Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].C(OC[O:10][CH2:11][CH3:12])C.P(Cl)(Cl)(Cl)=O.C[C@H:19]1[C@@:36]2([CH3:37])[C:23]([CH2:24][CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:22][C:21](=O)[CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:24][C@H:23]1[C@@:36]2([CH3:37])[C:19]([C:20](=[CH2:21])[CH2:25][C@@H:26]3[C@@H:35]2[CH2:34][CH2:33][C@@:31]2([CH3:32])[C@H:27]3[CH2:28][CH2:29][C:30]2=[O:38])=[CH:12][C:11](=[O:10])[CH2:22]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Reactant: CCOCOCC
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@]2(C)C1=CC(=O)C[C@H]2C
Yield: 60 %

Procedure:
A mixture of sodium acetate (1 g), absolute chloroform (30 ml), formaldehyde-diethylacetal (30 ml, 0.24 mol), phosphoryl chloride (3.8 ml, 0.04 mol), and 1β-methylandrost-4-ene-3,17-dione (0.811 g, 2.7 mmol) was stirred at reflux for about 7 hours, i.e. until the starting material had disappeared. The suspension was allowed to cool and under vigorous stirring a saturated sodium carbonate solution was added dropwise until the pH of the aqueous layer became alkaline (~1 hour). The organic layer was separated, neutralized with water, and dried with sodium sulfate. After concentration under reduced pressure the oily residue was purified by chromatography on silica gel using hexane/ethylacetate as eluent. Thus the pure 1β-methyl-6-methylenandrost-4-ene-3,17-dione was obtained in 60% yield (0.195 g); I.R. (KBr): 3100 (6=CH2), 1735 (17-oxo), 1680 (3-oxo), 1630, 1660 cm-1 (Δ4 and 6=CH2).
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].CO.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:23])=[CH:17][CH:16]=1
Reactant: CCC(C)S(N)(=O)=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(Cl)cc1
Yield: 18.6 %

Procedure:
The method of Example 10 was followed with 2-butanesulfonamide (6.85 g), methanol (250 ml), sodium methoxide (2.7 g), tetrahydrofuran (250 ml) and 4-chlorophenyl isocyanate (7.7 g) with the resulting solid being recrystallized from ethyl acetate to give 2.7 g of white crystals with a melting point of 172-174° C.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)C(C)=O.[Cl:12]CC1C=CN=CC=1>>[ClH:12].[Cl:12][CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][N:1]=1
Reactant: CC(=O)Nc1ccccc1O
Reactant: ClCc1ccncc1
Product: Cl
Product: ClCc1ccccn1

Procedure:
By following the procedure of Example 1, part A, but replacing 4-acetaminophenol with 2-acetaminophenol, and 4-chloromethylpyridine hydrocholoride, with 2-chloromethylpyridine hydrochloride, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([O:22][C:25](=[O:27])[CH3:26])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1OC(C)=O
Yield: 91 %

Procedure:
A solution of 2 (p-methoxybenzyl) 3 methyl 4-hydroxy 5-propyl 7 chlorobenzofuran (0.10 gm, 0.29 mmoles), acetic anhydride (0.5 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2-(p-methoxy benzyl)-3-methyl-4-acetoxy-5-propyl 7-chlorobenzofuran, mp. 119°-120° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]2[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([CH:17]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:2]1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O.[F:29][C:30]([F:47])([F:46])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37](N2C=CN=C2)=[O:38])=[CH:33][CH:32]=1.Cl>C(OCC)(=O)C.O>[F:29][C:30]([F:46])([F:47])[C:31]1[CH:45]=[CH:44][C:34]([CH2:35][O:36][C:37]([N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]3[CH:8]=[CH:9][C:10]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]=3)[CH2:2]2)=[O:38])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cc([C@H]2CCCNC2)ccc1C
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Agent: Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
(R)-Ethyl 5-(3-piperidinyl)-2-methylbenzoate-D-tartaric acid (2.02 g, 5.08 mmol) was dissolved in 100 mL ethyl acetate and washed with 100 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 10 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (1.37 g, 5.08 mmol) was added. The reaction was stirred for 72 h at room temperature under nitrogen. The reaction was diluted with water (200 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×150 mL). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 10% ethyl acetate/hexanes to yield 2.12 g (93%) of the desired (R)-3-(3-ethoxycarbonyl-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CN(C)CCO[C:15]1[CH:20]=[C:19]([B:21]([OH:23])[OH:22])[CH:18]=[CH:17][N:16]=1>>[N:4]1([CH2:3][CH2:2][O:1][C:15]2[CH:20]=[C:19]([B:21]([OH:23])[OH:22])[CH:18]=[CH:17][N:16]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CN(C)CCOc1cc(B(O)O)ccn1
Reactant: OCCN1CCOCC1
Product: OB(O)c1ccnc(OCCN2CCOCC2)c1

Procedure:
[2-(2-Morpholin-4-yl-ethoxy)-4-pyridinyl]-boronic acid is prepared from N-(2-hydroxyethyl)-morpholine according to the procedure described for the preparation of [2-(2-dimethylamino-ethoxy)-4-pyridinyl]-boronic acid. MS (m/z): 253 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([N:18]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[C:19]2=[O:36])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.[I-].[Na+]>C(#N)C>[CH2:1]([C:8]1[CH:9]=[C:10]([N:18]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)[C:19]2=[O:36])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(OCCBr)c(Cc2ccccc2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1n(-c2ccc(Oc3ccccc3)cc2)ccn1-c1ccc(OCCN2CCCC2)c(Cc2ccccc2)c1

Procedure:
A solution of 1-[3-benzyl-4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (60 mg) in acetonitrile (1 ml) was mixed with pyrrolidine (0.2 ml) and sodium iodide (5 mg) and boiled under reflux for 2 hours. The cooled solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 531.66 (C34H33N3O3); MS (ESI): 532 ([M+H]+), was obtained as hydroformate in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.Cl.C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Nc1c(F)cccc1Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
A mixture of 2-chloro-6-fluoroaniline (4.00 g, 27.5 mmol), 4-bromotoluene (4.70 g, 27.5 mmol), sodium tert-butylate (4.75 g, 49.4 mmol), and toluene (55 mL) is stirred at 25° C. under nitrogen for 30 minutes. To this mixture, a solution of palladium-bis-(dibenzylidenacetone) (15.8 mg, 55 mmol) and tri-tert-butylphosphine (1) (8.3 mg, 0.04 mmol) in toluene (5 mL) is added and the resulting suspension is stirred at 110° C. for 14 hours. The mixture is then cooled to 30° C. Water (30 ml), concentrated hydrochloric acid (10 ml), charcoal and cellite (1 g each) are added and stirring is continued for 1 hour. The mixture is filtered and the filtrate is separated into its phases. The organic phase is washed three times with water (10 mL) and concentrated in vacuo to give 6.5 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used directly in the next step (Step 1.2). Alternatively, it can be distilled in vacuo by Kugelrohr.
Reaction SMILES: [C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[C:11]([C:13](=[O:15])[NH2:14])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[C:1]1([CH3:35])[C:2]([NH:7][C:8]2[O:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[C:11]([C:13]([NH2:14])=[O:15])[N:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1Nc1nc(C(N)=O)c(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1Nc1nc(C(N)=O)c(-c2ccc(N3CCNCC3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of tert-butyl 4-(4-(2-(o-toluidino)-4-carbamoyloxazol-5-yl)phenyl)piperazine-1-carboxylate (0.012 g, 0.025 mmol) in DCM (0.5 ml) was added 0.5M HCl in dioxane (0.25 m, 0.125 mmol) and the resulting solution stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH (500 mg) cartridge to afford 2-(o-toluidino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.0087 g, 0.023 mmol, 92%). 1H NMR (DMSO) δ 2.30 (3H, s), 2.84 (4H, m), 3.15 (4H, m), 6.97-7.01 (3H, m). 7.19-7.23 (2H, m), 7.32 (1H, br. d), 7.41 (1H, br. d), 7.99 (1H, dd), 8.07 (2H, d), 9.26 (1H, s). LCMS (2) Rt: 2.32 min; m/z (ES+) 378.
Reaction SMILES: [C:1]([C:3]1[C:12](I)=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:14])[CH:4]=1)#[N:2].C(C1C(O)=CC([C:21](OC)=[O:22])=C(C)C=1)#N.C1([OH:35])C=CC=CC=1.IC>>[NH2:2][C:1]([C:3]1[C:12]([O:22][CH3:21])=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:14])[CH:4]=1)=[O:35]
Reactant: Oc1ccccc1
Reactant: COC(=O)c1cc(O)c(C#N)cc1C
Reactant: COC(=O)c1cc(I)c(C#N)cc1C
Solvent: CI
Product: COc1cc(C(=O)O)c(C)cc1C(N)=O

Procedure:
Synthesized according to the method of reagent preparation 41 by replacement of step 6 with the conversion of methyl 4-cyano-5-iodo-2-methylbenzoate to methyl 4-cyano-5-hydroxy-2-methylbenzoate according to the method described in Chemical & Pharmaceutical Bulletin (2007), 55(9), 1361-1364 followed by phenol alkylation with iodomethane then proceeding with steps 7 and 8. 1H NMR (400 MHz, DMSO-d6): 7.69 (b, 1H), 7.63 (b, 2H), 7.45 (s, 1H), 3.88 (s, 3H), 2.44 (s, 3H); MS (EI) for C10H11NO4: 210 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=2[C:10]([N:12]([CH2:15][CH:16]([CH3:28])[NH:17]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:13][CH3:14])=O)=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[ClH:1].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](=[O:7])[C:8]2[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=2[C:10]2[N:12]([CH2:13][CH3:14])[CH2:15][CH:16]([CH3:28])[N:17]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC(C)NS(=O)(=O)c1ccc(C)cc1)C(=O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCN1CC(C)N=C1c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Cl
Reaction time: 21 h

Procedure:
Forty grams of 2-(p-chlorobenzoyl)-N-[2-methyl-2-(p-toluenesulfonamido)ethyl]-N-ethylbenzamide and 100 ml. of 90% (v/v) sulfuric acid were mixed together and heated in a steam bath for 45 minutes. After standing at room temperature 21 hours, the solution was quenched with 500 ml. of ice water. The mixture was extracted with dichloromethane. The aqueous portion was cooled and made basic with 50% sodium hydroxide solution. The mixture was extracted with ethyl acetate. The ethyl acetate portion was extracted with water then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in diethyl ether and treated with hydrogen chloride. The solid was separated and recrystallized from ethanol-ethyl acetate to obtain 4'-chloro-2-(1-ethyl-4-methyl-2-imidazolin-2-yl)benzophenone hydrochloride, m.p. 212°-214°C.
Reaction SMILES: N[C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:24])[N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C(N(CC)CC)C.O.Cl>CN(C)C=O>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19]/[C:15](=[CH:14]\[C:6]3[CH2:5][S:4][CH:3]4[N:8]([C:9](=[O:10])[CH2:2]4)[C:7]=3[C:11]([OH:13])=[O:12])/[C:16]2=[O:24])[CH2:23][CH2:22]1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(CC4CC4)C3=O)CS[C@H]12
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)C1=C(/C=C2\CCN(CC3CC3)C2=O)CSC2CC(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere to a stirred suspension of 25.6 g (E)-(6R,7R)-7-Amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (73.3 mmol) in 120 ml dimethylformamide was added 20 ml triethylamine (143 mmol) at 10° C. After 15 min, the solution was cooled to 0° C. and 28.5 g (Z)-(2-aminothiazol-4-yl)-acetoxyiminoacetic acid diethoxy thiophosphonyl ester (74.8 mmol) was added in portions over 5 min. Stirring was continued at 0° C. with exclusion of light for 5 h. The reaction was followed by HPLC. The brown reaction mixture was poured at once into 550 ml water of 10° C. Over 30 min, 50 ml HCl 1N was added. The pH dropped from 4.6 to 3.2 and the product precipitated from the reaction mixture. Stirring was continued for 1 h at 0° C. The suspension was filtered. The product was washed with ice-cold water, re-suspended in water, stirred for 20 min at room temperature, filtered and again washed with water. (6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-acetoxyimino-acetylamino)]-3-[(E)-1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as a beige, wet solid. The product was used immediately and without drying for the next step.
Reaction SMILES: CCN(C1C=CC=CC=1)CC.O[CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19])[CH3:14].S(Cl)([Cl:26])=O.O>C(Cl)Cl>[Cl:26][CH:13]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([NH2:20])=[O:19])[CH3:14]
Reactant: CC(O)c1cccc(C(N)=O)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CC(Cl)c1cccc(C(N)=O)c1
Temperature: 0 °C
Yield: 75 %

Procedure:
Diethylaniline (390 μL, 2.45 mmol) was added 3-(1-hydroxyethyl)benzamide (400 mg, 2.45 mmol) slurried in DCM (20 mL) and the reaction mixture was cooled with an ice -bath. Thionyl chloride ((255 μL, 2.47 mmol) was added dropwise and the reaction was put in the refrigerator overnight. Water was added, the reaction mixture was extracted twice with DCM, washed with a 10% HCl solution, neutralized with a saturated bicarbonate solution, treated with brine, dried (MgSO4), filtered and evaporated to dryness. The crude product was recrystallized from diethylether/hexane to give 335 mg (75% yield) of the title compound as a white solid.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]([CH3:13])[N:6]=1.Cl[CH2:15][C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>CO.O>[NH2:12][C:11]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[CH:8][CH:9]=2)[S:4][C:15]=1[C:16](=[O:28])[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: O=C(CCl)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C#N)c(S)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(N)c(C(=O)CS(=O)(=O)c3ccc(Cl)cc3)sc2n1
Yield: 67.2 %

Procedure:
To a mixture of 5.4 g (0.1 mol) of sodium methoxide and 7.5 g (0.05 mol) of 2-mercapto-3-cyano-6-methyl pyridine in 100 ml methanol was slowly added 13.3 g (0.05 mol) of 3-chloro-1-(4-chloro-phenylsulfonyl)-2-propanone. The reaction mixture was refluxed for 7 hours. It was then cooled, diluted with water and filtered to give 15.5 g of crude product which was crystallized from acetonitrile to give 12.8 g of pure product, m.p. 265°-7° C.
Reaction SMILES: [OH-].[Na+].[C:3]([O:18]CC)(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16].O.Cl>CO>[C:3]([OH:18])(=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH3:16]
Reactant: CCOC(=O)CCCCSCCCCCSCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCSCCCCCSCCCCC(=O)O
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Sodium hydroxide (1M, 6.2 mL, 6.2 mmol) was added to a solution of ethyl 6,12-dithiatetradecanoate (0.9 g, 3.1 mmol) in MeOH (15 mL). After stirring for 4 hours, water (20 mL) was added and the reaction mixture was acidified (pH 1, HCl) extracted with EtOAc (2×100 mL), and the organic phase was washed with water (20 mL ), brine (20 mL ), and then dried (Na2SO4). The product crystallized from n-hexane to yield the title compound as a white solid (0.77 g, 95%, mp 49.5°-50.0° C). IR: 3000, 1720 cm-1 ; 1H NMR, 1.23 (t, 3H), 1.49 (quintet, 2H), 1.56-1.68 (m, 6H), 1.74 (quintet, 2H:), 2.38 (t, 2H), 2.51 (t, 2H), 2.53 (t, 4H), 2.54 (q, 2H), and 10.45 (b, 1H). Anal. Calcd for C12H24S2O2 : C, 54.50; H, 9.15%. Found: C, 54.59; H, 9.21%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](O)=[O:45])[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:35][C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](=[O:45])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:42][CH2:41]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a solution of 4-aminoacetophenone (6.76 g, 50 mmol) in DMF (250 ml) were added TOTU (16.40 g, 50 mmol), boc-isonipecotic acid (11.46 g, 50 mmol) and DIPEA (8.6 ml, 50 mmol). The reaction mixture was stirred at ambient temperature for 12 h. The solvent was removed in vacuo. The residue was redissolved in ethyl acetate (250 ml) and washed with sat. sodium hydrogen carbonate solution (2×50 ml), hydrochloric acid (1 N, 50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate, evaporated and recrystallized from ethyl acetate. The product was obtained as white crystalline solid (yield: 12.2 g, 70%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:22]=[CH:21][C:20](I)=[CH:19][N:18]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C1(N2CCC3C=CC(OC4N=CC(N5CCCC5=O)=CC=4)=CC=3CC2)CCC1>>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C:25]5=[O:30])=[CH:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCN1
Reactant: Ic1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Agent: O=C1CCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: O=C1CCCCN1c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1

Procedure:
Example 218 (E218) was prepared from 3-cyclobutyl-7-[(5-iodo-2-pyridinyl)oxy]-2,3,4,5-tetrahydro-1H-3-benzazepine (E207) and 2-piperidinone using the method described for Example 217 (E217); MS (ES+) m/e 392 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([CH3:29])[CH:28]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Product: Cc1cc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)ccc1[N+](=O)[O-]

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (382 mg, 1 mmol) was treated as described in general procedure B using 5-fluoro-2-nitrotoluene (310 mg, 2 mmol) to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1-(3-methyl-4-nitro-phenyl)-1H -imidazole.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(Cl)Cl.Cl>[Ti](Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:17])[C:7](=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21

Procedure:
In a 250 milliliter round-bottomed flask equipped with a pressure equalizing dropping funnel, there was discharged 10 grams of 1,8-dichloroanthraquinone, 16.5 milliliters of diethyl malonate, and 150 milliliters of methylene chloride under a nitrogen atmosphere. The resulting mixture was then mechanically stirred and cooled with an ice bath. Thereafter, 24 milliliters of titanium tetrachloride was added dropwise through the dropping funnel over a period of 20 minutes, followed by the addition of 45 milliliters of pyridine. The reaction mixture was then stirred at room temperature for 65 hours. Subsequently, 150 milliliters of a dilute aqueous hydrochloric acid solution was slowly added with stirring. The organic phase resulting was separated, washed twice with water, and dried with anhydrous magnesium sulfate. Evaporation of the dried organic solution yielded a yellowish solid which when recrystallized from methanol afforded 7.5 grams of the pure Compound (VIII), mp., 166°-167° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[OH:14])(=[O:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([C:8]1[C:9](=[O:21])[CH2:10][CH:11]([CH:15]2[CH2:20][CH2:19][CH2:18][S:17][CH2:16]2)[CH2:12][C:13]=1[O:14][C:1](=[O:3])[CH3:2])(=[O:7])[CH3:6]
Reactant: CC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=C(C(C)=O)C(=O)CC(C2CCCSC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.82 g (10.5 mmol) of acetyl chloride is added dropwise to a stirred solution of 2.54 g (10.0 mmol) of 2-acetyl-3-hydroxy-5-(tetrahydro-2H-thiopyran-3-yl)-cyclohex-2-en-1-one and 1.06 g (10.5 mmol) of triethylamine in 50 ml of dichloromethane. The mixture is stirred overnight at room temperature, and then is poured into 100 ml of ice-cold water. The organic layer is separated and washed with 20 ml of dilute sodium bicarbonate solution, followed by 50 ml of saturated sodium chloride solution. The washed extract is then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product can be purified by column chromatography employing tetrahydrofuran-hexane (1:2 by volume) as eluent to afford the title compound.