Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1[CH3:39])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([N:8]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([O:29][CH:26]([CH3:27])[CH3:28])=[C:31]([CH3:39])[CH:32]=3)=[O:35])[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Reactant: Clc1ccc(C2CN(Cc3ccccc3)CC3(CCNCC3)O2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccc(Cl)cc2)O3)ccc1OC(C)C
Reaction time: 0.17 h
Yield: 29.5 %

Procedure:
To a solution of 8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecane (100 mg, 0.28 mmol) and 4-isopropoxy-3-methyl-benzoic acid (54 mg, 0.28 mmol) in DMF (1 mL) was added DIEA (98 μL, 0.56 mmol) followed by the addition of HATU (128 mg, 0.34 mmol). The reaction mixture was stirred for 10 minutes, then quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water (twice). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 50% EtOAc/hexanes as eluent to obtain [8-benzyl-10-(4-chlorophenyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (44 mg, 29%). ESI-MS m/z calc. 532.2. Found 533.3 (M+1)+; Retention time: 2.17 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.[C:11]1([CH:18]=CC(O)=[CH:14][CH:13]=1)O.CCOCC>C1(C)C=CC=CC=1.C=CC=C>[CH3:1][O:2][C:3]1[C:4](=[O:10])[CH:5]2[CH:6]([C:7](=[O:9])[CH:8]=1)[CH2:14][CH:13]=[CH:11][CH2:18]2
Reactant: Oc1ccc(O)cc1
Reactant: COC1=CC(=O)C=CC1=O
Agent: C=CC=C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC1=CC(=O)C2CC=CCC2C1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of 2-methoxybenzoquinone (17, 750 mg, 5.43 mmol, TCI, used as received), hydroquinone (38 mg, Matheson, used as received) in toluene (7.5 mL) and butadiene (54, 7.5 mL, Matheson, used as received; Note: condensed butadiene into the toluene with ice bath cooling) contained in a screw top, sealed robe (Ace) was stirred overnight in a 60° C. oil bath. The resulting solution was allowed to cool to rt, then was further cooled in an ice bath. A precipitate formed. The sealed tube was opened. The solid was collected by filtration, washed with hexanes and allowed to air dry (930 mg). The solid was crystallized from hexanes (dissolved in 350 mL, hot filtered, concd to 200 mL, re-filtered, allowed to cool to rt) to yield a yellow powder (703 mg, 68%, >95% pure by 1H NMR analysis); mp 120°-122° C. (hexanes), lit. (Cavill et al., Aust. J. Chem. 26:595-601 (1993)) 126.5°-128° C. (ether); 1H NMR (CDCl3) δ2.21 (m, 2H), 2.51 (m, 2H), 3.16 (m, 1H), 3.26 (m, 1H), 3.79 (s, 3H), 5.69 (m, 2H), 5.90 (s, 1H).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[OH-].[Na+].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[OH:20])[CH:15]=O>C(O)C>[OH:11][C:12]1[CH:13]=[C:14]([CH:15]=[N:2][N:3]2[CH2:7][CH2:6][NH:5][C:4]2=[O:8])[CH:17]=[CH:18][C:19]=1[OH:20]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: NN1CCNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1NCCN1N=Cc1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 61.4 g (0.446 mol) of 1-amino-2-imidazolidinone hydrochloride in 300 ml of 80% aqueous ethanol were added 223 ml of 2N sodium hydroxide (0.446 mol) and a solution of 61.6 g (0.446 mol) of 3,4-dihydroxybenzaldehyde in 300 ml of 80% aqueous ethanol. The mixture was stirred for 20 minutes at room temperature, and the precipitate filtered off by suction, washed with ethanol and dried in vacuo (yield: 34.5 g; melting point 257° C., dec).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[S:7][C:6]=2[C:16]=1[Cl:17].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)(O)[O-].[Na+].CN(C)C=O>CC(=O)CC>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:18][C:3]1[C:2]([Cl:1])=[C:16]([Cl:17])[C:6]2[S:7][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][C:5]=2[CH:4]=1)[CH3:25]
Reactant: Oc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Reaction time: 16 h

Procedure:
A mixture of 5.1 g of 6,7-dichloro-5-hydroxy-2-phenylbenzo[b]thiophene 3.5 g of ethyl bromoacetate and 5 g of sodium bicarbonate in 100 ml of 2-butanone containing 10 ml of dimethylformamide is stirred at 85°-90° for 16 hours. The mixture is concentrated at reduced pressure to remove the sovents and the residue is triturated with 50 g of ice-water. After 30 minutes the solid is filtered and air dried. Recrystallization from ether-hexane gives 4.7 g of ethyl[ (6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate as fine needles, mp 116.5°-117°.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:10]1[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(CCCc1ccccc1)C1CCN(C(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2 mL of a methanol solution containing 0.60 g of tert-butyl(3-phenylpropyl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate, 0.4 mL of water was added, and 0.28 g of potassium carbonate was added under cooling with ice, and the mixture was stirred at the same temperature for 2 hours and 10 minutes and at room temperature for 2 hours and 15 minutes. Thereto was added 2 mL of methanol and 0.5 mL of water, and the mixture was left to stand at room temperature overnight. The solvent was removed under reduced pressure, and the residue thus obtained was added with ethyl acetate and water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.45 g of a colorless oily substance, tert-butyl(3-phenylpropyl)(piperidin-4-yl)carbamate.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([C:25]1[CH:29]=[C:28]([CH:30]=[O:31])[O:27][N:26]=1)([C:23]#[CH:24])[CH3:22]>>[F:19][C:3]1[C:2]([C:24]#[C:23][C:21]([C:25]2[CH:29]=[C:28]([CH:30]=[O:31])[O:27][N:26]=2)([OH:20])[CH3:22])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cc(C=O)on1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Yield: 10 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-(2-hydroxybut-3-yn-2-yl)-1,2-oxazole-5-carbaldehyde to give the titled compound as a light yellow solid (14 mg, 10%).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1C=[CH:5][C:6]([O:25][C:26]2[CH:31]=[C:30](F)[C:29]([S:33]([N:36](CC3C=CC(OC)=CC=3OC)[C:37]3[S:41][CH:40]=[N:39][N:38]=3)(=[O:35])=[O:34])=[CH:28][C:27]=2Cl)=[C:7]([C:9]2[N:13]([CH:14]3[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[N:12]=[CH:11][CH:10]=2)[CH:8]=1.[F:56]C(F)(F)C(O)=O.O.N.Cl[CH2:66][Cl:67]>>[NH:16]1[CH2:17][CH:14]([N:13]2[C:9]([C:7]3([F:56])[CH:8]=[C:3]([C:2]([F:55])([F:54])[F:1])[C:66]([Cl:67])=[CH:5][CH:6]3[O:25][C:26]3[CH:31]=[CH:30][C:29]([S:33]([NH:36][C:37]4[S:41][CH:40]=[N:39][N:38]=4)(=[O:35])=[O:34])=[CH:28][CH:27]=3)=[CH:10][CH:11]=[N:12]2)[CH2:15]1
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Agent: N
Solvent: O
Product: O=S(=O)(Nc1nncs1)c1ccc(OC2C=C(Cl)C(C(F)(F)F)=CC2(F)c2ccnn2C2CNC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88 %

Procedure:
tert-Butyl 3-{5-[5-trifluoromethyl-2-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-5-yl)amino]sulfonyl}-5-fluorophenoxy)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate (Preparation 35, 590 mg, 0.72 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2 mL) was added dropwise and the solution stirred at ambient temperature for 2.5 hours. The reaction mixture was concentrated in vacuo and the residue slurried in methanol (20 mL) before concentrating in vacuo again. This was repeated twice more. Finally the residue was again slurried in methanol (20 mL) and the solid removed by filtration. The filtrate was concentrated in vacuo to give a foam. Water (50 mL) was added followed by 0.880 aqueous ammonia (5 mL) to give a white solid which was collected by filtration, washed with methanol and dried in vacuo to afford the title compound as a white solid (360 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([CH:20]([CH3:22])[CH3:21])[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([N:8]([CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[C@H:7]([CH:20]([CH3:21])[CH3:22])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:23])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester (4.38 g, 13.0 mmol) in dimethylformamide (200 mL) is added 3-picolyl chloride hydrochloride (2.3 g, 14.0 mmol) followed by potassium carbonate (17.94 g, 130.0 mmol). The reaction mixture is stirred at room temperature for 2 days. The mixture is then diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (ethyl acetate) to give t-butyl 2(R)-[N-[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoate.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@H:7]1[CH2:8][NH:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:6]1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
The reaction mixture was composed of 80 mM TES buffer (pH 7.5), 4 mM L-proline, 8 mM 2-ketoglutaric acid, 2 mM ferrous sulfate, 4 mM L-ascorbic acid, 2 mg/ml catalase and a pre-determined amount of the pure enzyme, the total volume being 500 μl. The reaction was initiated by addition of the enzyme and continued for 15 minutes at 30° C. The reaction was stopped by heating the reaction mixture at 100° C. for 2 minutes. The amount of trans-4-hydroxy-L-proline formed in the reaction mixture was determined by the pre-column derivatization method. One hundred microliter of 0.3M boric acid buffer (pH 10.7), 4 μl of aqueous solution of 10% (v/v) mercaptoethanol and 16 μl of ethanol solution of 5% (w/v) OPA were added to 100 μl of the reaction mixture, and the mixture was allowed to stand at 60° C. for 30 seconds. In addition, 50 μl of ethanol solution of 2% (W/V) NBD was added thereto and the mixture was allowed to stand at 60° C. for 40 minutes. The reaction was stopped by adding 30 μl of 1 N HCl to the reaction mixture, and the precipitates formed were removed therefrom by centrifugation and filtration. The trans-4-hydroxy-L-proline formed by the reaction was quantitatively determined by HPLC analysis.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.[OH:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:36]4[CH2:37][CH:34]([OH:33])[CH2:35]4)[C:21]=3[F:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)c(F)cc1F
Reactant: OC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(O)C4)c(F)c32)c(F)cc1F
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To 280 mg of N,N-dimethylformamide were added 125 mg 1-(6-amino-3,5-difluoropyridine-2-yl)-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 60 mg of 3-hydroxyazetidine hydrochloride, and 120 mg of N-methylpyrrolidine together with 3 drops of ethanol, and the mixture was stirred at 85° C. for 10 minutes. After adding 0.8 ml of ethanol, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 90 mg of the title compound as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.F[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:20][C:16]1[N:15]=[C:14]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: Cc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3c(c2)CCCC3=O)n1
Temperature: 150 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A suspension of 6-hydroxy-1-tetralone (3.0 g, 18 mmol), 2-fluoro-6-methylpyridine (2.06 g, 18.5 mmol) and Cs2CO3 (12.1 g, 37.0 mmol) in DMF (150 mL) was stirred at 150° C. in a sealed vessel overnight under N2. The reaction was poured into water (300 mL) and extracted with EtOAc (3×50 mL). Organics were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (PE:EA=5:1) gave 1.2 g (26%) of the title compound as a red oil. [M+H] calc'd for C16H15NO2, 254. found 254.
Reaction SMILES: [OH:1][CH:2]1[C:6](=[CH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[CH3:17]I>C1COCC1>[CH3:17][O:1][CH:2]1[C:6](=[CH2:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CI
Reactant: C=C1CN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OC(C)(C)C)CC1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of tert-butyl 3-hydroxy-4-methylenepyrrolidine-1-carboxylate (0.257 g, 1.29 mmol; prepared as described by Alcaraz, Lilian; Cridland, Andrew; Kinchin, Elizabeth Organic Letters, 2001, vol. 3, #25 p. 4051-4054) in 8 mL of THF, stirred at r.t. under a nitrogen atmosphere was added NaH. After 0.5 h stirring at r.t., methyl iodide (0.057 g, 1.42 mmol) was added and the resulting mixture stirred at r.t. for 2 h. After overnight resting, the reaction was quenched with water, extracted with EtOAc which was washed with brine, dried over Na2SO4 and evaporated to dryness affording a crude, purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 9:1 to 7:3) giving 165 mg of the title compound. Yield: 60%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[I:22][C:23]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:24]=1[CH2:25]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:23]=5[I:22])[CH2:18][CH2:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Reactant: ClCc1cc(I)ccc1I
Product: Ic1ccc(I)c(CN2CCN(C3CC=C(c4ccc5c(c4)OCO5)CC3)CC2)c1

Procedure:
The title compound was prepared from 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.25 g, 0.87 mmole) and 2,5-diiodobenzyl chloride (0.33 g, 0.87 mmole) by the method described in example 45 to give the product (82%, mp: 174-175° C.). Calc'd for C24H26I2N2O2 : C, 45.89%; H, 4.18%; N, 4.46%. Found: C, 45.58%; H, 4.13%; N, 4.35%.
Reaction SMILES: [CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([N+:15]([O-])=O)[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(=O)C.[OH-].[NH4+]>CO.O.[Zn]>[CH:1]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCOc2ccc([N+](=O)[O-])cc2C1
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCOc2ccc(N)cc2C1
Reaction time: 3 h

Procedure:
To 4-isopropyl-7-nitro-2,3,4,5-tetrahydro-1,4-benzoxazepine (17.46 g) in methanol (1.5 1) was added acetic acid (36 ml) and zinc dust (36 g) portionwise, and the mixture was stirred for 3 h. The mixture was diluted with water (1 1), basified with conc. ammonium hydroxide (250 ml), and extracted with ethyl acetate (5×250 ml). The extracts were dried with magnesium sulfate, filtered and concentrated to an oil (11.34 g, 74%) which was used immediately in the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[C:27]([OH:30])(=[O:29])[CH3:28]>>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:24])[C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:17][CH:18]=2)=[O:12])=[CH:8][CH:9]=1)[CH3:26].[C:27]([O-:30])(=[O:29])[CH3:28].[NH4+:3]
Reactant: CC(=O)O
Agent: CCN(CC)c1ccc(C(=O)C(=O)c2ccc(N(CC)CC)cc2)cc1
Product: CC(=O)[O-]
Product: [NH4+]

Procedure:
In 100 g of acetic acid, 7.0 g of 1,2-bis(4-diethylaminophenyl)ethane-1,2-dione obtained in above (1), 3.6 g of syringaaldehyde (mfd. by tokyo Kasei Kogyo Co., Ltd.) and 4 g of ammonium acetate were reacted under reflux for 5 hours. After the reaction, 600 ml of water was poured into the reaction solution. The produced viscous residue was separated and the viscous residue was purified by silica gel chromatography (eluent: a mixed solvent of chloroform and methanol) to give 1.6 g of 2-(3,5-dimethoxy-4-hydroxyphenyl)-4,5-bis(4-diethylaminophenyl)imidazole.
Reaction SMILES: [Br:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Br-:1].[Br-:1].[CH2:2]([N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCCCCCCCC(Br)Br
Reactant: c1ccncc1
Product: [Br-]
Product: c1cc[n+](CCCCCCCCCCCC[n+]2ccccc2)cc1

Procedure:
Compounds 1-3 (FIG. 3) were prepared by reacting S-(−)-nicotine with the appropriate n-alkyl iodide in glacial acetic acid, utilizing the procedure described by Crooks, et al., Drug Dev. Res. 1995, 36, 91-102. The N-n-alkylpyridinium salts 4-7 (FIG. 3) were obtained via n-alkylation of pyridine with the appropriate n-alkyl halide. The conformationally restricted racemic syn- and anti-nicotine analogs 8-12 and 13-17, respectively (FIG. 3), were prepared via regiospecific alkylation of the pyridine-N atom of the corresponding free base. The syn-free base was synthesized from 7-aza-1-tetralone, and the anti-free base was prepared from 5-aza-1-tetralone. N,N′-Dodecanediyl-bis-nicotinium dibromide, 18 (FIG. 4), was prepared by dissolving S-(−)-nicotine in glacial acetic acid, stirring the mixture for five minutes and then adding dibromododecane. The solution was stirred under reflux for three days, the solvent was evaporated under reduced pressure, and the resulting residue was treated with an aqueous saturated solution of NaHCO3. The resulting mixture was then extracted with diethyl ether (3×50 mL), and then with chloroform (3×50 mL). The aqueous layer was collected and lyophilized for 24 hours, and the resulting solid was triturated with chloroform. After filtration, the filtrate was dried over anhydrous MgSO4 and removal of solvent afforded the bis-nicotinium salt, 18. N,N′-Dodecanediyl-bis-pyridinium dibromide, 19 (FIG. 4) was prepared by reacting an excess of pyridine with dibromododecane for 24 hours at 65° C. in the absence of solvent. The resulting solid was collected by filtration, dissolved in water, and the aqueous solution washed with diethyl ether (3×50 mL). The aqueous solution was then lyophilized to afford 19 as a crystalline solid.
Reaction SMILES: O[C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[Cl:23][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1NC(=O)C(c2ccccc2)=C1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a suspension of 3-hydroxy-4-phenyl-1H-pyrrole-2,5-dione (25.0 g, 0.13 mol) in dichloromethane (600 mL) under nitrogen was added DMF (36 mL). The suspension was cooled to ice temperature and treated with oxalyl chloride (40.0 g, 0.32 mol). The reaction mixture was subsequently refluxed overnight. After cooling to room temperature silica gel was added and the reaction mixture evaporated to dryness and subjected to flash chromatography (hexane:EtOAc 80:20). Trituration with dichloromethane, filtration and drying gave 17.6 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.96-7.89 (m, 2H), 7.88-7.77 (bs, 1H), 7.55-7.45 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.O.[NH2:24][NH2:25]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:24][NH2:25])=[C:6]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: NN
Reactant: Clc1ccc(-c2c(Cl)nnc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: NNc1nnc(Cl)c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a round bottom flask was added 3,6-dichloro-4,5-bis(4-chlorophenyl)pyridazine (1.55 gm, 4.201 mmol), pyridine(10 ml) and hydrazine hydrate (617 mg, 12.602 mmol). The reaction was stirred at 120° C. for 4 hrs. After this time, the reaction mixture was concentrated to near dryness. To the resulting residue was added water (50 ml) and a solid formed. The solid was collected by filtration to give product -chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyridazine as a beige solid (1.53 gm, 99% yield). HPLC retention time (method A) 2.740 min; LCMS (M+H)=365.1.