Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][N:13](C(=O)[C@H](OC)C3C=CC=CC=3)[CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[B-](CC)(CC)CC.Cl.[NH4+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:10][CH2:11][CH2:12][NH:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO[C@@H](C(=O)N1CCO[C@H](c2ccc(Cl)c(Cl)c2)C1)c1ccccc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1ccc([C@@H]2CNCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Synthesized according to General Procedure 35. To a stirring solution of (R)-1-((R)-2-(3,4-dichlorophenyl)-morpholino)-2-methoxy-2-phenylethanone (620 mg, 1.63 mmol) and THF (9 mL), under N2, at 0° C., was added a solution of Super-hydride in THF (1.0 M, 10.3 mL, 10.3 mmol) dropwise over 10 minutes. The solution was stirred at 0° C. for 30 minutes. The solution was poured into 1M aqueous HCl solution (20 mL). The solution was then basified with NH4OH and extracted with CH2Cl 2 (3×50 mL). Purified via silica gel chromatogrophy using 10% MeOH in CH2Cl2 to obtain the desired morpholine, arbitrarily assigned (R) configuration, as a clear oil (290 mg, 1.3 mmol, 80% yield). 1H-NMR (400 MHz, CDCl3) δ 7.50-7.49 (m, 2H), 7.19 (dd, J=1.6, 8.3 Hz, 1H), 4.47 (dd, J=2.4, 10.4 Hz, 1H), 4.09 (s, 1H), 4.08 (dd, J=1.9, 12.9 Hz, 1H), 3.82-3.75 (m, 1H), 3.09 (dd, J=2.5, 12.5 Hz, 1H), 2.97 (dd, J=3.1, 10.2 Hz, 2H), 2.72-2.69 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=232.3; tR=0.67 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[N:18]1([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CCc3ccccc32)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To toluene 30 mL solution of tert-butyl 4-bromo-2-nitrobenzoate 3.0 g were added indoline 2.1 mL, cesium carbonate 8.0 g,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 0.29 g, tris(dibenzylideneacetone)dipalladium(0) 0.11 g and palladium acetate 55 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 3 hours and 30 minutes. After the reaction mixture was cooled to room temperature,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 0.29 g, tris(dibenzylideneacetone)dipalladium(0) 0.11 g and palladium acetate 55 mg were added to it, and it was heated and refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. Toluene was added to the obtained residue,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=10:1] to give tert-butyl 4-(indolin-1-yl)-2-nitrobenzoate 2.0 g of yellow solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[C:15](O)=[O:16])([CH3:11])([CH3:10])[CH3:9]>>[CH:1]1([NH:7][C:15](=[O:16])[C:14]2[CH:18]=[C:19]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:20]([OH:21])=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(=O)NC2CCCCC2)cc(C(C)(C)C)c1O

Procedure:
In the manner of Example 7, cyclohexylamine was reacted with 3,5-di-t-butyl-4-hydroxybenzoic acid to produce N-cyclohexyl-3,5-di-t-butyl-4-hydroxybenzamide; melting point 236°-237°C. When tested by the procedure of Example 2, this compound lasted 1150 hours, about 3.8 times as long as the control.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:3]1=[O:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:48][C:49]1[C:54]([C:55]([F:58])([F:57])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH2:60]>ClCCl.CN(C)C=O>[Cl:48][C:49]1[C:54]([C:55]([F:57])([F:58])[F:56])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:59][NH:60][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:3](=[O:16])[N:2]1[CH3:1])=[O:9]
Reactant: CN1C(=O)N(c2ncccn2)CC1C(=O)O
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ncccn2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
A suspension of crude 3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxylic acid (0.6 mmol) in dichloromethane (10 ml) was treated with 1-hydroxybenzotriazole hydrate (98 mg, 0.72 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol) and N-ethyl morpholine (0.3 ml, 2.4 mmol) was stirred at room temperature for 10 minutes. {[2-Chloro-3-(trifluoromethyl)phenyl]methyl}amine (126 mg, 0.6 mmol) was added. The reaction was diluted with dichloromethane (10 ml) and N,N-dimethylformamide (1 ml) and stirred at room temperature for 18 hours. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (138 mg, 0.72 mmol) was added and the suspension was stirred at room temperature for 5 days. The mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water, citric acid solution, water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The solid was triturated with ether/hexanes, collected and dried to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-(2-pyrimidinyl)-4-imidazolidinecarboxamide (42 mg), LC/MS [M+H]+=414, retention time=2.30 minutes.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][C:5](O)=[O:6].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:28][C:29]1[CH:30]=[C:31]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]([NH2:46])=[O:45])[CH:42]=3)[N:37]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:36]=2)[CH:32]=[CH:33][CH:34]=1>ClCCl.CN(C)C=O>[CH3:2][N:3]([CH3:8])[CH2:4][C:5]([NH:28][C:29]1[CH:30]=[C:31]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[C:41]([C:44]([NH2:46])=[O:45])[CH:42]=3)[N:37]([CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)[N:36]=2)[CH:32]=[CH:33][CH:34]=1)=[O:6]
Reactant: CN(C)CC(=O)O
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(C(N)=O)cc23)c1

Procedure:
To a solution of 2-(dimethylamino)acetic acid hydrochloride (0.091 g, 0.649 mmol) in 6 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (EDCI) (0.135 g, 0.708 mmol) and triethyl amine (0.090 mL, 0.649 mmol). The reaction was stirred at room temperature for 10 min before 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.200 g, 0.59 mmol) dissolved in 1 mL of dichloromethane, was added to the solution. Dimethyl formamide (2 mL) was added to aid solubility. Additional reagent (1 equivalent) was necessary to drive the reaction to completion. The reaction mixture was then partitioned between water and dichloroethane. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 422 [M+H]+.
Reaction SMILES: [C:1](O)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[Ca+2].[Cl-].[C:18]1([CH:25]=[CH:24][CH:23]=[C:21]([OH:22])[CH:20]=1)[OH:19].C(Cl)(Cl)Cl>O.[Cl-].[Zn+2].[Cl-]>[C:1]([C:23]1[CH:24]=[CH:25][C:18]([OH:19])=[CH:20][C:21]=1[OH:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: Oc1cccc(O)c1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)c1ccc(O)cc1O
Yield: 41.4 %

Procedure:
68 g of granular zinc chloride and 250 g of lauric acid were melted togerther at 125° C., under nitrogen and with protection from moisture by calcium chloride. The mass was stirred and 55 g of resorcinol were added portionwise over 15 minutes. The mixture was stirred a further 2 hours, cooled and drowned in 500 ml of water. 100 ml of chloroform was added to break up the solid mass, and the crystalline solid remaining was filtered, washed with chloroform, then water, to give 60.4 g of a solid with a melting point of from 79°-83° C. This was used without further purification. The analytical sample was recrystallised from light petroleum (b.p. 60°-80° C.). The pure product had a melting point of from 83.5°-85° C.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])=[N:12]2)[S:8][CH:9]=1)([F:4])[CH3:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC(F)(F)c1csc(Cn2ccc(N)n2)n1
Product: CC(F)(F)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B, 1-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.04 min; [M+H]+=415.86.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([NH:21][C:22]([NH2:24])=[NH:23])([OH:20])[C@@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:7][CH2:8][N+:9]([O-:11])=[O:10].[OH-].[Li+]>CO.O>[N+:9]([CH2:8][CH2:7][CH2:6][C@H:5]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:4]([NH:21][C:22]([NH2:24])=[NH:23])([OH:20])[C:3]([OH:25])=[O:2])([O-:11])=[O:10]
Reactant: COC(=O)C(O)(NC(=N)N)[C@H](CCC[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC[N+](=O)[O-])C(O)(NC(=N)N)C(=O)O
Reaction time: 8 h
Yield: 87.1 %

Procedure:
A solution of the compound of Example 3 (5.0 g, 13.8 mmole) in 100 mL of methanol was treated with 17 mL of 1M lithium hydroxide. This solution was allowed to stir overnight and then treated with 20 mL of Dowex-50 resin X8 400 (H+ form) in 50 mL of deionized water. This solution was swirled for 15 minutes then passed through a 4×4 cm. column of the same resin, the column was washed with 1:1 methanol:water and the combined filtrates were concentrated to dryness under vacuum. The residue was dissolved in 100 mL acetonitrile and concentrated to dryness, this process was repeated two more times to give 4.2 g (87 % yield) of the above-identified compound as an off-white foam. 1H NMR (CD3OD) d 1.42 and 1.42 (s, 9H), 1.7 (m, 4H), 3.3 (m, 2H), 3.95 (m, 1H), 4.19 (bs, 0.65H), 4.33 (bs, 0.35H), 4.15 (d, J=1 Hz, 0.65H), 4.38 (d, J=4 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].F[B-](F)(F)F.[NH4+].Cl.[N:21]([O-])=O.[Na+].C([O-])(=O)C.[K+]>O.C1OCCOCCOCCOCCOCCOC1>[Cl:12][C:11]1[C:2]2[NH:1][N:21]=[CH:13][C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(Cl)c(N)c1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(Cl)c2[nH]ncc12
Reaction time: 0.58 h
Yield: 234.5 %

Procedure:
To a solution of methyl 3-amino-4-chloro-2-methylbenzoate (6.50 g, 32.6 mmol) and ammonium tetrafluoroborate (4.44 g, 42.3 mmol) in water (2.0 mL) and concentrated hydrochloric acid (17.6 mL, 212 mmol) was added a solution of sodium nitrite (2.25 g, 32.6 mmol) in water (8 mL) at 0° C. for 25 min, and the mixture was stirred for 35 min. The precipitated solid was collected by filtration, washed with ether, and dried under reduced pressure. The obtained solid was dissolved in chloroform (100 mL), and 18-crown-6 (258 mg, 0.98 mmol) and potassium acetate (3.52 g, 35.8 mmol) were added. The reaction mixture was stirred at room temperature for 2 hr, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with hexane, and collected by filtration to give the title compound (16.1 g, yield 50%). 1H-NMR (CDCl3) δ: 4.03 (3H, s), 7.45 (1H, d, J=7.6 Hz), 7.90 (1H, d, J=7.6 Hz), 8.64 (1H, s), 10.71 (1H, br s).
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)C>Cl.C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Oc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 90.8 %

Procedure:
Ethyl 2-(4-acetoxyphenoxy)propionate (5.01 g, 19.9 mmol) is hydrolyzed by refluxing for 2 hours at 80° C. with ethanol (40 mL) and concentrated HCl (36%, 2 drops). The reaction product is concentrated under reduced pressure to obtain ethyl 2-(4-hydroxyphenoxy)propionate (3.8 g) (yield 93%), 1NMR (CHCl3) delta 1.25 (t, J=7.0 Hz, 3H), 1.62 (d, J=6.8 Hz, 3H), 4.21 (q, J=7.0 Hz, 2H), 4.65 (q, J=6.8 Hz, 1H), 6.74 (M, 4H).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH2:25][OH:26])([CH3:4])([CH3:3])[CH3:2].Cl.O1CCO[CH2:30][CH2:29]1.[OH-].[Na+]>C(O)C>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[CH2:25][O:26][CH2:29][CH3:30])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1c(CO)c(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOCc1c(C(=O)OCC)c(C)n(CCc2ccc(F)cc2)c1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 719 mg portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-4-(hydroxymethyl)-2-methyl-1H-pyrrole-3-carboxylate was suspended in 10 ml of ethanol, and 2.0 ml of 4 M hydrogen chloride/1,4-dioxane was added, followed by stirring overnight at room temperature. By adding 10 ml of a 1 M sodium hydroxide aqueous solution, ethanol was evaporated under a reduced pressure. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (Chromatorex (registered trademark), ethyl acetate:hexane=1:30-1:20-1:15) to obtain 623 mg of ethyl 5-tert-butyl-4-(ethoxymethyl)-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless oil.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)C(C)C)(C)C>ClCCl>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1F

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-fluorophenylsulfonyl chloride in presence of N,N-diisopropyl ethyl amine in dichloromethane to give 2-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 499.3 ([M+NH4]+)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[CH:32][CH:31]=[CH:30]2)=[C:25]([CH:28]=1)[CH2:26]Br)([O-:20])=[O:19]>CN(C)C=O>[C:14]([O:13][C:11]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:26][C:25]1[CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:24]=1[N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a mixture of sodium hydride (60% content, 21 mg), iminodicarboxylic acid di-tert-butyl ester (117 mg) and dimethylformamide (5 ml), a solution in dimethylformamide (3 ml) of the compound (137 mg) obtained in Example 1c was added dropwise under cooling with ice. The reaction mixture was stirred for 2 hours at room temperature and then concentrated at reduced pressure. Brine was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:9) to give the titled compound (yield, 74%).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(P(N(C)C)(N(C)C)=O)C.[P:26](Cl)([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27].Cl>CN(C1C=CN=CC=1)C.CCOCC>[CH2:13]([O:12][C:10](=[O:11])/[CH:9]=[C:1](/[O:8][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:14]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: CCOC(=O)/C=C(/OP(=O)(OCC)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of ethyl benzoylacetate (10 g, 52.03 mmol) was added DMAP (699.2 mg, 5.72 mmol), HMPA (9.96 mL, 57.23 mmol), TEA (7.98 mL, 57.23 mmol). The resulting yellow solution was stirred at 0° C. for 30 minutes and then coiled to −20° C. Diethyl chlorophosphate was added dropwise to the cooled solution and a heavy precipitate began to form immediately. The yellow-orange paste was warmed to room temperature and stirred for another 4 hours. The reaction mixture was diluted with ether and acidified with 1N HCl. The ethereal extracts were washed with saturated aqueous CuSO4 to remove HMPA, dried over MgSO4, and concentrated. The residue was purified through flash column chromatography on silica gel (EtOAc:hexanes=2:3) to give 11.6 g in 68% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.ClC1C=CC([N+]([O-])=O)=C(C=1)N.[N-]=[N+]=[N-].[Na+].C(Cl)(C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CO[CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:59][CH:58](OC)O1>CS(C)=O.CC(O)=O.C1COCC1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH:58]=[CH:59][C:60]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:56]2)=[CH:7][C:6]=1[NH2:8])([O-:14])=[O:13]
Reactant: COC1CC(c2ccccc2)C(OC)O1
Reactant: CC(=O)Nc1cc(N)ccc1[N+](=O)[O-]
Agent: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: Nc1cc(-n2ccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from N-(5-amino-2-nitro-phenyl)-acetamide [prepared from commercially available 5-chloro-2-nitroaniline by the following sequence: i.) nucleophilic aromatic substitution with NaN3 in DMSO at 80° C. for 15 h; ii.) acetylation with AcCl in HOAc at 120° C. for 2 h according to Eur. J. Med. Chem. 1988, 23, 553; iii.) Staudinger-reduction with PPh3/H2O in THF at 23° C. for 1 h] and 2,5-dimethoxy-3-phenyl-tetrahydro-furan [CAS-no. 207119-66-2] in HOAc at 60° C. for 2 days according to the general procedure F. Obtained as a brown solid (414 mg). Deacetylation of this material was perfomed by stirring with 25% HCl in THF at 80° C. for 90 min. Obtained as a brown solid (179 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([CH2:15][C:16]([O:18]CC)=O)[NH:12][CH2:13][CH2:14][C:5]2=1.C1CCCCC1.[CH3:27][N:28]=[C:29]=[O:30].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]3[CH2:15][C:16](=[O:18])[N:28]([CH3:27])[C:29](=[O:30])[N:12]3[CH2:13][CH2:14][C:5]2=1
Reactant: CN=C=O
Reactant: CCOC(=O)CC1NCCc2c1[nH]c1ccc(Cl)cc21
Agent: Cl
Solvent: CCO
Solvent: C1CCCCC1
Product: CN1C(=O)CC2c3[nH]c4ccc(Cl)cc4c3CCN2C1=O

Procedure:
10 g of ethyl 6-chloro-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate (prepared according to the patent entitled Pyridoindoles, filed by the Applicant Company on this same day) are placed in a round-bottomed flask and 150 ml of cyclohexane and 2.5 ml (1.9 g) of methyl isocyanate are added. The mixture is heated at the reflux temperature for 1 hour. It is cooled in an ice bath and filtered. This yields a white solid which is taken up in 150 ml of ethanol. The mixture is stirred and ethanol saturated with hydrogen chloride (30 ml) is added. The mixture is heated under reflux for 1 hour. It is allowed to cool and filtered. The solid is recrystallised from ethanol.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS(O)(=O)=O.C(Cl)(Cl)Cl>C(OCC)C>[C:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[OH:8])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1-c1ccccc1)C(O)c1ccccc1
Yield: 62 %

Procedure:
168.18 g (1.0 mole) of benzil in 2 liters of ethyl ether was placed in a 5 liter, three necked round bottomed flask, fitted with a reflux condenser, mechanical stirrer, addition funnel and nitrogen bypass. All of the glassware was flame-dried before use while being flushed with nitrogen. A 3 molar solution in ethyl ether of phenyl magnesium bromide (181.23 g, 1.0 mole) was then placed in the addition funnel and added dropwise to the flask over a period of 1.5 hours. The solution was then refluxed overnight. Hydrolysis of the Grignard complex was then accomplished using a 10% solution of H2SO4 with the concurrent addition of 1.5 liters of CHCl3. After complete hydrolysis, the organic layer was separated and washed with one liter of water. The organic layer was dried with magnesium sulfate, concentrated and recrystallized with hexane to give phenylbenzoin (m.p. 87°-88°, lit 88° C.) of 99% purity in yield of 62%.