Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:23]=[C:24]([F:31])[C:25]([O:29][CH3:30])=[C:26]([F:28])[CH:27]=1.CN([CH:35]=[O:36])C>C1COCC1>[Br:21][C:22]1[C:27]([CH:35]=[O:36])=[C:26]([F:28])[C:25]([O:29][CH3:30])=[C:24]([F:31])[CH:23]=1
Reactant: COc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add n-butyl lithium 1.6N (22 ml, 35.2 mmol) to diisopropylamine (4.8 ml, 34.2 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.83 g, 26.17 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 50 min at −78° C. Add anhydrous DMF (2.7 ml, 34.8 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3/[CH:19]=[CH:20]/[C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3/[CH:19]=[CH:20]/[CH:21]([OH:30])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCC(=O)/C=C/c1ccccc1OCc1ccc(C2CCCCC2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)CCCCC(O)/C=C/c1ccccc1OCc1ccc(C2CCCCC2)cc1
Yield: 92.2 %

Procedure:
Methyl (7E)-8-{2-[(4-cyclohexylbenzyl)oxy]phenyl}-6-oxo-7-octenoate from Ex. XIII was converted analogously to Ex. XIId using sodium borohydride into the corresponding alcohol. The yield was 92.2%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]([CH2:43][CH2:44][OH:45])C(OC(C)(C)C)=O)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][CH:7]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:30][CH2:31][CH:32]([NH:35][CH2:43][CH2:44][OH:45])[CH2:33][CH2:34]1)#[N:27]
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)Nc2ccc(N3CCC(NCCO)CC3)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 9.2 %

Procedure:
The reaction and treatment in the same manner as in Example 64 were conducted using 1-(4-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (1.94 g) and 5-amino-2-[4-(N-tert-butoxycarbonyl-2-hydroxyethylamino)piperidin-1-yl]benzonitrile (2.59 g) and the resulting mixture was further stirred in trifluoroacetic acid (10 ml) under ice-cooling for 1 h. The reaction mixture was treated with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of dimethylformamide-water to give the title compound (0.34 g), melting point: 202° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>>[C:2]1([N:1]2[C:11](=[O:12])[C:10]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]3[C:8]2=[O:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1ccccc1

Procedure:
Phenylphthalimidine of the formula (II) [L. Butula, D. Kolbah and I. Butula, Croat. Chem. Acta, 44 (4), 481, (1972),], which is a starting compound of the method of this invention, may be produced according to conventional methods. For example, Compound (II) is preferably produced in a high yield by heating aniline and phthalic anhydride in the absence of a solvent to give N-phenylphthalimide in an almost quantitative yield, and then subjecting the obtained N-phenylphthalimide to reduction with zinc and acetic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([OH:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1.[H-].[Na+].O>O1CCOCC1>[O:15]1[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][O:19][C:2]3[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=3)=[CH:11][C:12]=2[O:13][CH2:14]1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cncc(OCc2ccc3c(c2)OCO3)n1
Reaction time: 8 h
Yield: 102 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and piperonyl alcohol (335 mg, 2.20 mmol) in dioxane (5 mL) was added NaH (55% in mineral oil, 96 mg, 2.2 mmol) at room temperature. The reaction mixture was stirred overnight. Water (0.5 mL) was added and the mixture was stirred for 15 min. Drying, Na2CO3, filtration and concentration in vacuo furnished an oil (0.54 g) that was used directly in the next step. HRMS m/z calcd for C12H9ClN2O3 (M)+ 264.0302, found 264.0303.
Reaction SMILES: [FH:1].C(Cl)(Cl)(Cl)Cl.[CH2:7]([C@H:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][C:24]3[CH:29]=[C:28]([F:30])[C:27]([O:31][CH:32]([F:34])[F:33])=[C:26]([F:35])[CH:25]=3)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>>[CH2:7]([C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([F:35])[C:27]([O:31][C:32]([F:1])([F:34])[F:33])=[C:28]([F:30])[CH:29]=3)[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)[CH2:8][CH3:9]
Reactant: F
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(OC(F)F)c(F)c3)CC2)CC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCc3cc(F)c(OC(F)(F)F)c(F)c3)CC2)CC1
Temperature: 0 °C

Procedure:
2 mol of anhydrous hydrofluoric acid is poured into an autoclave which has been cooled to 0° C. A mixture of 0.18 mol of carbon tetrachloride and 0.06 mol of 1-[trans-4-(trans-4-n-propylhexyl)cyclohexyl]-2-(4-hydroxy- 3,5-difluorophenyl)ethane (Example 1) is then added. The mixture is stirred at 150° for about 8 hors, cooled, poured into ice water, and the autoclave is subsequently washed out with ether. The two phases are combined, stirred for about 30 minutes, separated, and the ether solution is washed with 5% KOH solution until it remains alkaline. The organic phase is dried, filtered, evaporated, and the residue is purified to give 1-[trans-4-(trans-4-n-propylcyclohexyl)cyclohexyl]-2-(4-trifluoromethoxy-3,5-difluorophenyl)ethane.
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:26][O:27]CC1C=CC=CC=1)[CH2:12][S:13](=[O:25])(=[O:24])[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]1)C1C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[CH:21]([N:18]1[CH2:17][CH2:16][CH:15]([NH:14][S:13]([CH2:12][C@@H:11]([NH2:10])[CH2:26][OH:27])(=[O:25])=[O:24])[CH2:20][CH2:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCC(NS(=O)(=O)C[C@H](COCc2ccccc2)NC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)N1CCC(NS(=O)(=O)C[C@@H](N)CO)CC1
Temperature: 25 °C

Procedure:
80 mg (0.16 mmol) [(S)-1-Benzyloxymethyl-2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-carbamic acid benzyl ester were dissolved in 3 ml dichloromethane. At 0° C., 0.32 ml of a 1 M BBr3-solution in dichloromethane were added and the reaction mixture was allowed to warm to room temperature. After 24 h a few drops of water and 0.94 ml of a 1 M aqueous NaOH-solution were added. The mixture was concentrated under reduced pressure. The residue was taken up in DMF and filtered in order to get rid of salts. The filtrate was concentrated under vacuo to give crude (S)-2-amino-3-hydroxy-propane-1-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide, which was pure enough for further transformations. Yield:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24](=[O:26])[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: C1CNCCN1
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Product: O=C(O)c1c(CC(=O)N2CCNCC2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from example 34.1.) was ring opened with piperazine at 22° C. to give the title compound as a white solid. MS: 446.1 ([M+H]+).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51](O)=[O:52]>CN(C=O)C>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:51]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=3)=[O:52])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccccn1)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.174 g, 0.50 mmol), HOBt (0.068 g, 0.50 mmol), EDCI (0.115 g, 0.60 mmol) and picolinic acid (0.068 g, 0.55 mmol) were dissolved in 5 ml of dry DMF. The mixture allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure. Then residue was dissolved in EtOAc (30 ml) and the mixture was washed with saturated NaHCO3 (15 ml) and brine (15 ml). The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 0% to 10% MeOH in EtOAc to afford the title compound 7 (195 mg, 86%). The product was taken up in 2 ml of EtOAc. To the mixture, 2 ml of 4 N HCl in EtOAc was added. The solvent was removed and remaining material was the desired product 7 was obtained as a hydrochloride salt (pale yellow solid). LC: 100%. MS: m/z=453.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.[OH-].[Na+]>Cl.C(O)(=O)C>[CH2:15]([C:14]1[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:16]
Reactant: CCc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cccnc1N
Reaction time: 2 h
Yield: 95.1 %

Procedure:
2-t-Butoxycarbonylamino-3-ethylpyridine (4.9 g, 19.8 mmol) was dissolved in 90 ml of 3N HCl/Acetic acid and stirred for two hours. The solution was neutralized with 2N NaOH to pH 7 and then extracted with ethyl acetate (2×400 ml). The organics were dried over magnesium sulfate and concentrated giving 2.3 g (95%) of a yellowish solid. This solid was used in the next reaction without further purification.
Reaction SMILES: C1C=CC([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:16])=[O:8])=CC=1.C(O)[C@H]1[O:23][C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[OH:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[C:7]([OH:8])=[O:23]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Product: O=C(O)c1ccc(O)cc1O

Procedure:
The same methodology as described in Example 7 was repeated with 2,4-DHB in place of 3-HB, to produce the dose response curve for 2,4-DHB (FIG. 2). From FIG. 2 it can be seen that 2,4-DHB also enhances the sweetness of the sucrose solution but there is little difference between the 400 ppm solution (SEV 6.5%) and the 1000 ppm solution (SEV 6.7%). The maximum attainable sweetness would appear to be about 6.7% SEV (based on a 5% sucrose solution).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1CC#N.[C:18]([OH:21])(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[Cl:1][C:2]1[C:7]([C:8](=[O:14])[C:9]2[S:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: N#CCc1cccc(C(=O)c2cccs2)c1Cl
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cccc(C(=O)c2cccs2)c1Cl
Reaction time: 1 h

Procedure:
A mixture of 4.2 parts of 2-[2-chloro-3-(2-thenoyl)phenyl]acetonitrile, 7 parts of acetic acid, 7 parts of water and 12 parts of sulfuric acid is stirred and boiled for 1h. 30. The reaction mixture is cooled, poured onto water and extracted with ether. The extract is washed with water, extracted with 50 parts of a 5% sodium hydroxide solution and the alkaline solution is washed with ether. After acidification with diluted hydrochloric acid solution, the whole is extracted again with ether. The extract is washed with water, treated with charcoal, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated, yielding 2-[2-chloro-3-(2-thenoyl)phenyl]acetic acid; mp. 112.2° C.
Reaction SMILES: [C:1]([NH:4][C:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH3:22]O>>[C:1]([NH:4][C:5]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:15][CH:16]=1)([CH3:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(C)(C)c1ccc(C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(C)(C)NC(C)=O)cc1

Procedure:
A suspension of 4-(1-acetamido-1-methylethyl)benzoic acid (73.4 g) and sulfuric acid (0.7 ml) in methanol (370 ml) was refluxed for 16 hr. The solvent was evaporated and 10% aqueous sodium hydrogencarbonate (500 ml) was added and the mixture was extracted with ethyl acetate (500 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from ethyl acetate-isopropyl ether to give the title compound (39.0 g) as pale-yellow crystals, m.p.=165-167° C.
Reaction SMILES: [F:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[C:5]1[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]1=[O:14].[CH2:21]([Mg]Br)[CH3:22]>C1COCC1>[F:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]([CH:5]1[C:6](=[O:14])[O:7][C:8]([CH3:12])([CH3:13])[O:9][C:10]1=[O:11])[CH2:21][CH3:22]
Reactant: CC[Mg]Br
Reactant: COc1cccc(C=C2C(=O)OC(C)(C)OC2=O)c1F
Solvent: C1CCOC1
Product: CCC(c1cccc(OC)c1F)C1C(=O)OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A 500 mL round bottom flask was charged with 5-(2-fluoro-3-methoxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.B (5.00 g, 17.8 mmol) and THF (100 mL). The resulting slurry was cooled to 0° C., and to it was added ethylmagnesium bromide (available from Aldrich) (3.0 M/ether) (11.9 mL, 35.7 mmol) dropwise over 15 minutes. The cooling bath was removed, and the mixture was stirred for 1 hour at ambient temperature. The reaction was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to afford 5-(1-(2-fluoro-3-methoxyphenyl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.C (5.17 g, 93.4% yield) as a yellow oil (5.2 g, 93%). The product thus obtained was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][NH:24][CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[NH2:13][C:14]1[C:30]([Cl:31])=[CH:29][C:17]([C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[CH2:23][C@H:22]2[O:27][CH3:28])=[O:19])=[C:16]([O:32][CH3:33])[CH:15]=1
Reactant: O=C(CCCCl)c1cccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCC(=O)c2cccnc2)C[C@H]1OC
Temperature: 70 °C
Yield: 20 %

Procedure:
A mixture of 3.47 parts of 4-chloro-1-(3-pyridinyl)-1-butanone, 4.5 parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide, 1.94 parts of N,N-diethylethanamine, 0.1 parts of potassium iodide and 67.5 parts of N,N-dimethylformamide was stirred and heated for 48 hours at 70° C. The reaction mixture was evaporated. The residue was washed with a sodium carbonate solution in water and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.36 parts (20%) of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-[4-oxo-4-(3-pyridinyl)butyl]-4-piperidinyl]benzamide; mp. 166.2° C. (compound 1).
Reaction SMILES: [CH3:1][N:2]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]#[C:23][CH2:24][N:25]([CH3:29])[CH2:26][CH2:27][CH3:28])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[O-].[Na+]>CO>[NH2:12][C:9]1[CH:8]=[CH:7][C:6]([S:3]([N:2]([CH3:1])[C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]#[C:23][CH2:24][N:25]([CH3:29])[CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21]2)(=[O:5])=[O:4])=[CH:11][CH:10]=1
Reactant: CCCN(C)CC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(NC(C)=O)cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCN(C)CC#C[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 70 °C

Procedure:
A solution of 44.3 mg (0.1 mmol) of trans-N-[4-(Methyl-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-sulfamoyl)-phenyl]-acetamide in 5 ml MeOH was treated with 0.37 ml (2 mmol) of sodium methylate (5.4 M in MeOH) and heated at 70° C. for 30 h. The solvent was evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2MeOH 97:3) gave 31 mg (82%) of pure trans-4-Amino-N-methyl-N-{4-[3-(methyl-propyl-amino)-prop-1-ynyl]-cyclohexyl}-benzenesulfonamide, MS: 378 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[C:37](F)[CH:36]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]>CS(C)=O.O>[C:14]([C:16]1[N:21]=[CH:20][C:19]([C:22]2[C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([C:35]4[CH:36]=[CH:37][C:38]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[C:46]([NH:7][CH:8]5[CH2:13][CH2:12][O:11][CH2:10][CH2:9]5)[CH:47]=4)[C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: NC1CCOCC1
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NC1CCOCC1
Temperature: 90 °C
Yield: 40.1 %

Procedure:
0.95 g of potassium carbonate and 4.62 g of 4-aminotetrahydropyran are successively added to a solution of 1.06 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 3 hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 0.5 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in the form of a white foam, the characteristics of which are the following:
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:32])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: S
Reactant: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CN1CC=CC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbonitrile, L series (12.57 g) and triethylamine (5.5 cc) in pyridine (115 cc) is treated with hydrogen sulphide by bubbling in for 2 hours. After 16 hours' stirring at a temperature in the region of 25° C., the light brown solution obtained is purged with nitrogen for 2 hours, diluted with ethyl acetate (300 cc), washed with distilled water (10×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The yellow product (13.3 g) of meringue-like consistency is purified by chromatography on a column (height: 47 cm; diameter: 3.8 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (2 liters) and collecting 125-cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (10.6 g) in the form of a yellow product of meringue-like consistency.