Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Li+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>CN1CCCC1=O>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11](=[O:14])[CH:12]=[CH2:13]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccccc1O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=CC(=O)Nc1ccccc1O
Yield: 34.1 %

Procedure:
20 g of o-amino phenol was dissolved in 200 mL of N-methyl-2-pyrrolidone (NMP), and then the solution was ice-cooled. To the solution was added 8.546 g (1.1 times in mol) of lithium chloride. After lithium chloride was entirely dissolved, 17.42 g (1.05 times in mol) of acryloyl chloride was dropped into the solution, and the solution was stirred under ice-cooling for 5 hours. The reaction mixture was poured into 1.8 L of water, and an organic layer was extracted with 700 mL of diethyl ether. The diethyl ether layer was sequentially washed with 0.2 N hydrochloric acid, brine and water, and dried over magnesium sulfate. Diethyl ether was evaporated off under a reduced pressure. 80 mL of diisopropyl ether was added to the solidified residue, and the solution was heated and stirred to wash and filter the residue. The same washing process was carried out once again to obtain 10.2 g of N-(2-hydroxyphenyl)acrylamide as white powder (yield: 34%).
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:13][CH2:14]O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].O>C(#N)C>[Br:46][CH2:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: CCN(CC)C(=O)c1ccc(C(CCO)c2cccc(OC)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(CCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-(4-Diethylcarbamoylphenyl)-1-hydroxy-3-(3-methoxyphenyl)propane (215 mg) was dissolved in acetonitrile (4 ml), added with triphenylphosphine (304 mg) and carbon tetrabromide (385 mg) under ice cooling and stirred at room temperature for 30 minutes. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate=2:1) to obtain 189 mg of the title compound. Yield: 74%.
Reaction SMILES: [CH3:1][N:2]1[CH2:17][C:16]2[C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]=3[C:6]3[NH:18][C:19]4[C:20](=O)[CH2:21][CH:22]=[CH:23][C:24]=4[C:5]=3[C:4]=2[C:3]1=[O:26].C(C1C(=O)C(Cl)=C(Cl)C(=[O:32])C=1C#N)#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:3](=[O:26])[C:4]2[C:5]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][C:6]=3[C:7]3[NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[C:16]=2[C:17]1=[O:32]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CN1Cc2c(c3c4c([nH]c3c3[nH]c5ccccc5c23)C(=O)CC=C4)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)c2c(c3c4ccccc4[nH]c3c3[nH]c4ccccc4c23)C1=O

Procedure:
12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of dark yellow crystals which decompose from 310° C. The 12-(2-carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxoindolo[2,3-a]furano[3,4-c]carbazole used as starting material is prepared as follows: 980 mg (2.39 mmol) 12-(2-Carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole are heated under reflux for 1.5 hours in 200 ml 15% methanolic potassium hydroxide solution. After cooling, the reaction mixture is filtered, the filtrate is acidified with 2N hydrochloric acid and the product which precipitates out is filtered off and washed with water. 12-(2-Carboxyethyl)-6,7,12,13-tetrahydro-5,7-dioxo-indolo[2,3-a]furano[3,4-c]carbazole is obtained as a brownish amorphous powder. The 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]-carbazole used as starting material is prepared as follows: 500 mg (1.47 mmol) 6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole in 50 ml acetonitrile are stirred for 4 days at 20° C. with 1.05 g (14.8 mmol) acrylamide and 0.1 ml DBU. The suspension is evaporated, stirred with 30 ml dichloromethane/methanol (95:5 v/v) and the undissolved crystals are filtered off. 12-(2-carbamoylethyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole is obtained in the form of yellow crystals. The 6,7,12,13-tetrahydro-6-methyl-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole used as starting material is prepared as follows: 1 g (2.93 mmol) 3,4-bis-(indol-3-yl)-N-methyl-maleic acid imide is boiled under reflux for 1 hour with 800 mg (3.52 mmol) DDQ and 560 mg (2.94 mmol) p-toluenesulphonic acid hydrate in 200 ml toluene. Two thirds of the solvent are distilled off and the precipitate is filtered off and stirred with 100 ml 0.1N sodium hydroxide solution. It is filtered, the precipitate is washed with water, then suspended in ethanol and again filtered off. 6,7,12,13-Tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of a yellow amorphous powder; m.p. >350° C. The 3,4-bis-(indol-3-yl)-N-methylmaleic acid imide used as starting material is prepared in the manner described in the literature (see Tetrahedron, 1988, 44, 2887).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][S:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>O>[C:29]([O:33][C:34](=[O:37])[CH2:35][C:27]1[C:21]2[NH:20][C:19]([S:18][CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]([O:9][CH3:8])=[O:28])=[N:23][C:22]=2[CH:24]=[CH:25][CH:26]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1ccccc1CSc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1nc2cccc(CC(=O)OC(C)(C)C)c2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
Sodium hydride (400 mg, 10.0 mmol) and dimethylformamide (30 ml) were added to a previously dried reaction vessel. To the mixture were added 2-(benzimidazole-2-ylthiomethyl)benzoic acid methyl ester (1500 mg, 5.0 mmol) and bromoacetate t-butyl ester (1463 mg, 7.5 mmol), and the mixture was stirred at 80° C. for 2 hours. Water was added thereto, followed by extraction with ether. After the ether phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 2-(2-((2-(methoxycarbonyl)phenyl)methylthio)benzimidazolyl)acetic acid t-butyl ester (1298 mg, yield 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.Cl.CNC>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2 mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for 5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. The reaction mixture was stirred at RT overnight. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give 4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66) (220 mg, 0.85 mmol, 85% yield) as a light yellow oil.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([N:4]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NCCCN(CC(F)(F)F)C2CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (255 mg) and N,N-diisopropylethylamine (258 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[O:23]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25]1>>[O:23]=[S:24]1(=[O:30])[CH2:28][CH2:27][CH:26]([NH:29][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:19][CH:18]=2)=[O:22])[CH2:25]1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Reactant: NC1CCS(=O)(=O)C1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC2CCS(=O)(=O)C2)s1
Yield: 37 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using 1,1-dioxidotetrahydrothien-3-ylamine instead of isopropylamine, to the title compound (37 mg, 37%) which was obtained as a brown solid MS: m/e=433.3 [M+H]+.
Reaction SMILES: CN(C)C=O.O[CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1nc(-c2ccccc2)c(CCO)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(CCCl)o1

Procedure:
N,N-Dimethylformamide (4.0 ml) was added to a solution of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole (10.5 g) in chloroform (100 ml) and, under ice-cooling and stirring, thionyl chloride (11.4 ml) was added dropwise. The mixture was refluxed for 30 minutes and the solvent was distilled off. Then, ice water was added and the mixture was neutralized with sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-chloroethyl)-2-methyl-4-phenyloxazole, yield 11.0 g (96.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].CO.[C:15](=O)=[O:16]>O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc2[nH]ccc12
Temperature: 170 °C

Procedure:
To 4-chloro-1H-pyrrolo[2,3-b]pyridine [2.3 g, Reference Example 64] in a stainless steel pressure vessel was added sodium hydroxide (2 g), and methanol (40 mL). The pressure vessel was sealed and heated at 170° C. for 4 hours. After cooling, water (100 mL) was added and the mixture was neutralised by addition of excess solid carbon dioxide pellets (30 g). After concentration to a slurry and filtration, the residue was washed twice with water (5 mL) to afford 4-methoxy-1H-pyrrolo[2,3-b]pyridine as a solid. To a mixture of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (5.85 g) in toluene (150 mL) and water (150 mL) was added potassium hydroxide pellets (2.5 g), 4-methylbenzene sulfonyl chloride (7.53 g) and tetra-n-butyl ammonium hydrogen sulfate (0.02 g). This mixture was stirred at room temperature for 20 hours then extracted four times with ethyl acetate (100 mL). The combined organic extracts were concentrated and then subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and heptane (35:65, v/v) to afford the title compound as a white solid.
Reaction SMILES: NC1C=CC(N2CCCN(C(OC(C)(C)C)=O)CC2)=CC=1N.[F:23][C:24]1[CH:25]=[C:26]([S:30]([Cl:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.[NH2:34][C:35]1[CH:40]=[C:39]([N:41]2[CH2:47][CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]2)[CH:38]=[CH:37][C:36]=1[NH:55][S:56]([C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=1)(=[O:58])=[O:57].FC1C=C(S(N)(=O)=O)C=CC=1.Cl.CCOCC>CO>[ClH:33].[N:41]1([C:39]2[CH:38]=[CH:37][C:36]([NH:55][S:56]([C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([F:65])[CH:60]=3)(=[O:57])=[O:58])=[C:35]([NH:34][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)(=[O:32])=[O:31])[CH:40]=2)[CH2:47][CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(NS(=O)(=O)c3cccc(F)c3)c(N)c2)CC1
Agent: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(N)c2)CC1
Agent: Cl
Agent: NS(=O)(=O)c1cccc(F)c1
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.5 h

Procedure:
The compound was prepared from 2-amino-5-(4-t-butyloxycarbonyl-1-homopiperazinyl)aniline and 3-flourobenzenesulfonyl chloride. Purification by column chromatography (CH2Cl2/MeOH/heptane, 4:1:15) gave a mixture of N-{2-amino-4-[4-t-butyloxycarbonyl-homopiperazin-1-yl-]phenyl}3-fluorobenzenesulfonamide and N-{4-[4-t-butyloxycarbonyl]homopiperazinyl)-2-[(3-flourophenylsulfonyl)amino]phenyl}-3-fluorobenzenesulfonamide (0.180 g, 73%). Boc-deprotection was achieved by dissolving the mixture in small amount of MeOH and adding HCl/ether. The mixture was let at r.t. for 0.5 h. Purification by preparative HPLC gave N-(4-(1,4-diazepan-1-yl)-2-{[(3-fluorophenyl)sulfonyl]amino}phenyl)-3-fluorobenzenesulfonamide hydrochloride Anal. (C23H27ClN4O4S2) C, H, N, S.; M+ 524.4 Calcd 522.12.
Reaction SMILES: [Cl-:1].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]>C1COCC1.[Zn]>[Cl-:1].[CH:3]1([Ti+:13][CH:8]2[CH:12]=[CH:11][CH:10]=[CH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4]1
Reactant: [Ti+2]
Reactant: c1cc[cH-]c1
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C1=CC([Ti+]C2C=CC=C2)C=C1
Reaction time: 1 h

Procedure:
To a red solution of titanocene dichloride (0.500 g, 2.00 mmol) in anhydrous THF (4.0 mL) was added zinc dust (0.392 g, 6.00 mmol). The resulting suspension was vigorously stirred for 1 h under an argon atmosphere to give a green suspension. Excess zinc was removed by filtration through a 0.45 μm microfilter to give a green solution of dicyclopentadienyl titanium (III) chloride. To a solution of compound 505A (0.207 g, 0.399 mmol) and 1,4-cyclohexadiene (0.380 mL, 4.02 mmol) in anhydrous THF (1 mL) was added dropwise a 0.5 M solution of the above described dicyclopentadienyl titanium (D) chloride (0.9 mL, 0.45 mmol). After 1 h, an additional aliquot of the 0.5 M solution of dicyclopentadienyl titanium (D) chloride (0.9 mL, 0.45 mmol) was added and stirring was continued for 1 h. The reaction was then quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The layers were separated and the organic layer was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow gum. The crude material was dissolved in a minimum amount of methylene chloride and loaded on a 35 g silica gel ISCO column. Gradient elution with 0-80% ethyl acetate in hexane gave 0.043 g (21%) of compound 505Bi as a white solid and 0.023 g (11%) of compound 505Bii as a white solid. Compound 505Bi: HPLC: 3.92 min (retention time) (YMC CombiSreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521.36 [M+H]+. Compound 505Bii : HPLC: 91% at 3.97 min (retention time) (YMC CombiScreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 521.34 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[F:16][C:17]([F:28])([F:27])[CH2:18]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:18][C:17]([F:28])([F:27])[F:16]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(OCC(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2-chloro-4-fluorophenol (52, 1.58 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL), cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mmol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (124, 2.10 g, 85.3%).
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH:34][C:42](=[O:44])[CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
(2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one (100.0 g, 214.1 mmol) was dissolved in toluene (500 ml), to which pyridine (10 ml, 124.3 mmol) was added under a nitrogen stream. Acetyl chloride (25.7 g, 321.1 mmol) was slowly added to the resultant mixture while chilling with ice water so as not to raise the temperature above 10° C. The reaction mixture was further stirred at 50° C. for 5 hours and 25° C. for 16 hours. The mixture was then washed twice with a small amount of a 10% aqueous solution of sodium carbonate and with an aqueous sodium chloride, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from methanol (1000 ml), thereby obtaining the title compound (97.5 g, 89.4%) as pale yellow crystals.
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14](=[O:17])[CH2:15]Br>>[CH3:9][O:10][C:11](=[O:18])[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [S-]c1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Agent: [Na+]
Product: COC(=O)CCC(=O)CSc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 ml of a 1M methanolic sodium thiophenolate solution there was added 22 g (0.1 mole) 5-bromo-4-oxo-valeric acid methylester during 40 minutes and the reaction mixture was stirred for two hours at room temperature. The methanol was distilled off in vacuo, to the residue there was added 200 ml ethyl acetate, and the mixture was washed successively with 30 water, 30 ml sodium bicarbonate solution, 30 ml saturated saline solution, then dried over magnesium sulfate, filtered, and the solvent was distilled off. The residue was chromatographed on a column using a 4:1 mixture of hexane and ethyl acetate as an eluent.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:8]([C:10](=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C1CCCCC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
To a solution of cyclohexanone (1.50 ml, 14.47 mmol) in toluene (24.12 ml) was added ethyl cyanoacetate (1.556 ml, 14.62 mmol), acetic acid (0.166 ml, 2.89 mmol), and ammonium acetate (0.112 g, 1.447 mmol). The mixture was heated to a reflux at 150° C. in a Dean-Stark apparatus. After 5 h, the reaction was cooled and washed with water and saturated NaHCO3 solution. The organics were dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:13]([OH:21])[CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(N(CC)CC)C>[C:25]([O:21][CH:13]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:26])[CH2:24][C:23]([CH3:22])=[O:27]
Reactant: OC(CN1CCCCC1)c1ccccc1
Reactant: C=C1CC(=O)O1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)CC(=O)OC(CN1CCCCC1)c1ccccc1
Yield: 106.2 %

Procedure:
To 130 ml of benzene are added 14.7 g of 1-phenyl-2-piperidinoethanol, 7.1 g of diketene and 1 ml of triethylamine. The mixture is refluxed under heating for three hours. The reaction mixture is concentrated under reduced pressure to give 22 g of 1-phenyl-2-piperidinoethyl acetoacetate. A mixture of 22 of 1-phenyl-2-piperidinoethyl acetoacetate, 10.6 g of m-nitrobenzaldehyde and 12.7 g of (2-furyl)methyl β-aminocrotonate in 130 ml of isopropanol is refluxed under heating for 12 hours. The reaction mixture is concentrated under reduced pressure. To the viscous jelly-like oily substance thus obtaned is added an ethanol solution of hydrogen chloride and then the mixture is concentrated. The viscous jelly-like residue is crystallized from a mixture solvent of acetone-ether. The precipitated crystals are collected by filtration, and recrystallized from a mixture solvent of acetone-methanol to give α-diastereoisomer of 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-furyl)methylester-5-(1-phenyl-2-piperidinoethyl)ester in the form of hydrochloride as yellow crystals melting at 219°-221° C. (decomposition).