Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[C:28]([CH:35]=O)=[N:27]1>CO.N1CCCCC1>[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ncccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0366 g, 0.105 mmol) synthesized in Example B1, Step 1 in methanol (2 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (International Patent Publication WO2010/051561, 0.0162 g, 0.110 mmol) and piperidine (5 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0321 g, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.II>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Agent: II
Solvent: CO
Product: Brc1ccc(SSc2ccc(Br)cc2)cc1

Procedure:
4-Bromobenzene thiol (25.0 g, 132 mmol) and methanol (250 mL, Fisher Scientific) were added to a 500 mL round bottom flask containing a Teflon coated stir bar. Excess elemental iodine (36 g, 140 mmol) was added in 2 g portions directly to the rapidly stirred thiol solution, precipitating the disulfide. The reaction was complete when the dark color of iodine persisted. The reaction mixture was added to 250 mL of water, which was then carefully neutralized with solid sodium bicarbonate then with sodium bisulfite, to neutralize any remaining I2. The resulting slurry was then extracted three times with 50 mL of methylene chloride; the organic layers were combined, dried over magnesium sulfate, and filtered. Removal of the solvent on a rotary evaporator revealed a light yellow solid, crude 4-bromophenyl disulfide (24.5 g, 98.7%). The disulfide was recrystallized from boiling methanol then fused under vacuum to remove any remaining solvent.
Reaction SMILES: Br.Br[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[C:9]([Cl:21])[CH:8]=1)=[O:5].[Cl:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[NH2:33]>CN(C=O)C.O>[Cl:21][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][NH:33][C:24]2[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:23]=2[Cl:22])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18]
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(NC(=O)CNc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.228 g (0.511 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 0.200 g (1.023 mmol) of 2-chloro-4-trifluoromethyl-phenylamine in 5 mL DMF was stirred for 16 hours at 90° C. and then for 24 hours at 120° C. The reaction mixture was cooled to RT, diluted with water and exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The residue was dissolved in DMF and purified by HPLC-MS (Stable Bond C18; 3.5 μm; water:acetonitrile:formic acid 9:1:0.01→1:9:0.01 over 9 min).
Reaction SMILES: C(O[CH:4](O)[C:5]([F:8])([F:7])[F:6])C.[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([Cl:21])[C:12]=1[NH:22][NH2:23]>>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:19])([F:18])[F:20])[CH:14]=[C:13]([Cl:21])[C:12]=1[NH:22][N:23]=[CH:4][C:5]([F:6])([F:7])[F:8]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(O)C(F)(F)F
Product: FC(F)(F)C=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Yield: 89.2 %

Procedure:
A mixture of 100 g (0.69 mol) of trifluoroacetaldehyde ethyl-hemiacetal and 169.1 g (0.69 mol) of 2,6-dichloro-4-trifluoromethylphenyl hydrazine is heated at 100° C. for 6 hours. After the volatile components have been removed, the residue is recrystallized from petroleum ether. 200 g (89%) of trifluoroacetaldehyde N-(2,6-dichloro-4-trifluoromethylphenyl)-hydrazone of melting point 45° C. to 46° C. are isolated.
Reaction SMILES: Cl.Cl.[NH:3]1[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.F[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>O>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([N:11]2[CH2:12][CH2:13][C:8]3([NH:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:9][CH2:10]2)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: C1CCC2(CCNCC2)NC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC3(CCCCN3)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a mixture of 1,9-diazaspiro[5.5]undecane dihydrochloride (640 mg), potassium carbonate (1.26 g), and N,N-dimethylformamide (7 mL) was added 1-fluoro-4-nitrobenzene (426 mg), followed by stirring at 60° C. overnight. To the reaction mixture was added water, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 9-(4-nitrophenyl)-1,9-diazaspiro[5.5]undecane (0.69 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][NH2:9]>>[CH3:8][NH:9][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CC(=O)OCC
Reactant: CN
Product: CCOC(=O)CCNC
Reaction time: 3 h

Procedure:
At 0° C., a solution of ethyl acrylate in alcohol (2M, 1000 mL, 2 mol) was added drop wise to a solution of MeNH2 in alcohol (33%, 540 mL, 4 mol). The resulting mixture was stirred for 3 h. Upon completion of the reaction, monitored by TLC, the solvent and volatiles were removed under reduced pressure to give ethyl 3-(methylamino)propanoate (250 g, crude) as an oil, which was used in the next step without further purification.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH3:6].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(OCC)C>[Cl:10][CH2:11][C:12]([NH:4][C@H:5]([C:7]([OH:9])=[O:8])[CH3:6])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C[C@H](NC(=O)CCl)C(=O)O
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Into a 5-liter, 4-neck, round-bottom flask equipped with a mechanical stirrer, pH probe, thermometer, two 1-liter addition funnels and a nitrogen bubble were charged 157 g (3.93 mole) of sodium hydroxide and 1800 ml of water followed by 350 g (3.93 mole) of L-alanine. After all the solids dissolved, 600 ml of diethyl ether was added and solutions of chloroacetyl chloride (500 g, 4.43 mole) in 600 ml of diethyl ether and dilute sodium hydroxide (225 g in 500 ml water) were added concomitantly while maintaining the pH at about 11 and the temperature at about 0° C. by external cooling. The resulting mixture was allowed to warm to room temperature, and the ether layer separated. The aqueous layer was acidified with concentrated hydrochloric acid to pH 1 and extracted with four 1-liter portions of ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate and rotoevaporated to yield 550 g (85%) of 2-chloroacetyl-(L)-alanine as a white crystalline solid, melting point (mp) 93°-96° C. This material can be purified by recrystallization from ethyl acetate, but this is not necessary for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 72 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.38–7.25 (m, 5H), 7.03–6.97 (m, 3H), 6.49 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.98–2.94 (m, 2H), 2.55–2.49 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.01–1.95 (m, 4H), 1.86–1.62 (m, 10H); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[C:28](=O)([O:34]C(C)(C)C)[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:30]([O:29][C:28](=[O:34])[NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[CH2:3][CH2:4][C:5](=[O:8])[CH2:6][CH2:7]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cccc(C2(N)CCC(=O)CC2)c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCC(=O)CC1
Reaction time: 19 h

Procedure:
4-Amino-4-(3-tert-butyl-phenyl)-cyclohexanone (441 mg, 1.8 mmol) was dissolved in dry methylene chloride (10 mL), diisopropylethylamine (0.31 mL, 1.8 mmol) and di-tert-butyl carbonate (400 mg, 1.83 mmol) were added in succession at room temperature. After 19 h, the reaction was concentrated under reduced pressure, and the desired product isolated by chromatography (Rf=0.35 in 20% EtOAc/hexanes). The resulting oil was taken to the next reaction: retention time=2.57 min, method [7]; mass spec (ESI) 369 (24), 368 (100), 272 (42), 211 (24).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][S:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1.[OH-].[K+].Cl>C(O)C.O>[OH:4][C:3]1[CH2:2][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)[CH2:22][C:23](=[O:25])[CH:24]=1
Reactant: CSc1ccc(C=CC(C)=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C2CC(=O)C=C(O)C2)cc1
Reaction time: 4 h
Yield: 74.2 %

Procedure:
Diethyl malonate (7.3 g; 45.4 mmole) was added to a solution of sodium metal (1.0 g; 42.9 mmole) in anhydrous absolute ethanol (100 ml). 1-(4-Methylthiophenyl)but-1-en-3-one (9.0 g; 43.7 mmole) was added to the solution and the mixture was heated under reflux, under nitrogen, with stirring for a period of 4 hours. An aqueous solution of potassium hydroxide (5.3 g in 30 ml of water) was added and the mixture was heated under reflux for a further 4 hours. The solution was poured into water, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was extracted with an aqueous 10% sodium hydroxide solution, the aqueous extract was acidified with dilute aqueous hydrochloric acid extracted with ethyl acetate. The organic phase was washed with with water, dried over anhydrous sodium sulfate and the solvent was evaporated to give 3-hydroxy-5-(4-methylthiophenyl)cyclohex-2-en-1-one (7.6 g) as a yellow crystalline solid, mp 199° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[O:17]C)=[CH:8][CH:9]=1)=[O:4].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[OH:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc(N)c2OC)o1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cccc(N)c2O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
5-(3-Amino-2-methoxy-phenyl)-furan-2-carboxylic acid methyl ester 54b (350 mg, 1.42 mmol) was dissolved in dichloromethane followed by dropwise addition of boron tribromide (3.3 mL, 2.0 mol/L). The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with methanol. The mixture was adjusted to pH 5˜6 with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were concentrated and then the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-(3-amino-2-hydroxy-phenyl)-furan-2-carboxylic acid methyl ester 54c (170 mg, yield 45.1%) as a grey solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6](C2CCCCO2)[C:7]2[C:12]([N:13]=1)=[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[C:9]([Cl:20])[N:8]=2)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O.C(=O)(O)[O-].[Na+]>[CH3:1][NH:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[N:10]=[C:9]([Cl:20])[N:8]=2)=[O:4]
Reactant: CNC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: 25 °C
Reaction time: 68 h
Yield: 69.9 %

Procedure:
2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purine-8-carboxylic acid methylamide (104 mg, 0.27 mmol) was suspended in methanol (6 mL) and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) was added. The mixture was stirred at room temperature for 68 h, then diluted with water and neutralized with aqueous sodium bicarbonate. The solid precipitate was filtered off and dried at 50° C. under vacuum to give 2-chloro-6-morpholin-4-yl-9H-purine-8-carboxylic acid methylamide (56 mg, 70%). LCMS RT=2.43, [M+H]+=297/299
Reaction SMILES: [F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([C:8](N(OC)C)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>O1CCCC1>[F:1][C:2]1([F:14])[CH2:7][CH2:6][CH:5]([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CON(C)C(=O)C1CCC(F)(F)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=CC1CCC(F)(F)CC1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 115.1 %

Procedure:
A mixture of 4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide obtained in Example 2a (1.7 g, 8.21 mmol) and tetrahydrofuran (60 ml) was cooled to −70° C., a 1.0 M diisobutylaluminum hydride/toluene solution (9.85 ml, 9.85 mmol) was added, and the reaction mixture was stirred at −60° C. for 35 minutes. A 1.0 M diisobutylaluminum hydride/toluene solution (5 ml, 5 mmol) was further added at −65° C., and the reaction mixture was stirred at −70° C. for two hours. A 2 N aqueous hydrochloric acid solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to give a crude product of the title compound (1.4 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14].[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:19][CH2:18][CH2:17]1)=[O:14]
Reactant: Cc1cc(C)cc(B(O)O)c1
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)cccc12
Product: Cc1cc(C)cc(-c2cccc3c(N)c(C(=O)NC4CCC4)nnc23)c1
Yield: 37.7 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclobutyl-cinnoline-3-carboxamide (145 mg) and 3,5-dimethylphenyl boronic acid (169 mg) were reacted to afford the title compound (59 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.31 (d, 1H), 8.38 (d, 1H), 7.78 (m, 2H), 7.28 (s, 2H), 7.06 (s, 1H), 4.52 (m, 1H), 2.35 (s, 6H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=347 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:22][CH2:23][CH:24]([OH:29])C(F)(F)F)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC1C=CC(S(NC2CCC3C(=CC=CC=3CCCO)C2)(=O)=O)=CC=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[CH2:22][CH2:23][CH:24]=[O:29])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(NC1CCc2c(CCC(O)C(F)(F)F)cccc2C1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)(NC1CCc2c(CCCO)cccc2C1)c1ccc(F)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1cccc2c1CCC(NS(=O)(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Fluoro-N-(5-(4,4,4-trifluoro-3-hydroxybutyl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide, designated as 23 in FIG. 7, was prepared as follows. A mixture of 4-fluoro-N-(5-(3-hydroxypropyl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide (70 mg, 0.19 mmol) and pyridinium chlorochromate (60 mg, 0.28 mmol) in anhydrous dichloromethane (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was filtered through a pad of celite, and the solvent was evaporated. The residue was purified by a short silica gel column chromatography using ethyl acetate-hexanes 2:3 as eluent to give 4-fluoro-N-(5-(3-oxopropyl)-1,2,3,4-tetrahydronaphthalen-2-yl)benzenesulfonamide (20) that was dissolved in anhydrous tetrahydrofuran (1 mL) and cooled to 0 C. Tetrabutylammoniumfluoride in THF (5 μL, 1 M, 0.004 mmol) was added followed by trifluoromethyl trimethylsilane (30 mg, 33 μL, 0.21 mmol). The reaction was warmed to room temperature and stirred overnight. Hydrochloric acid (1 M, 1.5 mL) was added and stirring continued at room temperature for 1.5 hour. The aqueous layer was extracted with dichloromethane, dried over magnesium sulfate and concentrated to dryness. Silica gel chromatography (30% ethyl acetate in hexanes) gave the purified product as colorless oil. Yield: 13%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17](C4C=CC(C)=CC=4)=[CH:16][N+:15]=3[O-])[C:7]=2[CH:28]=1)#[N:2].NC1C=CC(C2C3C=C(C#N)C=CC=3OC(C)(C)C=2)=NC=1.N([O-])=O.[Na+].[I-:54].[K+].[OH-].[Na+]>C(O)(=O)C.O>[I:54][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[C:7]3[CH:28]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=2)=[N:15][CH:16]=1
Reactant: [I-]
Reactant: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)[n+]([O-])c2)cc1
Agent: CC1(C)C=C(c2ccc(N)cn2)c2cc(C#N)ccc2O1
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C=C(c2ccc(I)cn2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 4-[5-(4-methylphenyl)-2-pyridyl]-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile used as the starting material was prepared as follows: (A) 9.5 g of 4-(5-amino-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile were dissolved in 150 ml of acetic acid and 100 ml of water. 3.16 g of sodium nitrite in 10 ml of water were added at such a rate as to keep the temperature below 5° C. After 15 minutes 23 g of potassium iodide in 20 ml of water were added and the mixture was stirred at room temperature for 1 hour. The mixture was then poured into 1.1 of 2M sodium hyroxide solution and extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 4.78 g of 4-(5-iodo-2-pyridyl)-2,2-dimethyl-2H-1 -benzopyran-6-carbonitrile which was used without further purification. (B) 440 mg of 4-(5-iodo-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile, 386 mg of p-tolyltrimethyltin, 440 mg of lithium chloride and 16 mg of bis(triphenylphosphine)palladium dichloride in 4 ml of dimethylformamide were heated at 100° C. for 2 hours. After cooling to room temperature 10% aqueous ammonia and ethyl acetate were added, the phases were separated and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:4) for the elution to give 268 mg of 4-[5-(4-methylphenyl)-2-pyridyl]-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:7][C:6](=[O:17])[CH:5]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>O1CCCC1>[CH2:1]([O:3][C:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[CH2:7][C:6](=[O:17])[CH:5]=1)[CH3:2]
Reactant: COCCOCCl
Reactant: CCOC1=CC(=O)CC(c2ccccc2O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1=CC(=O)CC(c2ccccc2OCOCCOC)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A suspension of 3-ethoxy-5-(2-hydroxyphenyl)-2-cyclohexenone (32.4 g) in tetrahydrofuran (400 ml) was added slowly to an ice-cooled suspension of sodium hydride (3.34 g) in tetrahydrofuran (75 ml). The mixture was stirred at room temperature for 30 min, cooled in an ice-bath and a solution of methoxyethoxymethyl chloride (20.8 g) in tetrahydrofuran (50 ml) was added dropwise with stirring. The mixture was stirred overnight at room temperature and then was concentrated by the removal of most of the tetrahydrofuran under reduced pressure. The concentrate was diluted with water and extracted with ether. The ethereal extracts were dried and the solvent removed under reduced pressure. The residual oil was purified by column chromatography on silica gel using chloroform for elution to afford the title compound (36.23 g) as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:21])=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: NCCc1ccccn1
Product: CCOc1ccc(NC(=O)NCCc2ccccn2)cc1
Yield: 95 %

Procedure:
Prepared in a similar manner to example 158 using 2-(pyridine-2-yl) ethanamine and 1-ethoxy-4-isocyanatobenzene. Yield: 95%. mp: 163-164° C. 1H NMR (500 MHz, CDCl3): δ 1.43 (t, 3H), 3.03 (t, 2H), 3.68 (t, 2H), 4.03 (q, 2H), 5.69 (br s, 1H), 6.45 (br s, 1H), 6.84 (m, 2H), 7.14 (m, 3H), 7.20 (d, 1H), 7.64 (dt, 1H), 8.43 (dd, 1H). MS (M+H, 286).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[CH:20]1([C:23]([NH2:25])=[NH:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[N:24]=[CH:4][C:5]3[CH2:6][C:7](=[O:18])[NH:8][C:9]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=4[C:11]=3[N:25]=2)[CH2:22][CH2:21]1
Reactant: N=C(N)C1CC1
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)-c1nc(C3CC3)ncc1CC(=O)N2
Yield: 88 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and cyclopropanecarboxamidine hydrochloride. Yield: 88%.