Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].Br[CH2:12][C:13]([OH:15])=[O:14]>O.CC(C)=O>[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][C:13]([OH:15])=[O:14])[CH:10]=1)([O-:5])=[O:4]
Reactant: O=C(O)CBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)Cn1cc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of potassium hydroxide (32.7 g, 0.58 mol) in water (100 mL) was added to a stirred mixture of 4-nitro-1H-pyrazole (30 g, 0.27 mol) in acetone (500 mL) at room temperature. After 30 min, a solution of 2-bromoacetic acid (38.7 g, 0.27 mol) in acetone (100 mL) was added and the reaction was stirred overnight. The solvent was removed in vacuo, the residue was diluted with water then extracted three times with ethyl acetate and the combined organic layer was concentrated in vacuo. The residue was further extracted with dichloromethane and methanol and the combined organic layer was concentrated in vacuo to afford 2-(4-nitro-1H-pyrazol-1-yl)acetic acid (40 g, 88%).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[C:14]1([O:22][CH3:23])[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=1)[O:16][CH3:17]>C1(C)C=CC=CC=1>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:15]([O:16][CH3:17])[C:14]=1[O:22][CH3:23]
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)c2ccncc2)c1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 2 L flask, 72 g of veratrole was dissolved in 300 g of toluene and 155.3 g of butyl lithium in toluene were added at temperatures from −10° C. to over 30° C. The mixture was stirred from 1-4 hours at ambient temperature. Then 40 g of 4-pyridinecarboxaldehyde (9) in 180 mL of toluene was added at around ambient temperature. The reaction mixture was stirred from 30 minutes to 5 hours. The solution was then cooled to around 5° C. and quenched with 200 mL of water. The solution was then heated to 40-85° C. and subsequently cooled to −5° C. The product was collected by filtration and washed with 60 g of water and 60 g of toluene. The yield was about 80 g of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C)C=O>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:3]([C:11]([F:12])([F:13])[F:14])=[CH:4][CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1c([N+](=O)[O-])cccc1C(F)(F)F
Yield: 83 %

Procedure:
A solution of 17 mmol 2-methyl-3-nitrobenzotrifluoride and 43 mmol N,N-dimethylformamide-dimethylacetal in 30 ml N,N-dimethylformamide was hold at 120° C. overnight. The reaction mixture is concentrated in vacuo to give the crude title compound. Yield 83%. MS (m/e): 261.1 ([M+H]+, 90%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.C(N(C(C)C)CC)(C)C>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCCCC2)c(F)c1
Yield: 92.3 %

Procedure:
Piperidine (0.80 g, 9.42 mmol) was added to a solution of 3,4-difluoro-nitro benzene (1.0 g, 6.28 mmol) in acetonitrile (15 mL) and diisopropyl ethylamine (1.62 g, 12.57 mmol) and the mixture was refluxed for 3 h. The acetonitrile was removed in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo to afford 1-(2-fluoro-4-nitro-phenyl)piperidine (1.3 g, 92%) as a yellow liquid.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:3]3[N:11]=[C:10]([S:12][CH3:13])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CSc1ncc2ncnc(O)c2n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CSc1ncc2ncnc(Nc3ccc(F)c(Cl)c3)c2n1

Procedure:
This compound may be obtained in the following way: a mixture of 10 g 4-hydroxy-6-methylthio-pyrimido[5,4-d]pyrimidine, 16 ml hexamethyldisilazane, 32.5 g 3-chloro-4-fluoro-aniline and 1 g p-toluenesulphonic acid hydrate are heated at boiling point for 12 hours. Then 500 ml methanol is added and the mixture heated at boiling point for a further hour. The solvents are distilled off in a rotary evaporator, the residue is dissolved in methylene chloride, the solution is extracted with 100 ml 2N sodium hydroxide and dried over magnesium sulfate. After distilling off the solvent in a rotary evaporator the residue is triturated with 200 ml ether, filtered off and washed several times with ether.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 2,2-diphenylpropionic acid (0.200 mmol, 45.2 mg), N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.200 mmol, 60.7 mg), 1-[3-(dimethylamino)propyl]3-ethylcarbodiimide (EDC, 0.400 mmol, 62.0 mg) and 4-dimethylaminopyridine (5.00 mg) was dissolved in CH2Cl2/DMF (1.00/0.100 mL) and the mixture was shaken on an orbital J-KEM shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, purified by preparative TLC [silica, CH2Cl2:ammonia (2.0 M in methanol) 100:5] to afford the desired product (43.8 mg, 42% yield): 1H NMR (400 MHz, CDCl3) δ 7.50–7.43 (br, 1H), 7.43–7.39 (br, 1H), 7.39–7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (br, 1H) 3.42–3.32 (m, 2H), 2.85 (d, 2H, J=10.8 Hz), 2.50 (quintet, 1H, J=7.4 Hz), 2.45–2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.96–1.82 (m, 2H), 1.78–1.60 (m, 4H), 1.60–1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 [M+H]+.
Reaction SMILES: COC(OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:11]=[CH:12][N:13]=C2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:16](=O)[C:15]=12.[Cl-].[NH4+].C(O)(=O)C>CN(C)C=O>[CH:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:25])[C:5]3[C:15]4[C:10]([CH:9]=[CH:6][N:4]=3)=[CH:11][CH:12]=[N:13][C:16]=4[C:18]=2[CH:19]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2nccc3ccnc1c23
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Dimethylformamide dimethyl acetal (1.50 mL, 11.34 mmol, Aldrich) was added to a solution of cleistopholine, (1.95 g, 8.73 mmol) in dimethylformamide (5 mL). The mixture was then heated for 30 minutes by submerging the reaction vessel into an oil bath preheated to 120° C. At this point, ammonium chloride (4.5 g) and glacial acetic acid (15 mL) were added to the reaction and the heating (120° C.) continued for an additional 30 minutes. After allowing to cool, the reaction was poured onto water (200 mL) and partitioned with methylene chloride (5×100 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (3×100 mL), water (3×100 mL), dried over potassium carbonate, and concentrated to dryness. The residual dark brown solids were chromatographed on silica gel (4×70 cm column, Merck 230-400 mesh) while eluting with ethyl acetate. Concentration of the appropriate column fractions provided pure sampangine (1.60 g, 79%), mp 220-222 (lit. mp 216°-218° C.). IR 1670, 1615, 1590, 1400, 1380, 1320, 1275, 1225, 760, 725 cm−1; 1H and 13C NMR (see Tables I and II).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[CH:10]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h
Yield: 101 %

Procedure:
To a stirred suspension of sodium hydride (5.0 g; 167 mmol) in dimethylformamide (200 ml) at 0° C. under nitrogen was added 5-nitroindole (25 g; 154 mmol) in dimethylformamide. After stirring for 0.5 h, iodomethane (10.5 ml; 168 mmol) in dimethylformamide (50 ml) was added, and stirring was continued for 2 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (27.4 g; 94%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.C[O-].[Na+].[C:19](#[N:22])[CH:20]=[CH2:21]>N1C=CC=CC=1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:21][CH2:20][C:19]#[N:22])=[N:12][O:13][N:14]=1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: C=CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To an ice-cooled, stirred solution of 18.2 g of 4-(1H-benzoimidazol-2-yl)-furazan-3-ylamine (90.5 mmol, 1 eq) in 240 ml of pyridine are added 30 ml of sodium methoxide solution (30% in MeOH) (163 mmol, 1.8 eq) and subsequently 6 ml of acrylonitrile (90.5 mmol, 1 eq). The reaction mixture is stirred at room temperature overnight, before it is concentrated under reduced pressure. The residue is suspended in 250 ml of water and extracted with 4×400 ml of ethyl acetate. The combined organic layers are washed with 2×500 ml of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is dissolved in about 1000 ml of refluxing ethyl acetate. Then 1700 ml of n-hexane are added to the solution. The resulting turbid mixture is allowed to stand at room temperature overnight and the formed precipitate is filtered to provide 11.1 g of the product as light yellow solid. The filtrate is concentrated to dryness under reduced pressure and the residue is suspended in 100 ml of a 1/1 mixture of n-hexane/ethyl acetate. The suspension is filtered to provide 4.7 g additional product.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:16]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1
Yield: 90 %

Procedure:
A solution of diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (6.8 g, 28.3 mmol) (from Step A above) and 200 mg of 10% palladium-on-carbon in ethanol (150 mL) was hydrogenated at 20 psi in a Parr shaker for 1 hour. The mixture was filtered through Celite™ and the solvent was evaporated to give 5.36 g, (90%) 4-(2-diethylamino-ethoxy)-phenylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 4-fluorophenylacetic acid (11.2 g, 73 mmol.) in THF (125 ml) at 0° C. under nitrogen was added oxalyl chloride (7.1 ml, 82 mmol.) then DMF (4 drops) and the resulting effervescing mixture stirred at 0° C. for 30 minutes then at ambient temperature for a further 1 hour. The effervescence had ceased after this time and the solvent was evaporated. To the residue was added toluene (50 ml) and the solvent evaporated. The addition of toluene and evaporation was repeated to leave a residue of 4fluorophenylacetyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].CN(C=O)C>N(CC)CC.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCCCO
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCCCO)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2 (PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added 4-pentyn-1-ol (0.056 mL). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (5L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 117.5 mg (43%) of the desired product as a creme solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH3:14][C:15]([CH3:17])=[O:16]>[NH4+].[Cl-]>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:16])([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,5-dibromopyridine (1.0 eq.) in Tol (0.1M) at −78° C. was added dropwise n-BuLi (1.07 eq.). The mixture was stirred at −78° C. for 3 h then acetone (1.2 eq.) was added. The final mixture was stirred for an extra 2 h at −78° C., poured in saturated aqueous NH4Cl and extracted with Tol (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][CH:4]([F:10])[CH2:5][O:6][CH2:7][CH2:8][OH:9].[S:11](Cl)([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>C1COCC1.O>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH:4]([F:10])[F:3])(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reaction time: 0.17 h
Yield: 112.5 %

Procedure:
To a cooled (0° C.) solution of 4.6 N sodium hydroxide (20.6 mL) was slowly added 2-(2,2-difluoroethoxy)ethanol (4 g, 31.7 mmol) in THF (10 mL) at a rate that maintained the temperature below 5° C. The mixture was stirred for 10 minutes, and TsCl (6.1 g, 32 mmol) in THF (10.6 mL) was slowly added at a rate that maintained the temperature below 5° C. The mixture was stirred for 30 minutes below 5° C., and then diluted with water. The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with aqueous NH4Cl (30 mL), then with brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the crude product, which was purified by silica column chromatography (elution with PE:EtOAc=4:1) to give the title compound (10 g, yield 81.9%). 1H-NMR (CDCl3, 400 MHz): δ 7.78 (d, J=8.4 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 5.77 (ttt, J=4, 5.52 Hz, 1H), 4.16 (t, J=4.4 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 3.62 (dt, J=4, 14 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: [C:1]([CH:4]([C:9](=O)[CH3:10])[CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[CH:12]1[C:17]([NH:18][NH2:19])=[CH:16][CH:15]=[C:14]([Cl:20])[CH:13]=1.OS(O)(=O)=O.C([O-])(=O)C.[Na+]>C([O-])(=O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([OH:8])=[O:7])=[C:9]([CH3:10])[N:18]([C:17]2[CH:16]=[CH:15][C:14]([Cl:20])=[CH:13][CH:12]=2)[N:19]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CC(=O)C(CC(=O)O)C(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nn(-c2ccc(Cl)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Yield: 102 %

Procedure:
4.0 grams 3,3-diacetyl-propionic acid, 4.9 grams p-chlorophenylhydrazine-sulfate, 2.1 grams anhydrous sodium acetate and 30 milliliters glacial acetate acid were mixed and the mixture was heated to 60° C. for 3 hours. The reaction mixture was evaporated and water was added to the residue. The precipitate formed thereby was separated by filtration and recrystallized from a mixture of ethanol and of water. 5.5 grams 3,5-dimethyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 176°-177° C., were obtained, representing a yield of 82%.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1.P(=O)(O)(O)O>O.C(O)C>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:23]3[N:22]=[CH:21][C:25]([C:26]#[N:27])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole (1.08 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and ethanol (20 cm3). Phosphoric acid (85%) (0.67 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 8 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product that formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.95 g, 96.7%) in 99.09% purity as determined by HPLC.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:11])[C:8](Cl)=[O:9].[Br:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.O>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:11])[C:8]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([Br:12])=[CH:14][CH:15]=1)=[O:9]
Reactant: Brc1cccc2ccccc12
Reactant: COC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 37 %

Procedure:
To a suspension of AlCl3 (3.20 g, 24 mmol) in 100 mL DCM at 0° C., methylchloroglyoxylate (2.2 mL, 24 mmol) was added. The resulting solution was stirred for 5 min., after which 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring for 2 hrs at room temperature, water was added and the phases were separated, after which the organic layer was washed with water and dried over MgSO4. The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc/Hex), to afford 2.6 g of the target compound. 1H NMR (CDCl3): 8.92 (1H, d, J=9.3 Hz, H-arom); 8.31 (1H, d, J=9.3 Hz, H-arom); 7.82 (1H, d, J=8.8 Hz, H-arom); 7.72 (1H, d, J=8.8 Hz, H-arom); 7.57-7.68 (2H, m, H-arom); 3.94 (3H, s, OMe).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH2:21][CH3:22])([O-:20])=[O:19]>>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[C:21]([N+:18]([O-:20])=[O:19])[CH3:22])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Temperature: 105 °C
Yield: 50 %

Procedure:
4.99 g (30.0 mmol) 3,4-dimethoxybenzaldehyde (Aldrich, Milwaukee, Wis.), 15.0 g (194 mmol) ammonium acetate (Fluka), and 70 g (930 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a dark yellow liquid which was recrystallized from cold methyl alcohol three times to give yellow-orange needles in 50% yield. 1H NMR spectra is shown in FIG. 3.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:18]C(O)=O)([C:15]([OH:17])=[O:16])=[O:14].[OH-].[K+].Cl>O>[C:1]1([CH2:7][C:8]([OH:12])([C:9]([OH:11])=[O:10])[CH2:18][C:13](=[O:14])[C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)C(=O)O
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)CC(O)(Cc1ccccc1)C(=O)O

Procedure:
5.0 g (30.5 mmol) of phenylpyruvic acid and 12.1 g (91.4 mmol) of oxaloacetic acid were added to 25 ml of water preliminarily dissolving 13.8 g of potassium hydroxide (purity of 85%) therein, for reaction at ambient temperature for 72 hours. Using the conc. hydrochloric acid, the reaction solution was adjusted to pH 2.2, for extraction into ethyl acetate. The organic layer was rinsed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain the residue. The residue was recrystallized in ethyl acetate and toluene to obtain PHOG of 2.8 g (11.3 mmol.) in crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:19]3[S:18][CH:22]=[CH:21][N:20]=3)=[CH:30][CH:29]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2nccs2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (0.14 g, 0.59 mmol) and 4-thiazol-2-yl-benzaldehyde (0.105 g, 0.55 mmol) in 2 mL MeOH was stirred at room temperature for 1.5 hours. After cooling to 0° C., NaBH4 (0.033 g, 0.88 mmol) was added and the reaction was stirred for 10 minutes. The mixture was quenched with aqueous saturated NaHCO3:H2O (1:1) and the MeOH was removed in vacuo. The product was extracted into CH2Cl2 and the organic solution was dried over MgSO4, filtered, and concentrated in vacuo to afford a brown oil. The product was purified via flash chromatography on silica gel (6/4 EtOAc/Hexanes) to afford the title compound of Step A (0.140 g). 1H NMR (400 MHz, CDCl3) δ7.91 (d, 2H), 7.82 (s, 1H), 7.40 (d, 2H), 7.23-7.38 (m, 2H), 6.94 (m, 2H), 6.78 (d, 1H), 4.49 (s, 2H0, 3.80 (s, 2H), 3.76 (s, 2H), 1,45 (s, 9H); MS 411 (M+1).