Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[CH2:3]([N:10]1[CH2:33][CH2:32][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[NH:15][C:14]2=NC2CCCCC2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)CO>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:16](=[O:24])[NH:15][C:14]2=[O:1])[CH2:32][CH2:33]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NC(=NC2CCCCC2)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: OCCO
Product: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 50 °C
Yield: 69.9 %

Procedure:
Potassium hydroxide (50.4 g, 0.9 mol) was added to 300 mL of ethylene glycol followed by 8-benzyl-4-cyclohexylimino-1-phenyl-1,3,8-triazaspiro[4,5]decane-2-one (37.7 g, 0.11 mol) from Step A. The reaction mixture was heated slowly to a gentle reflux and 100 mL of solvent was removed by distillation over a 4.5 hour period. The reaction mixture was then cooled in ice to 50° C. and poured into water (500 mL). The aqueous solution was adjusted to approximately pH 8-9 by adding concentrated hydrochloric acid while cooling in ice. The precipitate was filtered and washed with water to give 25.8 g of solid. The solid was crystallized from boiling chloroform to give 19.45 g of the title compound, m.p. 159°-160° C.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:9][CH2:10][C:11]([CH3:13])=[O:12].[CH:18]([C:20]([CH3:22])=[O:21])=[CH2:19]>>[O:12]=[C:11]([CH2:13][CH2:22][C:20]1[O:21][C:5]([CH2:4][CH2:3][C:2](=[O:6])[CH3:1])=[CH:19][CH:18]=1)[CH2:10][CH2:9][C:8]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCC(C)=O
Reactant: O=Cc1ccco1
Reactant: C=CC(C)=O
Product: CCOC(=O)CCC(=O)CCc1ccc(CCC(C)=O)o1

Procedure:
Furfural, ethyl levulinate and methyl vinyl ketone were reacted to form the starting compound, ethyl 4-oxo-6-(5-(3-oxobutyl)furan-2-yl)hexanoate, according to a method described in the Gordon applications, the entire disclosure of which are incorporated herein by reference.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1CCOC[CH2:18]1.C[O-].[Na+].CO>O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:17][CH3:18])=[C:11]([Cl:16])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(Cl)cnn(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 93 %

Procedure:
To a round bottom flask was added 2-benzyl-4,5-dichloropyridazin-3(2H)-one (7.14 gm, 27.99 mmol), dioxane (125 ml, anhydrous). To the resulting reaction mixture was slowly added 25%/NaOMe in MeOH solution (6.98 ml, 30.51 mmol). The reaction was stirred at rt for 70 min. After this time, the reaction mixture was diluted with water (200 ml). The resulting solution was poured into a separatory funnel and extracted with CH2Cl2 (2×100 ml). The combined organic layers were washed with saturated aqueous NaCl (10 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with 0-5% MeOH/CH2Cl2 to give product 2-benzyl-5-chloro-4-methoxypyridazin-3(2H)-one as colorless oil (6.5 gm, 93% yield). HPLC retention time (method A) 3.090 min; LCMS (M+H)=251.2.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[F:19][C:20]([F:28])([F:27])[C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C.S(=O)(=O)(O)O>[F:19][C:20]([F:28])([F:27])[C:21]([C:22]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:24])=[O:26]
Reactant: Nc1sc2ccccc2c1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3ccccc3c2c(-c2ccccc2)c1C(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a stirred solution of 32 mg (0.13 mmol) (2-amino-benzo[b]thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 11) in 2 ml acetic acid was added 0.016 ml (0.13 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 20:1) afforded 8 mg (17%) 2,2,2-trifluoro-1-(2-methyl-4-phenyl-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light yellow solid. ES-MS m/e (%): 372 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)=[O:6])[CH:2]=[CH2:3].[CH2:38]([O:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][I:48])=[O:43])[CH:39]=[CH2:40]>CN(C)C=O>[I-:48].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[CH:37]=[CH:36][N:35]([CH2:47][CH2:46][CH2:45][NH:44][C:42]([O:41][CH2:38][CH:39]=[CH2:40])=[O:43])[CH:34]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3ccnc3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)NCCCI
Solvent: CN(C)C=O
Product: C=CCOC(=O)NCCCn1cc[n+](CC[C@@H]2C[C@H](SC3=C(C(=O)OCC=C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCC=C)c1
Product: [I-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(imidazol-1-yl)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (7.00 g) in dimethylformamide (35 ml) was added 3-allyloxycarbonylamino-l-iodopropane (4.26 g) and the solution was warmed to 50° C. After stirring at the same temperature for 8 hours, the solution was cooled to room temperature. The solvent was evaporated and the residue was washed with diisopropyl ether (175 ml×5) to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-[2-[3-{3-(allyloxycarbonylamino)propyl}-1-imidazolio]ethyl]-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate iodide (10.4 g) as a light brown paste. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1cccs1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1cccs1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.5 %

Procedure:
To a solution of a 1 g (4.7 mM) of [5-(2-thienyl)tetrazol-1-yl] acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 1 g (yield 88.5%) of [5-(2-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])[S:5]1(=[O:22])=[O:21].[CH3:23][C@H:24]1[CH2:29][NH:28][CH2:27][C@@H:26]([CH3:30])[NH:25]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[ClH:20].[ClH:20].[Cl:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([CH2:3][CH2:2][N:28]2[CH2:27][C@H:26]([CH3:30])[NH:25][C@H:24]([CH3:23])[CH2:29]2)[S:5]1(=[O:22])=[O:21]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=S1(=O)N(CCBr)c2ccccc2N1c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C[C@@H]1CN(CCN2c3ccccc3N(c3ccc(F)cc3Cl)S2(=O)=O)C[C@H](C)N1
Product: Cl
Temperature: 90 °C
Yield: 128.9 %

Procedure:
Step 2 0.20 g (0.5 mmol) of 1-(2-bromoethyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide, 0.09 g (0.75 mmol) of cis-2,6-dimethyl piperazine and 0.35 g (1 mmol) of cesium carbonate were dissolved in ethanol and heated to 90° C. for 30 hr. At the end of this time the solution was concentrated and the residue placed on a pad of silica gel eluting first with 20% ethyl acetate:hexane then 90% chloroform:methanol. The chloroform eluent was concentrated and the residue dissolved in ethanol, whereupon 2 mL of 2N HCl in ether added. The solution was concentrated to a smaller volume and triturated with ether and the solid removed by filtration to provide 0.11 g of 1-(2-chloro-4-fluorophenyl)-3-{2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]ethyl}-1,3-dihydro-2,1,3-benzothiadiazole-2,2-dioxide dihydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[C:14](Cl)=[O:15])[CH3:9]>>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14](=[O:15])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH3:22])[CH3:9]
Reactant: COC(=O)C(C)C
Reactant: CCOc1ccc(C(=O)Cl)cc1OCC
Product: CCOc1ccc(C(=O)C(C)(C)C(=O)OC)cc1OCC

Procedure:
Prepared analogously as described for example D1 using methyl 2-methylproponate and 3,4-diethoxybenzoyl chloride as starting compounds.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][CH2:7]1)=O)C.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>C(Cl)Cl>[NH:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:27]2=[S:28])[CH2:10][CH2:11]1
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)N1CCC(Nc2ccccc2N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: S=c1[nH]c2ccccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of 4-(2-amino-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.76 g, 2.9 mmol) and triethylamine (0.81 ml, 5.8 mmol) in methylene chloride (10 mL) at 0° C. was added a solution of thiophosgene (0.22 mL, 2.9 mmol) in methylene chloride (10 mL) at room temperature. The reaction mixture was stirred for 2 h then quenched with 1N sodium hydroxide. The organic phase was separated and dried over sodium sulfate, filtered and concentrated. The crude product (i.e.; 4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester) was treated with 10% sodium hydroxide (10 mL) and refluxed for 4 h. The reaction was allowed to cool to room temperature and the aqueous layer was washed with ethyl ether (50 mL), acidified to pH<2 with 6N hydrochloric acid, washed with ethyl ether (50 ml) and filtered (to remove a small amount of precipitated solid). The aqueous layer was adjusted to pH 10 by slowly adding sodium carbonate and then cooled to 0° C. The solid that formed was collected by filtration to give 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][S-:15].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][S:15][CH3:14])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)cc1CSC
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (12 g) and sodium thiomethoxide (2.5 g) in toluene was stirred at 100° C. for 2 hours. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (anhydrous sodium sulphate) and evaporated to afford a brown oil which was purified by column chromatography on silica gel giving methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (4.1 g) as white crystals, m.p. 79.3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Solvent: c1ccncc1
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Temperature: 20 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
To a solution of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinamine (0.5 g, 1.999 mmol) in pyridine (5 ml) was added methanesulphonyl chloride (0.309 ml, 4.00 mmol) and the mixture stirred at 20° C. for 18 hr then the solvent was removed in vacuo. The residue was partitioned between saturated sodium bicarbonate solution (10 ml) and dichloromethane (20 ml), separated by hydrophobic frit and purified by silica gel chromatography, eluting with a gradient of dichloromethane and methanol to give the title compound as a brown solid (0.46 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](O[C@H](C4C=CC=CC=4)[C@@H](N)C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.IC1C=CC=C2C=1C=NN2C1C=CC(F)=CC=1.[CH3:45][C@H:46]([NH2:55])[C@H:47]([OH:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[C:12]([O:54][C@H:47]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[C@@H:46]([NH2:55])[CH3:45])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: Fc1ccc(-n2ncc3c(I)cccc32)cc1
Product: C[C@H](N)[C@H](Oc1cccc2c1cnn2-c1ccc(F)cc1)c1ccccc1

Procedure:
Prepared according to the protocol described for 1a starting from 4-iodo-1-(4-fluorophenyl)indazole (3b, 332 mg, 0.98 mmol) and (1R,2S)-norephedrine (742 mg, 4.9 mmol). Yield: 150 mg (42%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][NH2:15]>C1COCC1.O>[CH3:14][NH:15][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc2ccc([N+](=O)[O-])cc2s1
Yield: 88 %

Procedure:
Place 2-chloro-6-nitro-benzothiazole (5.82 g, 27.1 mmol) in THF (130 mL). Add 40% methylamine in water (7 mL) and stir until the product precipitates out. Concentrate in vacuo and then triturate with methanol. Filter off the product and wash with methanol, Dry thoroughly to yield 4.99 g (88%) of the title compound: mass spectrum (ion-spray): (m/z)=210.0 (M+1).
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.Cl[C:23]1[N:24]=[C:25]([S:31][CH3:32])[N:26]=[N:27][C:28]=1[C:29]#[N:30]>C(O)C>[CH3:32][S:31][C:25]1[N:26]=[N:27][C:28]([C:29]#[N:30])=[C:23]([N:4]2[CH2:3][CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5]2)[N:24]=1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CSc1nnc(C#N)c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nnc(C#N)c(N2CCc3ccccc3CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.5 %

Procedure:
A solution of 395 mg (2.7 mmol) of 2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride [J. Heterocycl. Chem. 1971, 8(5), 779-83] in 5 ml of ethanol was treated at room temperature with 0.92 ml (5.4 mmol) of Huenig's base and, thereupon, with a solution of 501 mg (2.7 mmol) of crude 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile in 5 ml of ethanol. The dark brown reaction mixture was stirred during 18 h at room temperature. For the working-up, the product, partially precipitated in pure form, was filtered and the resulting mother liquor evaporated under reduced pressure. The residue was chromatographed on silica gel with a 2:1 v/v mixture of hexane and ethylacetate as the eluent. In total, 470 mg (58.5% of theory) of 3-methylsulfanyl-5-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-[1,2,4]triazine-6-carbonitrile were obtained in the form of a beige powder; MS: 298 (M+H)+.
Reaction SMILES: C[C:2]([N:14](C)[CH3:15])(CO)C[C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1.[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=[CH2:19].[Cl:23]C1C=C(C=CC=1Cl)N>>[Cl:23][C:18]([CH3:20])([CH2:19][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[C:17]([OH:22])=[O:21].[CH3:2][NH:14][CH3:15]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C(C)(CO)Cc1ccc(Cl)c(Cl)c1
Reactant: C=C(C)C(=O)O
Product: CC(Cl)(Cc1ccc(Cl)c(Cl)c1)C(=O)O
Product: CNC

Procedure:
Process for the preparation of cericlamine which consists: i) in arylating methacrylic acid with the diazonium chloride of 3,4-dichloroaniline, to obtain (+/-)2-chloro-3-(3,4-dichlorophenyl)-2-methylpropionic acid, ii) in aminating the acid with dimethylamine, to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropionic acid, or an alkaline metal salt thereof, iii) in esterifying the amino-acid or its salt, then, iv) in reducing the ester by a metal or organometal hydride to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methyl-propan-1-ol.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](=O)([O-])[O-].[K+].[K+].[CH3:23]OS(OC)(=O)=O>C(C(C)=O)C>[CH3:17][O:1][C:2]1[C:3](=[O:16])[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:23][O:16][C:3]1[C:2](=[O:1])[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)OC
Reactant: O=c1ccccc(Oc2ccccc2)c1O
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1c(Oc2ccccc2)ccccc1=O
Product: COc1ccccc(Oc2ccccc2)c1=O

Procedure:
A mixture of 2-hydroxy-3-phenoxy-2,4,6-cycloheptatriene-1-one (13.0 g), described by Y. Kitahara, Sci. Repts. Tohoku Univ. First Ser., 39, 265-74 (1956), (CA 51, 12874f) potassium carbonate (28.9 g), dimethylsulfate (26.5 g) and methyl ethyl ketone (680 ml) is healed at reflux for two hours. The hot mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is subjected to chromatography on silica gel using ether. The appropriate fractions of the eluate are combined and evaporated to give 2-methoxy-3-phenoxy-2,4,6-cycloheptatrien-1-one and 2-methoxy-7-phenoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[OH-].[K+].[CH3:15]S(C)=O.IC>O>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:15]
Reactant: Oc1ccc2ccccc2c1Br
Reactant: CS(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 500 mL three-necked round-bottomed flask was charged with 1-bromonaphthalen-2-ol (30.0 g, 134.5 mmol), potassium hydroxide (KOH) (11.3 g, 201.7 mmol) and DMSO (300 mL), and the mixture was stirred under nitrogen atmosphere for 10 minutes, After cooling the mixture by using ice-water bath, iodomethane (28.6 g, 201.7 mmol) was slowly added dropwise thereto. Then, the resultant mixture was stirred under nitrogen atmosphere at ambient temperature for 12 hours, and then at 50° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was mixed with water (500 mL), and extracted with diethyl ether. Organic mixture was washed three times with distilled water, and dried over anhydrous magnesium sulfate (MgSO4). After removing the solvent by using a rotary evaporator, the residue was purified via silica gel column chromatography (eluent: n-hexane) to obtain 1-bromo-2-methoxynaphthalene (22.0 g, yield: 69.0%) as white solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1.C1CCC(C(O)=O)CC=1.[N+:28]([O-:33])([N+]([O-])=O)=[O:29].O>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH3:14][C:9]1[CH:8]=[C:7]([C:6]2[C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[O:3][C:2]=2[N+:28]([O-:33])=[O:29])[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(-c2c(Br)oc3ccccc23)cc1C
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(-c2c([N+](=O)[O-])oc3ccccc23)cc1C
Reaction time: 16 h

Procedure:
To a solution of 12.4 g (0.041 mole) of 2-bromo-3-(3',4'-dimethylphenyl)benzofuran in 400 ml of acetic acid is added 7.8 g (0.062 mole) of cyclohexene-4-carboxylic acid and a solution of 5 g (0.062 mole) of dinitrogen tetroxide in 25 ml of acetic acid. After stirring for about 16 hours the mixture is poured into cold water to give a gummy solid. The solid is collected, washed with water and dissolved in diethyl ether. The ether solution is washed with water, 10% sodium bicarbonate solution and saturated sodium chloride solution, then dried. Evaporation provides a residue which is dissolved in carbon tetrachloride and chromatographed on silica gel, eluting with carbon tetrachloride and combining the fractions consisting of chiefly one component according to thin layer chromatography. The solid is recrystallized from aqueous ethanol, then from isopropanol to provide yellow solid 3-(3',4'-dimethylphenyl)-2-nitrobenzofuran, m.p. 125°-133° C. which is about 90% pure, containing about 10% of monobromo-3-(3',4'-dimethylphenyl)-2-nitrobenzofuran.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)=[O:4].[S:10]1[CH:14]=[C:13]([CH:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2>CCOC(C)=O>[Br-:1].[S:10]1[CH:14]=[C:13]([CH:15]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]([O:18][C@@H:19]2[CH:24]3[CH2:25][CH2:26][N+:21]([CH2:2][C:3](=[O:4])[C:5]4[CH:9]=[CH:8][S:7][CH:6]=4)([CH2:22][CH2:23]3)[CH2:20]2)=[O:17])[C:12]2[CH:34]=[CH:35][CH:36]=[CH:37][C:11]1=2
Reactant: O=C(CBr)c1ccsc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1csc3ccccc13)C2)c1ccsc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
2-Bromo-1-(thiophen-3-yl)ethanone (52.2 mg, 0.25 mmol) was added portion-wise to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (C19) (100 mg, 0.25 mmol) in EtOAc (2 ml). The reaction was stirred at room temperature for 3 hours. The precipitate was filtered, washed with EtOAc and purified by preparative HPLC (Eluent: CH3CN, H2O) to obtain (R)-3-(2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiophen-3-yl)ethyl)-1-azoniabicyclo[2.2.2]octane bromide (32 mg, 21.0% yield).