Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:4]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CCc1cc(OC)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccnc(CCC(=O)O)c1
Temperature: 25 °C

Procedure:
41.95 g of methyl 3-(4-methoxypyridin-2-yl)propionate (compound F2) are dissolved in 700 ml of tetrahydrofuran, and 217 ml of 1N sodium hydroxide solution are added. The mixture is stirred at RT until no more starting material is detectable (TLC). The mixture is neutralized using 217 ml of 1N hydrochloric acid solution, evaporated to dryness using a rotary evaporator and dried under high vacuum. The colorless residue is ground and extracted four times with dichloromethane/methanol (9:1). The combined extracts are evaporated to dryness. This gives 332 g of the title compound as a colorless powder of m.p. 131-132° C. The mass spectrum shows the molecular peak MH+ at 182 Da
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C>[O:22]1[C:19]2([CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:17][CH2:18]2)[CH2:2]1
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reaction time: 2 h
Yield: 71 %

Procedure:
Trimethylsulfoxonium iodide (580 mg, 2.64 mmol) was added to a suspension of NaH (106 mg, 2.64 mmol) at 0° C. under nitrogen atmosphere. After 15 min. under stirring at the same temperature, N-Boc-4-piperidone (500 mg, 2.51 mmol) dissolved in DMF (5 mL) was added. Stirring was continued and, after 2 h at r.t., the reaction mixture was quenched with water and EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness. The crude residue was purified by flash chromatography (EtOAc—Petroleum Ether 9:1) affording the title product (380 mg).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:17]O>>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:17])=[O:10])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-nitro-1H-pyrazole-3-carboxylic acid (3.0 g, 19.1 mmol) in methanol (50 mL). Sulfuric acid (3 mL) was carefully added and the resulting solution was stirred overnight at 80° C., then concentrated under reduced pressure. The pH of the solution was carefully adjusted to 7 with aqueous sodium bicarbonate (sat.), then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a yellow solid (2.3 g, 70%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=1)([O-:3])=[O:2].[CH3:12]O>>[CH3:12][O:10][C:9]([C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)=[O:11]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: CO
Product: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Temperature: 25 °C

Procedure:
A solution of 5-nitro-1H-pyrazole-3-carboxylic acid (17, Aldrich, cat. no. 41,483-2) in MeOH was prepared. While stirring, HCl was bubbled through the solution for 2 min. The reaction mixture was refluxed for a time sufficient for complete esterification and allowed to cool to rt. The solvent was removed by rotary evaporation. The crude material was basified by addition of saturated aqueous NaHCO3 and extracting with EtOAc. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was rotary evaporated and dried under vacuum to yield 18.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O>[C:16]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To an ice cold solution of isonipecotic acid (90 g, 0.697 mol) and potassium carbonate (81 g, 1.31 mol) in water (1.3 liter) was added dropwise benzoyl chloride (81 ml, 0.697 mol) over a period of about an hour at about 5° C. The mixture was stirred at room temperature overnight. The reaction mixture was acidified with 6N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water and then dried over magnesium sulfate and the solvent was evaporated in vacuo. Crystallization from isopropyl alcohol-diethyl ether to give the titled compound (154.4 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OC(F)(F)F)cc1

Procedure:
4-(trifluoromethoxy)phenol (1.36 ml, 10.6 mmol), 2-fluoro-1-nitrobenzene (0.74 ml, 7 mmol), potassium carbonate (1.46 g, 10.5 mmol) were mixed together in DMF (4 ml) and heated at reflux for 5 h. Allowed to cool and evaporated in-vacuo. Residue partitioned between diethyl ether and sodium hydroxide (1 M). Organic layers combined and dried over anhydrous magnesium sulphate and evaporated in-vacuo, 2.34 g, >100%. Rf: 0.72 (DCM), 1HNMR (CDCl3, 270 MHz) δ 7.03 (3H, m, Ar HD, Ar HF), 7.20 (2H, dd, J=0.9, 10.1 Hz, Ar HE), 7.23 (1H, m, Ar HB), 7.53 (1H, m, Ar HC), 7.97 (1H, dd, J=1.5, 8.2 Hz, Ar HA).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: CCc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Product: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 4.5 °C
Reaction time: 0.67 h
Yield: 94.8 %

Procedure:
4-Ethylbenzoic acid (20 g, 133 mmol) was ice-cooled and fuming nitric acid (94%, d=1.50, 50 ml) was dropwise added thereto for 40 min. The mixture was stirred at 4-5° C. for 1.25 hr. The resulting yellow suspension was poured into ice-water and the precipitated crystals were collected by filtration. The crystals were dissolved in ethanol, and water was added for recrystallization to give the objective compound (24.6 g, 94.8%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].Cl>O1CCCC1.O>[N+:22]([C:13]1[CH:14]=[C:15]([S:18]([NH2:21])(=[O:19])=[O:20])[CH:16]=[CH:17][C:12]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:24])=[O:23]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL) was treated with 60% NaH (1.377 g). The solution was stirred for 20 minutes at the room temperature. To this solution was added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reaction was stirred for another 2 hours. The mixture was poured into water, neutralized with 10% HCl, and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20-60% ethyl acetate in hexanes.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(-c2ccncc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C

Procedure:
Bromine (26.0 g, 163 mmol) is added to a stirred solution of 4-(4-methoxyphenyl)pyridine (13.6 g, 73.5 mmol) in acetic acid (500 mL) and heated at 60° C. for 72 h. The mixture is then evaporated to dryness under reduced pressure and the residue is treated with aqueous ammonia (400 mL of 6M) and extracted with ethyl acetate (3×200 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 95% t-butylmethyl ether/4.5% methanol/0.5% aqueous NH3(25%)) and recrystallised from ether-cyclohexane to give 4-(3-bromo-4-methoxyphenyl)pyridine as a pale-yellow crystalline solid, m.p. 82-84° C.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (4.0 g, 0.0182 mol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 0.0200 mol), K2CO3 (3.0 g, 0.0218 mol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and-water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butoxy]-3-methoxyphenyl]ethanone as a white solid, m.p.=114°-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)cn1
Solvent: ClCCl
Product: ClCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the stirred solution of (5-Bromo-pyridin-2-yl)-Methanol (5 gm, 26.59 mmol, 1 eq) in DCM (50 mL) at 0° C. is added Thionyl chloride (3 mL) drop wise at RT then stirred at RT for 4 h. After completion, the reaction mixture quenched with saturated sodium bicarbonate solution and extracted with DCM (3×100 mL). The combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude is purified by column chromatography using silica 100-200 mesh using 10% EtOAc: Hexane as eluent to afford title compound (4 g) as brown colored liquid. 1NMR (400 MHz, DMSO) δ: 4.77 (s, 2H), 7.54 (d, J=8.64 Hz, 1H), 8.09-8.12 (dd, J1=2.4 Hz, J2=8.32 Hz, 1H), 8.70 (d, J=5.96 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(Br)c1
Temperature: -78 °C
Yield: 16 %

Procedure:
1-bromo-3,5-dimethyoxybenzene (3.0 g, 13.8 mmol) was dissolved in dichloromethane (45 mL) and the solution was cooled to −78° C. Boron tribromide (1M in dichloromethane, 41 mL, 41 mmol) was added and the solution was warmed gradually to room temperature over 18 hours. After cooling to −78° C., the reaction was quenched with water (100 mL). The organics were separated and washed with sodium thiosulphate solution then water, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate 100:0 to 80:20, to afford the title compound in 16% yield (470 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.CC(C)([O-])C.[K+]>CN(C=O)C.O>[Br:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 28 °C
Reaction time: 12 h

Procedure:
Ph3CCl (10.4 g, 37 mmol) was added to a mixture of 4-bromopyrazole (5.0 g, 34 mmol) and potassium tert-butoxide (4.58 g, 41 mmol) in DMF (15 mL) at 0° C. then the mixture was stirred at 28° C. for 12 hours. The mixture was diluted with water and extracted with ethyl acetate, filtrated and recrystallized. The solid was dried under reduced pressure to afford 4-bromo-1-trityl-1H-pyrazole. MS ESI calc'd. for C22H18BrN2 [M+H]+389 and 391. found 389 and 391. 1H NMR (400 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.50 (s, 1H), 7.38-7.34 (m, 10H), 7.04-7.01 (m, 5H).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Yield: 93 %

Procedure:
Thionyl chloride (191.4 g, 1.61 mol) was added to a solution of 4-fluoro-3-nitrobenzoic acid (150.0 g, 810.81 mmol) in methanol (500 ml) at 0° C. The resulting solution was heated to reflux overnight, concentrated in vacuo, the product was precipitated by the addition of petroleum ether (200 ml), and the solids were collected by filtration to afford methyl 4-fluoro-3-nitrobenzoate as a light yellow solid (150 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(O)(=O)C>[Fe].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)ccc1Br
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 1-bromo-2-methoxy-4-nitrobenzene (3.0 g, 12.9 mmol) and glacial acetic acid (25 ml) was heated at 100° C. under an atmosphere of nitrogen. Iron powder (2.2 g, 38.8 mmol) was added and the mixture was stirred for one hour at a temperature of 100° C. The mixture was cooled to ambient temperature, water (100 ml) was added and the mixture was then extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate (3×25 ml) and then brine. The organic solution was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (6:4) as an eluent yielded 4-bromo-3-methoxyaniline (1.22 g): 1H NMR (DMSO-d6, 400 MHz) δ 7.1 (d, 1H), 6.31 (s, 1H), 6.1 (d, 1H), 5.27 (bs, 2H), 3.72 (s, 3H); TLC (heptane/ethyl acetate 1:1) Rf 0.33; RP-HPLC (Hypersil HyPurity Elite C18, 5 μm, 200 A, 250×4.6 mm; 25-100% acetonitrile-0.1 M ammonium acetate over 25 min, 1 ml/min) tr=11.05 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17](/[CH:19]=[C:6]1/[CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:2]/1=[O:1])[CH3:18]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Temperature: 105 °C

Procedure:
tert-Butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol) was treated with N,N-dimethylformamide dimethyl acetal (267 g, 2241 mmol) and heated at 105° C. for 40 min. The solution was cooled and evaporated under reduced pressure and the resulting orange solid was treated with hexane (200 mL) and cooled in the refrigerator for 64 h. The resulting brownish-yellow solid obtained as such was collected by filtration, dried and used in the next step without further purification. LC/MS: 241.1 (M+1).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([N:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(C)C>[C:1]1([NH:7][N:8]=[CH:20][C:19]2[CH:18]=[CH:17][C:16]([N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: C(=NNc1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, commercially available from Aldrich, Milwaukee, Wis.) and 4-(Diphenylamino) benzaldehyde (0.1 mole, available from Fluka, Buchs SG, Switzerland) were dissolved in 100 ml of isopropanol in a 250 ml 3-neck round bottom flask equipped with reflux condenser and mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The 4-(diphenylamino) benzaldehyde phenylhydrazone crystals that formed upon standing were filtered off and washed with isopropanol and dried in vacuum oven at 50° C. for 6 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C([O-])(O)=O.[Na+].O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5,6-dichloro-3-pyridinemethanol (2.9967 g, 16.8 mmol) in DCM (3.00 mL, 46.6 mmol) was treated with Dess-Martin periodinane (7.14 g, 16.8 mmol) at room temperature and the mixture was stirred at room temperature overnight. The resulting reaction mixture was diluted with NaHCO3(aq) and water (5 mL each) and diluted with DCM (5 mL). The separated aqueous layer was extracted with DCM (2×10 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a pale-yellow solid which was used directly for the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.O.[Br:12]Br>C(O)(=O)C>[Br:12][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: O=C1CCCc2sccc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
In a 500 mL round bottomed flask was placed 6,7-dihydro-4-benzo[b]thiophenone (8.3 g, 54 mmol) and then dissolved in acetic acid (30 mL). To the mixture was added water (30 mL) and the solution was stirred for 30 min at rt. To the mixture was dropwise added freshly prepared solution of bromine (9.4 g, 59 mmol) in acetic acid (50 mL) over 10 min. After addition of the Br2, the mixture was stirred for 1.5 h at the same temperature. The mixture was concentrated under reduced pressure and the residue was diluted with ether (150 mL), which was washed with 1N NaOH aq (100 mL). The aqueous phase was extracted with ether (100 mL) and the combined organic phase was washed with brine (100 mL), dried over anhydrous MgSO4 and then decolorized with activated carbon. Insoluble materials were removed by filtration through Celite pad and the filtrate was concentrated under reduced pressure. The residue was suspended in 50 mL of MeOH and then stirred for 15 min for washing. The precipitate was collected by filtration to obtain the title compound (5.65 g; 45%) as a yellowish crystalline solid. From the mother liquid, 2nd crop of the title compound (6.66 g; 53%) has been obtained. LCMS: (FA) ES+ 231, 233. 1H NMR (300 MHz, d1-chloroform) δ: 7.35 (s, 1H), 2.95 (t, 2H), 2.52-2.56 (m, 2H), 2.17-2.25 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:25])[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:24])=[CH:9][CH:10]=2)[O:5]1.Cl[CH2:27][C:28]#[N:29].CCOCC>CN(C)C=O>[C:28]([CH2:27][O:24][C:8]1[CH:7]=[C:6]2[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[CH:15]=3)[CH2:13][C:4]([CH3:25])([CH3:3])[O:5]2)=[CH:10][CH:9]=1)#[N:29]
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Temperature: 60 °C

Procedure:
Sodium hydride (0.93 g, 80% dispersion in oil) was added to a solution of 2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman-7-ol (containing 1 mole of carbon tetrachloride of crystallisation) (7.5 g) in dimethylformamide (25 ml). Chloroacetonitrile (1.76 g) was added and the mixture heated at 60° C. for 3 hours. The solvent was removed under reduced pressure and the resulting oil was poured into water. The aqueous solution was extracted with ether and the ethereal extracts were dried (Mg SO4) and evaporated under reduced pressure to yield an oil. Chromatography on alumina with ether -- petrol (40°-60° C.), 1:3 as eluate gave the title compound which crystallised on standing.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.C([O-])(=O)C.[NH4+].C(O)(=O)C.[N+:21]([CH3:24])([O-:23])=[O:22]>>[N+:21](/[CH:24]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:10]2[O:11][CH2:1][O:2][C:3]=2[CH:4]=1)([O-:23])=[O:22]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc2c(c1)OCO2
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
3,4-methylenedioxybenzaldehyde (15.55 Kg) was treated sequentially with ammonium acetate (13.4 Kg,), acetic acid (45.2 Kg) and nitromethane (18.4 Kg), warmed to 70° C., stirred for 30 minutes, warmed to 80° C., stirred for 10 hours, cooled to 10° C. and filtered. The filtrant was washed with acetic acid (2×8 Kg) and water (2×90 Kg) and dried under a nitrogen stream then in under vacuum at 50 ° C. for 2 days.