutralized to pH 7 using 3N HCl. The precipitate is collected and recrystallized from toluene to give 2.79 g (5.98 g theor., 47%) of the product as a white solid, mp 233°-235° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])=[O:10].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:34][C:35]#[N:36].[NH4+].[Cl-]>C1COCC1>[C:35]([CH2:34][C@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:9]([N:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][O:13][C:12]1=[O:22])=[O:10])#[N:36]
Reactant: N#CCBr
Reactant: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC[C@@H](C(=O)N1C(=O)OC[C@H]1c1ccccc1)c1ccccc1F
Temperature: -30 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-[(2-fluorophenyl)-acetyl]-4(R)-phenyl-2-oxazolidinone (435 g, 1.45 mol) in THF (6000 mL), is added sodium hexamethyldisilazide [(TMS)2NNa, 1M in THF, 1480 ml, 1.48 mol] dropwise at -78° C. The resulting mixture is then warmed to -30° C. and stirred for 2.5 hours. After this time the reaction mixture is recooled to -78° C. and a solution of BrCH2CN (175 g, 1.46 mmol) in THF (200 mL) is added. The reaction mixture is then warmed to -40° C. and stirred for 2 hours. Subsequently the resulting solution is treated with saturated NH4Cl (1×3000 ml) and extracted with EtOAc (1×3000 mL). The organic layer is separated, washed with H2O (1×1500 mL), saturated NaCl solution (2×1500 mL), dried over MgSO4 and concentrated in vacuo, to provide 3-[(R)-β-cyano-α-(2-fluorophenyl)-propionyl]-4-(R)-phenyl-2-oxazolidinone, m.p. 179-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26](Cl)=[O:27]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[N:12]([C:26](=[O:27])[C:25]3[C:24]([F:23])=[CH:32][CH:31]=[CH:30][C:29]=3[F:33])[C:11](=[O:15])[O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)c(Cl)c2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2ccc(Cl)c(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3,4-Dichlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3,4-dichlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl[C:31]([O:33][CH2:34][CH:35]=[CH2:36])=[O:32].O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:34]([O:33][C:31]([N:24]1[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=[C:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)=[O:32])[CH:35]=[CH2:36]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: C=CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C=CCOC(=O)N1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In pyridine (4.3 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.43 g). To the solution was added allyl chloroformate (0.23 ml), and the mixture was stirred at room temperature for 14 hours. To the mixture was added 4-dimethylaminopyridine (40 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate→3/1) to give methyl 1-(allyloxycarbonyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylate (0.30 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]([NH:26][NH2:27])=[O:25])[N:4]=1)[CH3:2].[C:28](C1NC=CN=1)(C1NC=CN=1)=[O:29].O>O1CCOCC1>[CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19][CH3:20])=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]2[O:25][C:28](=[O:29])[NH:27][N:26]=2)[N:4]=1)[CH3:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Solvent: C1COCCO1
Solvent: O
Product: CCc1nn(Cc2n[nH]c(=O)o2)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Temperature: 92.5 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To a stirred solution of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid hydrazide (1.5 gm, 0.0041 mole) in 1,4-Dioxane (70 ml), Carbonyl-diimidazole (2.0 gm, 0.0121 mole) was added at 20-30° C. The reaction mixture was stirred for 8 hours at 90-95° C. The reaction mixture was cooled and poured into water (200 ml), stirred for 2 hours and then separated solid was filtered. Further the solid was stirred in Diethyl ether (25 ml) and filtered, dried to give 900 mg of desired product as a solid.
Reaction SMILES: Br[C:2]1[C:3]([CH2:9]Br)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:14]([C:11](=[O:13])[CH3:12])[CH2:9][C:3]=2[N:4]=1
Reactant: Clc1ccc(Br)c(CBr)n1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Yield: 28 %

Procedure:
Compound 55C (27.7 mg, 28%) was prepared from bb (56.4 mg, 0.35 mmol) and 55B (100 mg, 0.35 mmol) in two steps by a route analogous to that used for the preparation of 1D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][CH2:11][CH:12]=O.C(N(CC)CC)C.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[CH:12][CH2:11][CH2:10][C:3]1[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=CCCc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=CCCc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Yield: 104.2 %

Procedure:
To a solution of 3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45 g, 1.8 mmol) in methanol (5 ml), triethylamine (0.4 ml, 2.8 mmol) followed by O-methylhydroxylamine-hydrochloride (0.24 g, 2.8 mmol) was added and the mixture was heated at 60° C. for 2 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and quenched with water and methanol was removed with a rotavapor. The resulting aqueous solution was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water and dried over sodium sulfate before complete evaporation of the solvents to give the crude mass. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 1% ethyl acetate in hexane) to afford 3-(2,4,6-trichloro-phenyl)-propionaldehyde O-methyl-oxime (0.5 g, 80%)
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[C:6]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[N:27]=[C:26]4[C:21]([CH2:22][CH2:23][CH2:24][NH:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][C@@H:30]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.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]>[CH3:46][C:45]([O:44][C:42](=[O:43])[C@H:30]([CH2:29][NH:28][C:2]1[C:7]([CH2:8][CH:9]([CH3:11])[CH3:10])=[C:6]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[N:27]=[C:26]4[C:21]([CH2:22][CH2:23][CH2:24][NH:25]4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: CC(C)Cc1c(Cl)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)Cc1c(NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Yield: 83.6 %

Procedure:
A mixture of 450 mg (1.17 mmoles) of 4-chloro-5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 413 mg (1.4 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 275 mg (1.81 mmoles) of caesium fluoride, 55 mg (0.060 mmole) of tris(dibenzylideneacetone)dipalladium(0), 75 mg (0.12 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 35 ml of dioxane is heated under reflux for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of methylene chloride-diisopropyl ether-ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0 then 0-0-100-0 and finally 0-0-90-10. 630 mg (Yield=83%) of expected product is obtained in the form of an amorphous yellow solid.
Reaction SMILES: [Si]([C:8]1[N:9]([S:23]([N:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[C:10]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[OH:14])=[CH:11][N:12]=1)(C(C)(C)C)(C)C.CC(O)=O.O>C1COCC1.O>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:13]([OH:14])[C:10]2[N:9]([S:23]([N:26]([CH3:27])[CH3:28])(=[O:24])=[O:25])[CH:8]=[N:12][CH:11]=2)=[CH:20][CH:19]=1)#[N:22]
Reactant: CN(C)S(=O)(=O)n1c(C(O)c2ccc(C#N)cc2)cnc1[Si](C)(C)C(C)(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cncc1C(O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
The compound obtained in Step C (4 g, 9.5 mmol) is brought to solution in 40 ml of THF. A mixture of AcOH/H2O (7:3) (40 ml) is then added, and the whole is stirred at room temperature for 2 hours. The reaction mixture is then hydrolysed in a mixture of ice and H2O, extracted with AcOEt and washed with a saturated NaHCO3 solution, and then with a saturated NaCl solution, dried over MgSO4 and concentrated to dryness. The residual solid is then triturated in heptane, and the title product is obtained in the form of white crystals, 2.57 g, in a yield of 89%. IR: 3200 2700 ν(OH); 2230 ν(CN); 1390 and 1152 ν cm−1 (NSO2). NMR (CDCl3): 7.9, s, (1H); 7.75 and 7.55 2d, (4H); 6.55 s (1H); 6.15 d (1H); 3.25d(1H,OH); 3.0,s,(6H).