Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:2].[CH3:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([C:27]([F:30])([F:29])[F:28])=[CH:19][C:17]=1[NH2:18]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11]([NH:18][C:17]1[CH:19]=[C:20]([C:27]([F:28])([F:29])[F:30])[CH:21]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:16]=1[CH3:15])(=[O:13])=[O:12])[CH3:2]
Reactant: Cc1c(N)cc(C(F)(F)F)cc1C(F)(F)F
Reactant: CCc1cccc(CC)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to a solution of 2-methyl-3,5-bis(trifluoromethyl)aniline (0.106 g, 0.434 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was purified by silica gel chromatography using hexanes/ethyl acetate (4:1) to afford the title compound (0.080 g, 42% yield). LCMS (M+Na) 461.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[C:13](=[O:17])[NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[C:13]1(=[O:17])[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:15](=[O:16])[NH:14]1
Reactant: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: CCO
Product: O=C1NC(=O)C2CNCC12
Reaction time: 16 h

Procedure:
A solution 5-benzyl-tetrahydropyrrolo[3,4-c]pyrrole-1,3-dione, (11.5 g; 49.9 mmol) in ethanol (200 ml) is placed in a 1000 ml autoclave and palladium-on-charcoal (5%; 2 g; 0.9 mmol) is then added. After having purged the reactor with nitrogen, the autoclave is placed under 58 bars of hydrogen at 70° C. for 16 hours. After returning to 20° C., filtration and washing of the catalyst, evaporation is carried out under reduced pressure and the solid obtained is then recrystallized from methanol (100 ml) and drying is carried out under reduced pressure at constant weight. Perhydropyrrolo[3,4-c]pyrrole-1,3-dione, (3.6 g) is isolated, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[CH2:6]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCNCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A solution of 3-aminopropan-1-ol (3 g, 39.9 mmol) and benzaldehyde (4.05 mL, 39.9 mmol) in methanol (200 mL) was stirred at room temperature overnight. The solution was cooled to 0° C., and sodium borohydride (1.813 g, 47.9 mmol) was added slowly in several portions. The resulting mixture was stirred at room temperature for three hours, and then it was partitioned between water and dichloromethane (3×). The organic extracts were combined and dried over Na2SO4, the drying agent was removed by filtration, and the solution was concentrated in vacuo to give the title compound as an oil (6.5 g, 98%).
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:36][C@H:37]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]>CN(C=O)C>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:36][C@H:37]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:5]
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
44 g BocGlyOH (0.25 moles) is dissolved in 250 ml DMF, together with 29 g HOSu. After cooling to -20° C. 52 g DCC dissolved in 250 ml DMF is added. After 4 hours stirring at room temperature 95 g ValOBzl, pTos is added together with 35 ml TEA. After stirring overnight at room temperature, DCU is filtered off, DMF removed and the resulting oil taken up in EtAc and washed with sat. NaCl, sat. NaHCO, and 10% citric acid. The EtAc is dried with Na2SO4, removed by vacuum evaporation and the resulting crystalline mass dried in a desiccator. Yield: 59 g (65%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.2 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 10 mg of 7-hydroxy-2-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Reactant: Nc1cccc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(F)c2)c1C

Procedure:
m-Fluoroaniline (5 mmol, 0.6 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid were combined in ethanol, then heated under reflux. The resulting solid was resuspended in chloroform, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents removed under vacuum. The named product was recrystallized from ethanol (m.p. 96.3° C.-98.0° C.).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:24][C@H:25]1[CH2:44][N:28]2[C:29](=[O:43])[N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=3)[CH2:31][C@@H:27]2[CH2:26]1)(C)(C)C.O>C1COCC1>[OH:24][C@H:25]1[CH2:44][N:28]2[C:29](=[O:43])[N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:40])[F:41])=[CH:34][CH:33]=3)[CH2:31][C@@H:27]2[CH2:26]1
Reactant: CC(C)(C)[Si](O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
Tetrabutyl ammonium fluoride (1.0 g, 3.8 mmol) was added to a solution of (6R,7aS)-6-(tert-Butyl-diphenyl-silanyloxy)-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (1.8 g, 3.3 mmol) in anhydrous THF (20 mL). The mixture was stirred for 2 hours at room temperature. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The organic layers was combined, washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH/CH2Cl2=1:20) to give 0.95 g (94%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[NH:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[C:1]([N:10]1[C:6]([NH2:5])=[N:7][C:8]([S:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1nc(SCc2ccccc2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1nc(SCc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
Acetyl chloride (12.57 g) in methylene chloride (30 ml) was added to the product of stage (a) (30 g) and triethylamine (25 ml) in methylene chloride (300 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. It was then treated with 1N sodium hydroxide (160 ml) and extracted with methylene chloride. The product, after drying, was recrystallised from ethyl acetate to give 33 g of the desired product, mp 146° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 25.8 %

Procedure:
Analogously to the general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 1-bromo-2-butanone (1.7 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 30° C. for 24 h. After aqueous work-up and purification by RP chromatography the pure material (0.65 g) is de-acetylated in MeOH (70 ml) using DBU (0.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(2-oxo-butyl)-1,3-dihydro-indol-2-one (0.57 g) is obtained and used without further purification.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13].Cl[CH2:15][C:16]([OH:18])=[O:17]>O>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCl
Reactant: Oc1ccc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc2ccccc2c1
Temperature: 70 °C
Yield: 14.5 %

Procedure:
To a solution of potassium hydroxide (10.0 g, 0.175 mol) in H2O (100 mL) was added 2-naphthol (10.43 g, 72 mmol), followed by 2-chloroacetic acid (7.79 g, 83 mmol). The resulting mixture was heated at 70° C. for 4 h, then allowed to cool. The mixture was filtered, and the filtrate was extracted with EtOAc. The aqueous phase was made acidic by the addition of 3N HCl and extracted with EtOAc. The organic phase from the acidic extraction was washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (2.11 g, 14%).
Reaction SMILES: Cl[CH2:2][C:3](=[O:18])[C:4]([CH3:17])([CH3:16])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>CC(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][CH2:5][C:4]([CH3:17])([CH3:16])[C:3](=[O:18])[CH2:2][N:25]1[CH:29]=[N:28][CH:27]=[N:26]1
Reactant: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)CCl
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
30.9 g (0.1 mol) of 1-chloro-5-(2,4-dichlorophenoxy)-3,3-dimethyl-2-pentanone, dissolved in 80 ml of acetone, are added dropwise, with stirring, to a mixture of 13.8 g (0.1 mol) of potassium carbonate and 13.8 g (0.2 mol) of 1,2,4-triazole in 200 ml of boiling acetone. The mixture is boiled for a further 3 hours, cooled down to 0° to 10° C., the salt is filtered off and the filtrate is evaporated in vacuo. After trituration of the oily residue with a little petroleum ether, 32.4 g (94.6% of theory) of 5-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-pentanone are obtained as colorless crystals of melting point 62° C.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[N:19]=[CH:18][C:17]=3[N:34]=2)=[CH:10][CH:9]=1.Cl.[C:37](OCC)(=O)C>C(OCC)(=O)C>[F:35][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:37])[CH3:25])[N:19]=[CH:18][C:17]=3[N:34]=2)=[CH:12][CH:13]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-(2-(2,2-difluorocyclopropyl)ethoxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (239 mg), 4M hydrogen chloride/ethyl acetate (3 mL) and ethyl acetate (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was mixed with acetic anhydride (0.138 mL) and pyridine (3 mL), and the obtained mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (155 mg).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]#[N:23]>CS(C)=O.C(OCC)(=O)C>[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[CH:20]1[CH2:4][CH:21]1[C:22]#[N:23]
Reactant: Cn1cc2c(/C=C/C#N)c(Br)ccc2n1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cn1cc2c(C3CC3C#N)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a suspension of sodium hydride (19.6 mg, 0.490 mmol) in dimethyl sulfoxide (2 mL) was added trimethylsulfoxonium iodide (117 mg, 0.531 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Thereto was added a solution of (2E)-3-(5-bromo-2-methyl-2H-indazol-4-yl)acrylonitrile (107 mg, 0.408 mmol) in dimethyl sulfoxide (2 mL), and the mixture was stirred for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (50.0 mg, yield 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.[CH2:19]=O.[BH4-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]2)=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2
Reactant: C=O
Reactant: COc1ccc(C2CCCNC2)c2c1NC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C2CCCN(C)C2)c2c1NC(=O)C2
Temperature: 5 °C

Procedure:
4.5 g of the product of Example 1 were dissolved in 100 ml of methanol with stirring under an inert atmosphere and after cooling to about 5° C., 3.4 ml of 40% formic aldehyde were added dropwise. After stirring for 1 hour, 1.8 g of 95% sodium borohydride were added in small fractions and the mixture was stirred for 1 hour. The temperature was allowed to return to ambient and after diluting with iced water, extracting with methylene chloride, drying and evaporating to dryness under reduced pressure, filtering, washing with ether and drying, 4 g of 1,3-dihydro-7-methoxy-4-(1-methyl-3-piperidinyl)-2H-indol-2-one were obtained in the form of a base melting at ≈170° C.
Reaction SMILES: C(O)(C)C.FC(F)(F)C([NH:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12])=O.[OH-].[K+]>C(O)C>[NH2:9][CH:10]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)[C:11]([CH3:14])([OH:13])[CH3:12]
Reactant: CC(C)(O)C(NC(=O)C(F)(F)F)c1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CC(C)(O)C(N)c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
180 mL of isopropanol and 180 mL of ethanol were added to 36.0 g of the 1-(trifluoroacetylamino)-1-(1-naphthyl)-2-methyl-2-propanol obtained, and 63 g of an aqueous solution of 22% by weight of potassium hydroxide was added-dropwise thereto over 30 minutes at room temperature. The inner temperature of the mixture was raised to 50° C. and, at the same temperature, the mixture was stirred for 2 hours to effect reaction. The reaction mixture was concentrated, and 500 mL of chloroform and 180 mL of water were added to the resulting concentrated residue to carry out extraction treatment. The organic layer obtained was washed with 100 mL of water and the organic layer obtained was dried over dehydrated sodium sulfate and then concentrated. The resulting concentrated residue was dried at an inner temperature of 30° C. under reduced pressure to obtain 28.0 g of brown, viscous and oily 1-amino-1-(1-naphthyl)-2-methyl-2-propanol.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:16][CH:13]1[CH2:15][CH2:14]1
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nc2cnccc2nc1NC1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
A solution of 2,3-dichloropyrido[3,4-b]pyrazine (3.55 g, 17.75 mmol) in dioxane (71.0 mL) at room temperature was treated with cyclopropanamine (1.63 mL, 23.07 mmol), followed by dropwise addition of DIPEA (6.51 mL, 37.3 mmol). The resulting reaction mixture was stirred at room temperature for 12 h. Purification by flash silica gel chromatography using a gradient of 25% to 100% EtOAc in hexanes gave the title compound (3.15 g, 80%) as an orange solid. ESI-MS m/z [M+H]+ 221.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]#[N:22])=[CH:16][C:15]=1[O:30][CH3:31].[CH3:32][CH2:33][O:34][C:35](C)=[O:36]>C1COCC1>[CH2:33]([O:34][C:35](=[O:36])[C:20]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:21]#[N:22])[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[C:15]([O:30][CH3:31])[CH:16]=1)[CH3:32]
Reactant: COc1cc(C(C#N)Cc2ccccc2)ccc1F
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1ccc(F)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a −78° C. cooled solution of diisopropylamine (5.11 ml, 35.8 mmol) in THF was added n-butyllithium (22.40 ml, 35.8 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up <−40° C. 2-(4-Fluoro-3-methoxyphenyl)-3-phenylpropanenitrile (6.1 g, 23.89 mmol) dissolved in THF was added followed by ethyl chloroformiate (3.42 ml, 35.8 mmol). The reaction mixture was stirred over night and was allowed to heat up to room temperature. Evaporated solvents and redissolved in EtOAc, washed with 10% citric acid, water and brine and the combined organic layers were dried over MgSO4, filtered and evaporated to obtain 7.2 g of a yellow oil, that was purified by flash chromatography on 330 g SiO2 using 20% EtOAc in cyclohexene to obtain 18.26 g of the desired product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4-methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide. MS (Q1) 421.0 (M)+. The product was then dissolved in 1 N HCl solution followed by freebasing with 0.5 N NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C>[Br:21][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:2]([F:10])([F:11])([F:12])([F:13])[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of 3-(pentafluoro-λ6-sulfanyl)aniline (13.46 g, 61.4 mmol) in DMF (123 ml) stirred in a 500 mL round-bottomed flask in an ice bath under a nitrogen atmosphere, NBS (12.02 g, 67.6 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 4 hr. The reaction was worked up by the addition of H2O and extracted with EtOAc (2×100 mL). The combined organic layer was washed with H2O and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by CombiFlash Rf system eluted with a gradient up to 20% EtOAC/hexanes of EtOAc on a 120 g column to afford the desired 4-bromo-3-(pentafluoro-λ6-sulfanyl)aniline (11 g, 36.9 mmol, 60.1% yield).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].N.[H][H]>[Ni].CO>[CH3:15][N:14]([CH3:16])[C:11]1[CH:12]=[CH:13][C:8]([C:3]2([CH2:1][NH2:2])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:9][CH:10]=1
Reactant: CN(C)c1ccc(C2(C#N)CCCC2)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN(C)c1ccc(C2(CN)CCCC2)cc1
Yield: 100.2 %

Procedure:
In a pressure reactor was placed 281.2 g (1.3 mole) of 1-cyano-1-(4-dimethylaminophenyl)cyclopentane, 3500 ml of methanol, 600 g of anhydrous ammonia, and 200 g of Raney nickel. Hydrogen was charged into the stirred reaction vessel. The reaction was stirred at room temperature until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered and the filtrate concentrated in vacuo to yield 284.4 g of the title compound, melting point 87°-89° C.