Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.O[CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCN(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8582.6 %

Procedure:
4-Chloro-7-hydroxy-6-methoxyquinazoline (1.7 g, 0.08 mmol), (prepared as described for the starting material in Example 4), tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (2.17 g, 8.89 mmol), (prepared as described for the starting material in Example 15), and triphenylphosphine (2.97 g, 11.3 mmol) were added to dichloromethane (42.5 ml). Diisopropyl azodicarboxylate (1.91 ml, 9.70 mmol) was added and the reaction mixture stirred at ambient temperature for 1.5 hours and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 92/8) to give the product containing a single impurity. A second column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) gave tert-butyl 4-{3-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]propyl}piperazine-1-carboxylate (3.0 g, 99%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[C:32](Cl)=[O:33]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32](=[O:33])[C:31]3[CH:30]=[C:29]([Cl:28])[CH:37]=[C:36]([Cl:38])[CH:35]=3)=[CH:15][CH:14]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCc3cc(F)ccc32)cc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
6-Fluoro-1-(4-aminobenzoyl)-1,2,3,4-tetrahydroquinoline (0.15 g) is dissolved in dichloromethane (10 ml) and thereto is added triethylamine (0.31 ml). To the mixture is added dropwise a solution of 3,5-dichlorobenzoyl chloride (0.14 g) in dichloromethane (2.0 ml) under ice-cooling, and the mixture is stirred for 30 minutes under ice-cooling, and further, at room temperature for 1 hour. To the mixture are added triethylamine (0.31 ml) and 3,5-dichlorobenzoyl chloride (0.14 ml). The mixture is stirred at room temperature for 4 hours. The reaction mixture is washed with water, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:5→1:4), and recrystallized from ethyl acetate/n-hexane to give 6-fluoro-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.12 g) and 6-fluoro-1-{4-[bis-(3,5-dichlorobenzoyl)amino]benzoyl}-1,2,3,4-tetrahydroquinoline.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]1([CH3:30])[CH:15]([CH2:16][CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7]1>O.C(O)C>[N:1]([CH2:17][CH2:16][CH:15]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:29])[CH:12]=2)[O:7][C:6]1([CH3:5])[CH3:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3cc(F)ccc3OC2(C)C)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccc(F)cc2CC1CCN=[N+]=[N-]

Procedure:
A solution of 1.62 g (24.9 mmol) of sodium azide in 10 ml of water is added to a solution of 6.3 g (16.6 mmol) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)-ethyl]-chroman in 100 ml of ethanol. The mixture is boiled under reflux for 18 hours. After cooling, the ethanol is evaporated off in vacuo and water is added to the residue. The aqueous mixture is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 4.13 g (100% of the theoretical yield) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluoro-chroman in the form of a light-yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH2:30]([N:32]=[C:33]=[S:34])[CH3:31]>>[CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23]([NH:24][C:33]([NH:32][CH2:30][CH3:31])=[S:34])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCN=C=S
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(N)(=O)=O)cc32)C1=O
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)N1CC(C)=C(CC)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR48## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothio-carbonylaminosulfonyl)-7-methoxychroman is prepared analogously to Example 14 from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-methoxychroman and ethyl isothiocyanate. Melting point: 147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][N:37]1[C:33](=[O:43])[C:34]3[C:35](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:36]1=[O:38])=[C:12]2[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(CCl)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccc(Cl)cc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 96.2 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-4-(4-chlorophenyl)-2-isobutyl-1(2H)-isoquinolinone (3.96 g, 8.5 mmol) and potassium phthalimide (2.37 g, 12.8 mmol) in N,N-dimethylformamide (40 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-[[6-benzyloxy-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (4.72 g, 96.3%) as crystals.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:46])([CH3:45])[C@@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:22]1[C:23]3[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][C:24]=3[O:25][C:21]=1[C:20]2([CH3:44])[CH3:43])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[CH3:53][N:54](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([SiH2:5][O:6][C:7]([CH3:45])([CH3:46])[C@@H:8]1[O:12][C:11]([CH3:13])([CH3:14])[O:10][C@@H:9]1[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[C:22]1[C:23]3[CH:29]=[CH:28][C:27]([C:53]#[N:54])=[CH:26][C:24]=3[O:25][C:21]=1[C:20]2([CH3:44])[CH3:43])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(OS(=O)(=O)C(F)(F)F)ccc4c2C3=O)O1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)[C@@H](COc2ccc3c(c2)C(C)(C)c2oc4cc(C#N)ccc4c2C3=O)O1
Temperature: 200 °C

Procedure:
Trifluoro-methanesulfonic acid 8-[(4R,5R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy]-6,6 dimethyl-11-oxo-6,11-dihydro-benzo[b]naphth[2,3-d]furan-3-yl ester (Compound Z14, 24 mg) was dissolved in DMF (0.5 mL), added with zinc (II) cyanide (8.2 mg) and palladium tetrakistriphenylphosphine (2.0 mg), and the mixture was stirred under heating at 200° C. for 20 min with microwave irradiation. To the reaction mixture, ethyl acetate was added and the organic layer was washed with saturated brine. Thereafter, the organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (15 mg).
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][NH:36][OH:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O1CCCC1.Cl>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:37]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(CNO)cc2)cc1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was added dropwise into a cold (−5° C.) mixture of N-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine (1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL). The reaction mixture was stirred for 30 minutes, poured into water, acidified with HCl (2 N), and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtOAc 2:1) gave a white solid (0.68 g, 53% yield): mp 196-198; MS m/e 493 (M+);
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=2[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[O:5])C.CO.[ClH:28]>>[ClH:28].[CH3:18][O:17][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:10]=1)[O:7][C:6]([C:4]([OH:5])=[O:3])=[CH:15][C:14]2=[O:16]
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCN(C)CC3)c2o1
Agent: Cl
Solvent: CO
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1

Procedure:
Ethyl-6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate (1.0 g, 2.89 mmol), as prepared in Reference Example 2d above, was suspended in 6 M HCl (60 ml) and methanol (10 mL) and warmed to reflux for 3.0 h. The reaction was allowed to cool. The solution was concentrated in vacuo and anhydrous toluene was added (×3) and the solution was again concentrated in vacuo. The residue was dried under vacuum (17 h) to yield 6-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride as a yellow powder (1.0 g, quantitative yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:34][C:35]1[C:40]([Pb+3])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:34][C:35]1[C:40]([CH:10]2[C:11](=[O:13])[CH2:12][CH:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH2:8][C:9]2=[O:14])=[C:39]([CH3:42])[CH:38]=[C:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)CC(C2CCOCC2)C1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C

Procedure:
To a mixture of 5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione (196 mg; 1 mmol) and 4-dimethylaminopyridine (610 mg; 5 mmol) is added dry chloroform (4 ml) under an atmosphere of nitrogen, and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml) and a solution of 3,5-dimethylbiphen-4-yllead triacetate (1.2 mmol) in chloroform. The reaction mixture is heated under reflux for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered and the filtrate is extracted with dichloromethane (2×40 ml). The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by column chromatography on silica gel to give 2-(3,5-dimethylbiphen-4-yl)-5-(tetrahydropyran-4-yl)cyclohexane-1,3-dione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:33])[C:11]([CH3:32])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([O:23]C(C)C)=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:33])[C:11]([CH3:32])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:31])=[C:18]([CH:27]=[CH:28][C:29]=3[CH3:30])[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)O)c2C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a solution of isopropyl 2-[3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (80 mg, 0.17 mmol, 1.0 eq) in a mixture of THF (5 mL) and MeOH (5 mL) was added NaOH (2M aqueous solution, 3 mL, 6.0 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The organic solvent was removed in vacuo and the remaining aqueous solution diluted with water and acidified to pH 4-6 with diluted HCl. The solid precipitate that formed was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (20 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30](O)[CH2:31][OH:32]>ClCCl>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=2)[C:5]([CH3:15])=[N:4][C:3]=1[CH:16]1[O:32][CH2:31][CH2:30][O:17]1
Reactant: OCCO
Reactant: Cc1nc(C=O)c(Cl)n1-c1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C2OCCO2)c(Cl)n1-c1ccc(C#N)cc1
Reaction time: 70 h

Procedure:
A stirred solution of the aldehyde from (c) (0.24 g, lmmol) and 4-toluenesulphonic acid hydrate (0.21 g, 1.1 mmol) and ethane-1,2-diol (0.5 ml, 8 mmol) in dichloromethane (8 ml) was heated at reflux through a Dean-Stark trap containing 4A molecular sieves for 6 hours. After standing at 25° C. for 70 hours the mixture was washed with aqueous sodium bicarbonate and evaporated to a yellow solid.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].[CH2:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCCCC1
Reactant: CC1(C)CCCC(C)(C)N1O
Product: CC1(C)CCCC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO) and cyclohexane according to the procedure of Example 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)[CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: ClCC1CC1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CC2)c1=O
Yield: 54.7 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 54.7%.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([S-:23])[CH3:22].[Na+]>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[CH:2]([S:23][CH2:21][CH3:22])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)#[N:14]
Reactant: N#Cc1ccc(CNC(=O)C(Br)c2ccccc2)cc1
Reactant: CC[S-]
Agent: [Na+]
Product: CCSC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
In analogy to example 83.1 (RS)-2-bromo-N-(4-cyano-benzyl)-2-phenyl-acetamide (example 81.1) was reacted with sodium ethanethiolate to give (RS)-N-(4-cyano-benzyl)-2-ethylsulfanyl-2-phenyl-acetamide. Off-white solid. MS 311.2 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[CH:17][C:16]=1[F:31].Cl>CN1C(=O)CCC1>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[C:11]3[CH2:10][N:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[C:16]([F:31])[CH:17]=1)=[O:30]
Reactant: CN1Cc2c(Cl)ccnc2NC1=O
Reactant: Nc1ccc(NC(=O)c2cccc(F)c2)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN1Cc2c(Nc3ccc(NC(=O)c4cccc(F)c4)cc3F)ccnc2NC1=O
Temperature: 170 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
19 (40.0 mg, 0.20 mmol), N-(4-amino-3-fluorophenyl)-3-fluorobenzamide (50.2 mg, 0.20 mmol), and HCl (51.0 μl, 0.18 mol) were suspended in NMP (1 mL), and stirred for 1 h at 170° C. in a microwave. The resulting mixture was purified by HPLC to provide 20 (17 mg, 20% yield) as a solid. LC-MS (M+H=410, obsd.=410).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:42])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14].NN>O1CCCC1.CO>[NH2:20][CH2:19][C@@H:18]([NH:17][C:15]([C:9]1[S:10][C:11]([CH2:12][CH2:13][CH3:14])=[C:7]([C:6]2[N:5]([CH3:42])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:16])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39]
Reactant: CCCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1sc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1-c1c(Cl)cnn1C
Reaction time: 12 h
Yield: 80 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-propyl-2-thiophenecarboxamide (245 mg, 0.40 mmol) in tetrahydrofuran (2.4 ml) and methanol (2.4 ml) at 25° C. was added hydrazine (0.12 ml, 3.98 mmol) dropwise. After 12 h, the solution was concentrated, dry loaded onto silica and purified by column chromatography (5% MeOH in DCM (1% NH4OH)). The free base was transferred to the HCl salt by addition of excess 4M HCl in dioxane (1 ml) to the residue in MeOH (2 ml) affording the HCl salt of N-((1S)-2-amino-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxamide (178 mg, 0.32 mmol, 80% yield) as a yellow solid: LCMS (ES) m/z=485, 487 (M, M+2)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (br. s., 1H) 8.13 (br. s., 3H) 7.93 (s, 1H) 7.66-7.73 (m, 2H) 7.62 (br. s., 1H) 7.55 (t, J=7.45 Hz, 1H) 7.42 (t, J=7.45 Hz, 1H) 4.48 (br. s., 1H) 3.71 (s, 3H) 2.99-3.08 (m, 4H) 2.63 (t, J=7.20 Hz, 2H) 1.53-1.57 (m, 2H) 0.83 (t, J=7.33 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:23])[CH3:2].[CH3:24][N:25]([CH3:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([CH3:34])[CH3:33])[CH:27]=1.C(OC(=O)C)(=O)C>C(O)C>[CH3:33][N:32]([CH3:34])[C:28]1[CH:27]=[C:26]([N:25]([CH3:35])[CH3:24])[CH:31]=[CH:30][C:29]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
In a procedure similar to that described above in part B of this example, 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 8.57 g (0.05 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and 6.0 ml of acetic anhydride were interacted with stirring at room temperature overnight. The reaction mixture was then diluted with 13.0 ml of ethanol and the precipitate which separated was filtered and washed with 6.0 ml of ethanol. The filter cake was then reslurried in 30 ml of methanol, filtered and washed successively with methanol and diethylether. The material was dried in vacuo to obtain 15.8 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =Y1 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3), a white crystalline solid which melted at 218°-222° C. The infrared spectrum was consistent with the structure. A benzene solution of the above product developed an intense grape-red color when streaked on a phenolic resin coated paper.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH:21]3[CH2:23][O:22]3)[N:9]=2)=[CH:4][CH:3]=1.[OH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>C(Cl)Cl>[OH:22][CH:21]([CH2:23][N:34]1[CH2:33][CH2:32][N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[OH:24])[CH2:36][CH2:35]1)[CH2:20][N:10]1[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:19])[CH3:18])[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[N:9]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC2CO2)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCc2c(c(-c3ccc(I)cc3)nn2CC(O)CN2CCN(c3ccccc3O)CC2)C1
Reaction time: 72 h

Procedure:
1-[3-(4-Iodo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (62 mg, 0.15 mmol) and 4-(2-hydroxyphenyl)-piperazine (34 mg, 0.19 mmol) were combined in CH2Cl2 (0.5 mL) and the solution treated with Yb(OTf)3.H2O (44 mg, 0.071 mmol). The mixture was shaken for 72 h then diluted with CH2Cl2 (1 mL). Purification by preparative TLC (silica, 10% MeOH/CH2Cl2) grave 45 mg (51%) of an off-white powder. TLC (silica, 8% MeOH/CH2Cl2): Rf=0.2. MS (electrospray): m/z calculated for C27H33IN5O3 [M+H]+ 602.15, found 602.2. 1H NMR (CDCl3, 500 MHz, a mixture of amide rotamers): 7.76 (d, J=8.6 Hz,1H), 7.72 (d, J=8.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.14 (m, 1H), 7.80 (t, J=7.7 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.7 Hz, 1H), 4.83 and 4.72 (A and B of AB quartet, Jab=15.6 Hz, 1H), 4.61 (s, 1H), 4.22-4.15 (m, 2H), 4.02 (m, 2H), 3.88 (m, 1H), 3.76 (m, 3H), 3.00-2.49 (m, 11H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).