Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: BrCCc1ccccc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(CCc2ccccc2)n1
Yield: 78.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, (2-bromo-ethyl)-benzene (426 mg, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 3-nitro-1-phenethyl-1H-pyrazole (301 mg, 78%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 3.21 (3H, t, J=7.0 Hz), 4.41 (3H, t, J=6.9 Hz), 6.76 (1H, d, J=2.3 Hz), 7.07 (2H, m), 7.15 (1H, d, J=2.3 Hz), 7.27 (3H, m).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>[Pt].C(#N)C.C1(C)C=CC=CC=1>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][C:17]([CH3:18])([OH:19])[CH3:20])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Reaction time: 5 h
Yield: 92.9 %

Procedure:
A glass Parr vessel was charged with 5% platinum on carbon catalyst (5 g), 1-(7-bromo-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol (57 g, 0.17 mol), and a 1:1 solution of acetonitrile/toluene (1800 mL). The vessel was evacuated, charged with hydrogen gas (50 psi, 3.4×105 Pa), and shaken for 5 hours. The reaction mixture was then filtered through a 0.2 micron polytetrafluoroethylene (PTFE) membrane filter. The filtrate was concentrated to provide 49 g of 1-[(3-amino-7-bromoquinolin-4-yl)amino]-2-methylpropan-2-ol as a bright yellow-orange solid.
Reaction SMILES: CO[Na].[CH3:4][O:5][C:6]([CH:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:9]1)=[O:7].CCOC(C)=O>CO>[CH3:4][O:5][C:6]([C@@H:8]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[CH2:12][CH2:11][N:10]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:9]1)=[O:7]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: CO[Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 47.3 %

Procedure:
MeONa (2.27 g, 42 mmol) was added to a sol. of compounds D5 (22.6 g, 42 mmol) in MeOH (200 mL). The mixture was stirred at 70° C. for 6 h, and MeONa (2.27 g, 42 mmol) was added again. The mixture was stirred at 70° C. for 2 days, and was allowed to cool to rt. EtOAc was added, and the resulting mixture was washed with aq. 1M HCl and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95→10:90) yielded the title compound (10.7 g, 47%). LC-MS: tR=1.19 min, ES+=538.39.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:11]=[CH:10][C:9]=2[N+:23]([O-])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C>C1COCC1.[Pt]>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:23])=[CH:10][CH:11]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3)c2)nc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc(N)c(NCc3ccc(Br)cc3)c2)nc1
Reaction time: 6 h

Procedure:
To a solution of N-(4-bromobenzyl)-5-((5-methylpyridin-2-yl)methoxy)-2-nitroaniline (4.1 g, 9.6 mmol) in THF (75 mL) was added DIPEA (0.8 mL, 4.8 mmol) followed by 5% platinum on carbon (0.4 g, 2.1 mmol). The reaction vessel was evacuated and then placed under 1 atmosphere of H2 for 6 h. The mixture was then flushed with N2 and filtered through a pad of Celite. The Celite was rinsed with THF. The resulting filtrate was concentrated to dryness to afford the title compound, which was used without further purification. MS (ESI): mass calcd. for C22H26BrN3O, 397.08; m/z found, 398.0 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]12[CH2:28][NH:27][CH2:26][C:25]=1[CH2:24][NH:23][CH2:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:23]4[CH2:24][C:25]5[CH2:26][NH:27][CH2:28][C:21]=5[CH2:22]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
0.28 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.16 g of 3,7-diazabicyclo-[3.3.0]oct-1(5)-ene and 0.3 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 20 ml of acetonitrile and refluxed in 100° C. oil bath for 5 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and was washed with ethanol-ethylether (1:1) solvent. 0.3 g of the title compound was obtained (yield 80%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of p-hydroxybenzoic acid (3 g) and triethylamine (2.4 g) in dichloromethane (30 ml) were added undecanoyl chloride (4.5 g) and dimethylaminopyridine (0.2 g). The mixture was stirred at room temperature for about 20 hours. After dilute aqueous hydrochloric acid solution was added, an organic layer was separated by a funnel. After the solution was distilled to remove the solvent, the residue was washed with n-hexane and dried to obtain the titled compound (about 5 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:11]([O:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O.O>[CH2:11]([O:18][C:19]([NH:1][CH2:2][CH2:3][OH:4])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NCCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (84.8 g.) is dissolved in acetone-water (1:1) (500 ml.) and benzylchloroformate (83.9 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 2.5 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform and filtered. The filtrate is evaporated to dryness. The residue is chromatographed on a silica gel column (140×5 cm.) using chloroform and then 10% methanol in chloroform as the eluant to give 2-benzyloxycarbonylaminoethanol, which crystallizes from hexane as colorless needles; m.p. 53°-55° C.; γ max (CCl4) 3450, 3325, 1720, 1510, 1245 cm-1 ; δ (CDCl3) 3.29 (2H, m HOCH2CH2NH--), 3.57 (2H, m, HOCH2CH2NH--), 5.07 (2H, s, --CH2C6H5) and 7.31 ppm (5H, s, --CH2C6H5).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>ClCCl>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:15](=[O:16])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)CCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 3-methylbutylamine (20 g, 229 mmol) in 840 ml of dichloromethane were added 35.6 ml triethylamine (255 mmol) and 28.8 ml of phenyl chloroformate (230 mmol) at 0° C. The mixture was stirred for three hours at room temperature. After distilling off the solvent under reduced pressure, 200 ml of ethyl acetate and 200 ml of water were added to the residue. The organic layers were separated and water layer was extracted with ethyl acetate (100 ml×3). The organic layers were combined, washed with water and saturated sodium chloride solution successively and dried over magnesium sulfate. The solvent was distilled off and the crystals separated out were collected by filtration, and washed with petroleum ether to give 39.5 g of phenyl 3-methylbutylcarbamate (83%) as colorless crystals.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 118.9 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 12 mL of DMF to the stirred solvent was added K2CO3 (2.2 g, 16 mmol), 4-methoxyphenol (1 g, 8 mmol) and ethyl bromoacetate (1.1 mL, 9.6 mmol) Then the reaction mixture was Stirred at RT for 5 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was concentrated and extracted with ethyl acetate. Then the organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure to get the compound (2 g, Yield: 90%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1>C1COCC1>[CH3:1][C:11]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:10]1
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -50 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a cold (−78° C.) solution of lithium diisopropylamide (LDA) (23.3 mmol) in THF (10 mL) under an argon atmosphere was added dropwise a solution of 1-tert-butyl 3-ethyl 1,3-piperidinedicarboxylate (3.0 g, 11.6 mmol) in THF (5 mL), then stirred at −50° C. for 2 hrs. To the resulting mixture was added a solution of Mel (1.98 g, 14 mmol) in THF at −50° C. The reaction mixture was allowed to warm to room temperature, and quenched with saturated aqueous NH4Cl solution. The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (hexane:ethyl acetate, 9:1) to give 1-tert-butyl 3-ethyl 3-methyl-1,3-piperidinedicarboxylate as a pale yellow oil (2.27 g, yield; 72%).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[C:1]1([C:7]#[C:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1ccc(C#Cc2ccccc2)cc1
Yield: 70 %

Procedure:
By the method of example 53(A), but using bis(triphenylphosphine)palladium(II) acetate as catalyst (3 mol %), phenylacetylene and 4-bromobenzaldehyde are coupled to give 4-(2-phenylethynyl)benzaldehyde in 70% yield after distillation. By the methods of example 1, this is converted into the title compound, obtained as a colorless solid, mp 190°-191° after recrystallization from hexane-ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][CH:12]([CH2:15][CH3:16])[CH2:13]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][CH:12]([CH3:13])[CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCC(C)CO
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCC(C)COC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
4.0 g of p-hydroxybenzoic acid and 12.5 g of (-)-2-methylbutanol were refluxed for 6 hours in toluene in the presence of sulfuric acid, while removing the generated water out from the reaction system. Subsequently, the reaction solution was washed with water to remove sulfuric acid out. The reaction solution was then dried and concentrated, and the concentrate was purified by column chromatography, to obtain 5.0 g of the objective ester compound (liquid state at room temperature, [α]D23 =4.9° (CHCl3)). (Yield: 83%)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[CH2:24]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol) and n-butylbromide (0.25 mL, 2.6 mmol) was stirred at ambient temperature for 30 min after which an additional amount of n-butylbromide (0.12 mL, 1.25 mmol) was added and the mixture was stirred for 1 h. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.35 g). [α]D=−26° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 155.3° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 8), 182 (30), 98 (25), 57 (16), 212 (bp).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(#N)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5.28 g, 28.9 mmol), cyclohexylamine (5.0 mL, 43.7 mmol), and triethylamine (6.0 mL, 43.0 mL) in acetonitrile (75 mL) was stirred at 50° C. for 15 h. The reaction mixture was cooled to rt and then poured into 100 mL ice water. The solid precipitate was filtered, washed with water, and dried to afford compound 3 as a yellow solid (6.42 g, 90%). ESI-MS m/e 246.3 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:22].O>C(#N)C>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
The suspension of the title A compound, 4,5-dimethyl-2-(4-trifluoromethylphenyl)-oxazole 3-oxide hydrochloride (500 g, 1.70 mol) in 4.06 L of acetonitrile is stirred for 15 minutes at room temperature, then cooled to 10° C. 491 g (3.17 mol) of POCl3 are added at 15° C. over a period of 30 minutes. The suspension is stirred at room temperature for 16 hours, and the mixture is cooled to 10° C., and 6 L of water are added into the reaction mixture slowly (first 400 mL of water addition is very exothermic). The suspension is then stirred at room temperature for 6 hours further, and the solids are collected by filtration, washed with 2 L of water and dried to a constant weight at 50° C. (20 mbar) to afford 4-chloromethyl-5-methyl-2-[4-(trifluoromethyl)phenyl]-oxazole as a white solid (400 g, 85% yield): m.p. 97–98° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution (10 mL) of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol) in N,N-dimethylacetamide was added cyclopropylcarbonyl chloride (0.38 mL, 4.23 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (4/1) to give the title compound (1.01 g, 80%) as a dark brown powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH2:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.C1COCC1.[OH-].[K+:29]>CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@H]32)O1.C1COCC1>[CH3:1][C:2]1([CH3:22])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:18]([NH-:21])(=[O:20])=[O:19])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1.[K+:29]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS([NH-])(=O)=O)OC(C)(C)O[C@@H]23)O1

Procedure:
A 20 mL scintillation vial was loaded with 556.8 mg (1.641 mmols) of topiramate (Cheminor Drugs Ltd., Hyderabad, India, Batch TP001.J00) and 1 mL THF (Sigma, St. Louis, Mo. USA, 99.0+%, Lot 50k1485), and all of the topiramate dissolved. 89.9 mg (1.602 mmols) of solid KOH (Spectrum, Lot PN0690) was dissolved in the topiramate/THF solution. The solution was allowed to evaporate overnight at room temperature leaving an amorphous solid. The solid was further dried by placing it in a vacuum desiccator 1 white brittle solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[Na+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
3-Chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole (187.0 g) was dissolved in dimethyl sulfoxide (1000 ml) and a solution was stirred at room temperature. Then sodium cyanide (134.0 g) which had been ground in a mortar was added thereto. The reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was returned to room temperature, poured into water (15000 ml) and stirred for 1 hour. The solid thus precipitated was collected by filtration, washed with water (1000 ml×3), dissolved in chloroform (5000 ml), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue thus obtained was purified by using silica gel columns (chloroform/ethanol 50/1, silica gel 2 kg, followed by silica gel 2 kg, ethyl acetate/hexane=3:1) to give 111.0 g of a pale brown solid product. This solid product was used in the subsequent reaction without purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CS(O[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[O:23]1[CH2:24][CH2:25][CH:20]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:21][CH2:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2cnn(C3CCOCC3)c2)OC1(C)C
Temperature: 100 °C
Yield: 16.4 %

Procedure:
In 8 mL of N,N-dimethylformamide were combined 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.75 g, 3.87 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (1.04 g, 5.80 mmol), and Cs2CO3 (2.01 g, 6.18 mmol) in a glass bomb and then sealed under nitrogen and heated to 100° C. After one hour the reaction was cooled and water was added to dissolve all solids. The solution was diluted with water and then extracted with EtOAc (250 mL). The organic layer was then washed with water and brine. The combined aqueous layer was then extracted with EtOAc (200 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was dried overnight on high vacuum. The crude was purified by way of silica gel chromatography eluting with a gradient of 15-25% EtOAc in DCM to afford 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.176 g, 0.633 mmol, 16.4% yield). MS (apci) m/z=279.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[CH:7][C:8]=1[O:11][CH3:12])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1
Product: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 4-tert-butylanisole with nitric acid to produce 2-nitro-4-tertbutylanisole;