Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl.[Cl:3][CH2:4][C:5]1[N:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:8]=[N:7][CH:6]=1.[CH3:18][OH:19]>>[ClH:3].[CH3:18][O:19][CH2:4][C:5]1[N:9]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH:8]=[N:7][CH:6]=1
Reactant: CC(c1ccccc1)n1cncc1CCl
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COCc1cncn1C(C)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 1.38 parts of sodium in 40 parts of methanol were added 3.84 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride. Stirring was continued for one hour at reflux. The reaction mixture was evaporated. Water was added to the residue and the product was extracted with 2,2'-oxybispropane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 4-methyl-2-pentanone. The salt was filtered off and dried, yielding 1.8 parts of 5-(methoxymethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride; mp. 166.3° C. (compound 8.37).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](O)(=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC>[CH3:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]/[CH:14]=[CH:13]\[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH:4][CH2:3][CH2:1][OH:2])=[O:23]
Reactant: NCCO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
This experiment was carried out according to the procedure of using free fatty acid as acyl donor (Plastina et al., Lett. Org. Chem. 6:444-47 (2009), which is hereby incorporated by reference in its entirety). Ethanolamine (1 mmol) in hexane (1 mL) was mixed with oleic acid (1 mmol) in a 10-mL round bottom flask in the presence of the lipase (50%, relative to total reactants). The reaction was conducted with agitation at ambient temperature for 4, 8, and 24 hours or at 65° C. for 4, 8, and 20 hours before hexane was removed under reduced pressure.
Reaction SMILES: [C:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH:2]=1.[CH2:8](I)[CH3:9].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:8]([O:6][C:5]([C:1]1[CH2:4][CH2:3][CH:2]=1)=[O:7])[CH3:9]
Reactant: O=C(O)C1=CCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1=CCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 108.4 %

Procedure:
To a solution of 3.2425 g (33.09 mmol) of 1-cyclobutenecarboxylic acid in 60 ml of dimethylformamide were added 12 ml (150 mmol) of ethyl iodide and 5.53 g (40 mmoL) of potassium carbonate, followed by 20 hours of stirring at room temperature. The reaction solution was poured into water and extracted with ether. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent, 4.5267 g of the title compound was obtained as a mixture with ethyl iodide and ether.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]#[CH:23])[CH:15]=1.[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N+:33]([O-])=[O:34])[CH3:25].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:24]([O:26][C:27](=[O:36])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:23]=[C:22]([C:16]2[CH:15]=[C:14]([Cl:13])[CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[O:34][N:33]=1)[CH3:25]
Reactant: C#Cc1cc(Cl)ccc1OC
Reactant: CCOC(=O)CCCCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCc1cc(-c2cc(Cl)ccc2OC)on1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
Add 1,4-phenylenediisocyanate (8.41 g, 52.5 mmol) to a stirred solution of 4-chloro-2-ethynyl-1-methoxy-benzene (4.0 g, 30.3 mmol) and 6-nitro-hexanoic acid ethyl ester (8.6 g, 45.4 mmol) in toluene (300 mL, anhydrous) and stir at room temperature under N2. Add triethylamine (7.3 mL, 52.5 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 6.6 g of a orange oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-40% EtOAc/hexanes to afford the title compound (4.51 g, 76%). MS (IS) 338 (M+1)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17]Cl)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]1[CH:45]=[CH:44][C:34]([CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH:38]([CH2:42][NH2:43])[CH2:37]2)=[CH:33][CH:32]=1.CCCCCC.CC(=O)[O:54]CC>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:22]=[CH:21][CH:20]=[CH:19][C:16]=2[C:17]([NH:43][CH2:42][CH:38]2[O:39][CH2:40][CH2:41][N:36]([CH2:35][C:34]3[CH:44]=[CH:45][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:37]2)=[O:54])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(C)=O
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(NCC1CN(Cc2ccc(F)cc2)CCO1)c1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
The solution obtained in step 1 was cooled to 4-5° C. in an ice bath, followed by dropwise adding triethylamine (0.42 ml, 3.0 mmol) for 5 min. To the reaction solution was added with 4-(4-fluorobenzyl)morpholin-2-ylmethylamine (1.2 mmol), and stirred for 30 min at a room temperature and then for an additional 4 hrs under reflux. The reaction mixture was cooled to a room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated saline. After water was removed with a desiccant, the resulting solution was concentrated in a reduced pressure. In order to obtain a desired fraction, the residue was subjected to silica column chromatography (mobile phase: 30 (v/v) % Hexane in EA) to afford the title compound (Total yield: 53.0%)1H NMR (CDCl3) δ 8.20 (d, 1H), 8.12 (d, 1H), 7.54 (d, 1H), 7.36-7.24 (m, 7H), 7.01 (t, 2H), 6.46-6.38 (m, 1H), 4.08-3.98 (m, 1H), 3.87 (d, 1H), 3.73-3.61 (m, 4H), 3.53 (s, 2H), 3.45 (s, 2H), 3.32-3.19 (m, 2H), 2.85-2.61 (m, 4H), 2.32-2.14 (m, 3H), 2.08-1.88 (m, 3H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]([CH2:20][C:21]([O:23]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:35]1[C@@H:43]2[C@@H:38]([CH2:39][CH:40]=[CH:41][CH2:42]2)[CH2:37][NH:36]1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:20][C:21]([N:36]2[CH2:37][C@H:38]3[C@H:43]([CH2:42][CH:41]=[CH:40][CH2:39]3)[CH2:35]2)=[O:23])[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:33][CH:34]=1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Reactant: Cc1ccc(CC(CC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CC(CC(=O)N2C[C@H]3CC=CC[C@H]3C2)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Yield: 75.3 %

Procedure:
To a solution of di(4-nitrophenyl) 2-(4-methylbenzyl)succinate (2.4 g) in N,N-dimethylformamide (30 ml) was added a solution of cis-3a,4,7,7a-tetrahydroisoindoline (0.62 g) in N,N-dimethylformamide (10 ml) with stirring at 0° C. After stirring at 0° C. for 3 hours, water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed successively with three 1N sodium hydroxide solutions, 1N-hydrochloric acid, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was recrystallized from hexane-ethyl acetate (4:1) to give 1.7 g of 4-nitrophenyl 2-(4-methylbenzyl)-3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionate.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C:41]4[CH:50]=[CH:49][C:48]5[C:43](=[C:44](O)[CH:45]=[CH:46][CH:47]=5)[N:42]=4)=[N:39][N:40]=3)[CH:37]=2)[CH2:31][CH2:30]1>>[CH:29]1([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([C:38]([C:41]4[CH:50]=[CH:49][C:48]5[C:43](=[C:44]([O:9][C@H:8]6[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]6)[CH:45]=[CH:46][CH:47]=5)[N:42]=4)=[N:39][N:40]=3)[CH:37]=2)[CH2:31][CH2:30]1
Reactant: Oc1cccc2ccc(-c3nnc4ccc(C5CC5)cn34)nc12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cccc3ccc(-c4nnc5ccc(C6CC6)cn45)nc23)CC1

Procedure:
Prepared according to the method of Example 90 using cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate in place of trans-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate and 2-(6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol in Step C and running the reaction at 50° C.
Reaction SMILES: [CH2:1]([C@@H:5]([C:11]([OH:13])=[O:12])[C@H:6]([OH:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH3:4].[C:14]1(C)[CH:19]=CC(S(O)(=O)=O)=C[CH:15]=1>COC(OC)(C)C.ClCCl>[CH3:15][C:14]1([CH3:19])[O:8][C:7](=[O:9])[CH:6]([CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:11]([OH:13])=[O:12])[O:10]1
Reactant: CCCC[C@@H](C(=O)O)[C@H](O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: ClCCl
Product: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2S, 3R)-3-(n-butyl)-2-hydroxysuccinic acid F-4 (300 mg, 1.58 mmol) in 2,2-dimethoxypropane (10 mL) was added p-toluenesulfonic acid (20 mg) and the reaction was stirred at room temperature for 16 h. The solution was diluted with dichloromethane and washed with brine, dried (Na2SO4) and then purified by silica gel chromatography to afford 1.2 mmol 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid F-5 (78%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([CH:26]=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl.[NH2:29][OH:30]>CO.N1C=CC=CC=1>[OH:30][N:29]=[CH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([S:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[CH:15]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C=O)CCOCC3)c2)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C=NO)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
4-[3-[4-(2-Methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carbaldehyde (178 mg, 0.47 mmol) and hydroxylamine hydrochloride (210 mg, 3 mmol) were dissolved in a mixture of methanol (4 ml) and pyridine (1 ml) and the reaction mixture was stirred for 5 h at ambient temperature. Volatiles were removed in vacuo and the resultant residue was diluted with 0.1N aqueous NaOH (20 ml) and extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo. The residual solids were recrystallized from ethyl acetate to afford 130 mg (70%) of the titled compound as white solids.
Reaction SMILES: C[C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11](NC(C)C)(C)C.[Li].[CH3:19][O:20][C:21](Cl)=[O:22]>C1COCC1>[C:2]1([C:8]([O:10][CH3:11])=[O:9])([C:21]([O:20][CH3:19])=[O:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)NC(C)C
Reactant: CC1(C(=O)O)CCCCC1
Reactant: COC(=O)Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A solution of methyl cyclohexanecarboxylic acid (2.0 g, 14.06 mmol) in THF (5 mL) was added dropwise to a solution of lithium diisopropylamine (2.28 g, 21.1 mmol) in THF (20 mL) at −78° C. After stirring for 1 h at the same temperature, a solution of methylchloroformate (2.0 g, 21.1 mmol) in THF (5 mL) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (20 mL). THF was removed in vacuo and the aqueous residue was extracted with EtOAc (50 mL×3). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (80:20) yielded the title compound (2.8 g, 99%). MH+201.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.C(O)CCO.O[N:17]1[C:21](=[O:22])[CH2:20][CH2:19][C:18]1=[O:23].C1(N(C2CCCCC2)C(N)=O)CCCCC1>O1CCOCC1>[C:18]([OH:23])(=[O:9])[CH2:19][CH2:20][C:21]([NH2:17])=[O:22].[NH2:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1O
Agent: NC(=O)N(C1CCCCC1)C1CCCCC1
Agent: Nc1cccc(B(O)O)c1
Solvent: C1COCCO1
Solvent: OCCCO
Product: NC(=O)CCC(=O)O

Procedure:
PBA-XX-CO2H(6.3 g, 0.018 moles) was suspended in dry dioxane (60 mL). 1,3-Propanediol (1.4 g, 0.018 moles) was added, and the mixture was gently heated until all solid dissolves (about 10 minutes). The solvent was removed by rotary evaporation to leave a pale yellow syrup, which was co-evaporated twice with dioxane (30 mL each). The residue was then dissolved in dioxane (225 mL) and N-hydroxysuccinimide (2.3 g, 0.20 moles) was added, followed by N,N-dicyclohexylcarbodiimide (4.1 g, 0.020 moles). The solution was stirred under an atmosphere of dry nitrogen for 6 hours at room temperature, during which time the white precipitate of N,N-dicyclohexylurea formed. The precipitate was filtered and washed with dioxane (50 mL). The combined filtrates were concentrated to about 30 mL. Dry diethyl ether (200 mL) was slowly added to the stirred concentrate, causing precipitation of a white solid. The mixture was chilled in an ice/water bath for 1 hour, then filtered. The solid was washed with dry ether (50 mL), and dried in vacuo. Yield: 8.0 g (91%); M.P. 111°-117° C. (open capillary, uncorrected). 1H NMR (300 MHz, DMSO-d6) δ 9.85 (singlet, 1H, ArNHCOR), 7.85 (singlet, 1H, ArH), 7.82 (triplet, J=5.7 Hz, 1H, CONHCH2), 7.64 (doublet, J=7.9 Hz, 1H, ArH), 7.29 (doublet, J=7.3 Hz, 1H, ArH), 7.22 (doublet of doublets, J=7.6 Hz, 1H, ArH), 4.07 (triplet, J=5.4 Hz, 4H, BOCH2CH2), 3.05-2.95 (multiplet, 2H, CONHCH2), 2.79 (singlet, 4H succinimidyl COCH2), 2.62 (triplet, J=7.3 Hz, 2H, CH2CO2.R), 2.50 (triplet, J=6.7 Hz, 2H, NHCOCH2), 2.36 (triplet, J=6.7 Hz, 2H, NHCOCH2, 1.50-1.41 (multiplet, 2H, NHCH2CH2), 1.97 (quintet, J=5.4 Hz 2H, BOCH2CH2), 1.61-1.51 (multiplet, 2H, CH2), 1.41-1.30 (multiplet, 4H, CH2). 13C NMR (75.5 MHz, DMSO-d6) δ 171.3, 170.6, 170.5, 169.2, 138.9, 128.1, 128.0, 124.3, 121.4, 61.5, 38.2, 31.7, 30.4, 30.1, 28.6, 26.8, 25.4, 23.9, 15.1. HPLC: Retention time of product, 18.2±0.1 minutes under the conditions described above.
Reaction SMILES: N1CCCC1.C(O)(=O)C.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.[O:23]=[C:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[OH:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:42]/[C:24](=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)=[O:30])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: CC(=O)CCCCC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1CCNC1
Product: O=C(/C=C/c1cc(O)c(O)c([N+](=O)[O-])c1)CCCCC(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 56 h

Procedure:
0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran is treated at 5° with 0.605 ml of acetic acid and subsequently with 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4'-(trifluoromethyl)-heptananilide and stirred at 23° under argon for 56 hours. The residue obtained after evaporating the reaction mixture is partitioned between ethyl acetate and 1N sodium hydroxide solution. The combined sodium hydroxide extracts are made acid with conc, hydrochloric acid, extracted with ethyl acetate, the combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and the residue is chromatographed on 120 g of silica gel with methylene chloride/methanol (91:9). After recrystallization from ethyl acetate/petroleum ether there is obtained (E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-oxo-4'-(trifluoromethyl) -7-octenanilide of m.p. 194°-197°.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>[Ti](Cl)(Cl)(Cl)Cl.C1(OC)C=CC=CC=1>[CH3:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1c(sc3ccccc13)N2

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-methylanilino)benzo[b]thiophene-3-carboxylate (3.7 g), 1-methylpiperazine (19 ml), anisole (60 ml) and titanium tetrachloride (3.0 ml), 9-methyl-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine (1.18 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1I)[CH3:2].C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCc1nc(N)sc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc(N)sc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a stream of Ar the above prepared 4-ethyl-5-iodo-thiazol-2-ylamine (1.67 g, 6.57 mmol) was dissolved in 40 mL of acetonitrile and treated successively with triethylamine (2.73 mL, 3 eq.), Cul (0.125 g, 0.1 eq.), (Ph3P)2PdCl2 (0.46 g, 0.1 eq.) and ethynyltrimethylsilane (2.73 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 15 h at ambient temperature. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded finally 0.598 g of the title compound as brown viscous oil, contaminated with some des-iodo-compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C[O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[CH:13]=[C:12](Br)[CH:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C@@:26]2([CH3:38])[C@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C@:26]2([CH3:38])[C@@:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]([C:12]4[CH:11]=[C:10]([CH:15]=[C:14]([N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])[CH:13]=4)[C:9]([OH:8])=[O:18])[C:29]3=[O:37])[CH2:27]2)=[CH:24][CH:25]=1
Reactant: C[C@@]1(c2ccc(Cl)cc2)C[C@]12C(=O)Nc1ccccc12
Reactant: COC(=O)c1cc(Br)cc(I)c1
Reactant: O=C1NCCO1
Product: C[C@]1(c2ccc(Cl)cc2)C[C@@]12C(=O)N(c1cc(C(=O)O)cc(N3CCOC3=O)c1)c1ccccc12

Procedure:
The title compound was prepared in analogy to Example 95 starting from oxazolidin-2-one (commercially available), 3-bromo-5-iodobenzoic acid methylester prepared in Example 92, (1R,2R) and (1S,2S)-2-(4-chlorophenyl)-2-methylspiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 2. LC/MS m/e calcd. for C27H21ClN2O5: 488, observed (M+H)+: 489.1 1H NMR (400 MHz, DMSO-d6) δppm 1.66 (s, 3 H) 2.18 (d, J=4.80 Hz, 1 H) 2.38 (d, J=5.05 Hz, 1 H) 4.12 (t, J=8.08 Hz, 2 H) 4.47 (t, J=7.96 Hz, 2 H) 6.95 (d, J=8.08 Hz, 1 H) 7.15 (t, J=7.45 Hz, 1 H) 7.25-7.34 (m, 5 H) 7.45 (d, J=7.33 Hz, 1 H) 7.59-7.62 (m, 1 H) 7.85 (t, J=2.02 Hz, 1 H) 8.12 (s, 1 H).
Reaction SMILES: BrC1C=CC(N2[C:12](C[N+](C)(C)C)=[C:11]([CH3:18])N=C2)=C(C#N)C=1.[I-].[O:22]=[C:23]1[CH:28]=CN(CC(NN)=O)C=[CH:24]1>>[CH3:23][OH:22].[CH:23]([O:22][CH:11]([CH3:12])[CH3:18])([CH3:28])[CH3:24]
Reactant: Cc1ncn(-c2ccc(Br)cc2C#N)c1C[N+](C)(C)C
Reactant: NNC(=O)Cn1ccc(=O)cc1
Agent: [I-]
Product: CC(C)OC(C)C
Product: CO

Procedure:
As described for example 84d, [3-(4-bromo-2-cyano-phenyl)-5-methyl-3H-imidazol-4-ylmethyl]-trimethyl-ammonium; iodide (example 84c) was reacted with (4-oxo-4H-pyridin-1-yl)-acetic acid hydrazide. After evaporation of the solvent the residue was concentrated and chromatographed (SiO2, dichloromethane:methanol=100:0 to 92:8). Trituration with methanol/diisopropylether afforded the title compound as an off-white solid (yield: 33%). MS: m/e=425.0/423.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.Cl[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[CH2:33][CH2:32]1>CN(C)C=O.O>[CH3:44][O:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][CH2:28][N:16]2[CH2:17][CH2:18][CH:13]([O:12][C:11]3[C:19]([F:26])=[C:20]([F:25])[C:21]([F:24])=[C:22]([F:23])[C:10]=3[F:9])[CH2:14][CH2:15]2)[CH2:36][CH2:35]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCN2CCC(Oc3c(F)c(F)c(F)c(F)c3F)CC2)CC1
Temperature: 75 °C
Reaction time: 7 h
Yield: 51.4 %

Procedure:
A mixture of 10 g of potassium carbonate, 0.18 g of potassium iodide, 4.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 50 ml of dimethylformamide was treated with a solution of 4.56 g of 1-(3-chloropropyl)-4-(2-methoxyphenyl)piperazine in 25 ml dimethylformamide and stirred for seven hours at 75° C. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 7.5% methanol/dichloromethane). Evaporation of the appropriate fractions afforded 3.84 g of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and acidified to pH 1 with etheral hydrogen chloride to precipitate the corresponding dihydrochloride salt. Recrystallization from isopropanol afforded 3.34 g (44.6%) of 1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-4-(2,3,4,5,6-pentaflurophenoxy)piperidine hydrochloride, m.p. 261°-263° C.