Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[CH:10]=[CH:11][C:12]([CH:14]([C:17](=O)[C:18]4[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=4)[C:15]#[N:16])=[CH:13][C:8]=3[N:7]([CH3:26])[C:6]2=[O:27])[CH2:4][CH2:3][CH2:2]1.[OH:28][CH2:29][CH2:30][NH:31][NH2:32].C(=O)(O)[O-].[Na+]>CC(O)C.C(O)(=O)C>[NH2:16][C:15]1[N:31]([CH2:30][CH2:29][OH:28])[N:32]=[C:17]([C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)[C:14]=1[C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[C:6](=[O:27])[N:7]([CH3:26])[C:8]=2[CH:13]=1
Reactant: Cc1cccc(C(=O)C(C#N)c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Reactant: NNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1cccc(-c2nn(CCO)c(N)c2-c2ccc3c(c2)n(C)c(=O)n3C2CCC2)c1
Temperature: 70 °C

Procedure:
2-(1-Cyclobutyl-3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile (66.5 mg, 0.19 mmol) was diluted with 2-propanol (0.4 mL) and acetic acid (0.8 mL). Hydroxyethyl hydrazine was then added (0.1 mL) and the mixture was heated to 70° C. for 8 hours. The reaction was cooled, poured onto saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated. Preparative thin layer chromatography gave 5-[5-Amino-1-(2-hydroxy-ethyl)-3-m-tolyl-1H-pyrazol-4-yl]-1-cyclobutyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (27.6 mg).
Reaction SMILES: [NH3:1].CS(O[CH:7]1[CH2:10][N:9]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8]1)(=O)=O>CO>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:9]2[CH2:10][CH:7]([NH2:1])[CH2:8]2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: N
Solvent: CO
Product: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -60 °C
Reaction time: 24 h

Procedure:
1-[Bis(4-chlorophenyl)methyl]azetidin-3-ylamine may be obtained in the following manner: 400 cm3 of a mixture of methanol and liquid ammonia (50/50 by volume) are added to 27 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-yl methylsulfonate contained in an autoclave previously cooled to around −60° C. The reaction medium is then stirred at 60° C. for 24 hours and then abandoned in the open air to allow the evaporation of the ammonia and finally concentrated under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of a 0.37 N aqueous sodium hydroxide solution and extracted with four times 500 cm3 of ethyl ether. The combined organic phases are washed successively with twice 100 cm3 of distilled water and 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluant: dichloromethane/methanol (95/5 by volume)]. 14.2 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine are obtained in the form of an oil which solidifies into a cream-colored solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.O[N:29]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[OH-].[NH4+]>CN(C=O)C.C(#N)C.O>[NH2:1][C:2]1[C:7]([C:8]([NH2:29])=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ncc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
300 mg (0.82 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylic acid (example 102A) and 139 mg (0.91 mmol) of 1-hydroxyl-1H-benzotriazole were dissolved in 2.2 ml of DMF, and 174 mg (0.91 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. While cooling with ice, 140 ml (0.99 mmol) of ammonium hydroxide (28%) were added, and the mixture was reacted at room temperature overnight. 4 ml of acetonitrile/water (1/1) were added and the precipitate formed was filtered off. After drying under high vacuum, 145 mg (48% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](O)[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-:36])=[O:35])[CH:28]=2)[CH2:24][O:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].ClC(Cl)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:21]3([CH3:20])[CH2:22][O:23][CH2:24]3)=[CH:28][C:29]=1[N+:34]([O-:36])=[O:35])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccc(OCc3ccccc3)c2n1
Reactant: CC1(COc2ccc(N)c([N+](=O)[O-])c2)COC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(Nc3ccc4cccc(OCc5ccccc5)c4n3)c([N+](=O)[O-])c2)COC1
Temperature: 100 °C
Yield: 71.6 %

Procedure:
The compound, 8-Benzyloxy-quinolin-2-ol (5 g, 18.5 m,mol, 1.0 equivalent), 4-(3-Methyl-oxetan-3-ylmethoxy)-2-nitro-phenylamine (5.3 g, 22.2 mmol, 1.2 equivalents), cesium carbonate (8.46 g, 26 mmol, 1.4 equivalents), DIPHOS (1,2-Bis(diphenylphosphino)ethane; 443 mg, 111 μmol, 0.06 equivalents) and toluene (75 mL, 15 volumes) were charged to a 100 mL round bottom flask. The reaction was deoxygenated. Palladium acetate (83 mg, 37 μmol, 0.02 equivalents) was added and the reaction was deoxygenated again. The reaction was heated to 100° C. for 24–30 hours. At reaction completion, the reaction was cooled to 55° C. and dichloroethane (“DCE”; 75 mL, 15 volumes) was charged. The slurry was filtered through a pad of Celite and then the flask and filter were rinsed once with additional DCE.(50 mL, 10 volumes). The organics were concentrated to low volume and ethyl acetate (50 mL, 10 volumes) was added. The reaction was heated to reflux and allowed to cool to 20–25° C. The solids were granulated for 10–20 hours, filtered, and dried under vacuum at 40° C. with a slight nitrogen bleed to yield 6.72 g (8-Benzyloxy-quinolin-2-yl)-[4-(3-methyl-oxetan-3-ylmethoxy)-2-nitro-phenyl]-amine as an orange solid (77% yield). The material was judged to be about 95% pure by NMR, with ˜5% of the DIPHOS bis-oxide.
Reaction SMILES: CS[C:3](=[N:17][CH3:18])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[OH-].[K+].[CH2:21]([NH2:26])[CH2:22][CH2:23][CH2:24][CH3:25].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH3:18][NH:17][C:3]([NH:26][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCCCCN
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCNC(=Nc1ccccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea (4 g prepared from the hydroiodide salt described in Example 210), potassium hydroxide (1.7 g), n-pentylamine (2.1 g), lead acetate trihydrate (5.8 g) and ethanol (20 ml) were heated at 90°-95° C. for 40 minutes to yield an oil which was extracted with hexane to give 1-methyl-2-(2-morpholinophenyl)-3-(n-pentyl)guanidine which was converted into its monofumarate salt (m.p. 148°-149° C.) which was recrystallised from a 3:5 mixture of methanol and ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH:15]=O)[CH3:14]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:12][N:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 2-chloro-4-methyl-5-nitro-pyridine (2 g, 11.59 mmol) in DMF (11.6 mL) was treated with 3.08 mL (23.2 mmol, 2 eq) of DMF-dimethylacetal and the reaction mixture was stirred at 100° C. for 4 h. All volatiles were removed under reduced pressure. Column chromatography (silica, 20% EtOAc/hexanes) provided 2.37 g (90%) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine. TLC (silica, 20% EtOAc/hexanes): Rf=0.30. MS (electrospray): exact mass calculated for C9H10ClN3O2, 227.05; m/z found, 228.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.79 (s, 1H), 8.02 (s, 1H), 7.35 (d, J=13 Hz, 1H), 5.94 (d, J-=13 Hz, 1H), 2.96 (s, 3H), 2.87 (s, 3H).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CCCCCC.CO[C:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[N:24]=[CH:25]N(C)C)=[O:18]>O1CCCC1.C(O)(=O)C>[O:18]=[C:17]1[C:2]([C:1]#[N:3])=[CH:25][NH:24][C:23]2[CH:22]=[CH:21][S:20][C:19]1=2
Reactant: CC#N
Reactant: COC(=O)c1sccc1N=CN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1c[nH]c2ccsc2c1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
A solution of 1.04 ml (20 mmol) of acetonitrile in 7 ml of tetrahydrofuran was added to a solution of 12.5 ml of 1.6 M n-butyl lithium in hexane (20 mmol) in 25 ml of tetrahydrofuran at −78° C. After 15 minutes, a solution of 2.019 g (9.5 mmol) of 3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester in 25 ml of tetrahydrofuran was added dropwise over 1 h. The reaction mixture was stirred at −78° C. for 30 minutes, and then allowed to warm to room temperature. After stirring at room temperature for 1 h, the reaction mixture was cooled to −50° C. and 1.4 ml of acetic acid was added. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetone and hexanes to give 0.668 g (40%) of red-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.94 (d, J=5.4 Hz, 1H), 7.25 (d, J=6 Hz, 1H); LC-MS (ESI) m/z 177.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22]C)=[O:21])[CH:15]=1.[OH-].[Na+].Cl>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=1
Reactant: COC(=O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cccc(C(=O)Nc2cccc3cc(Br)cnc23)c1
Yield: 115.7 %

Procedure:
A mixture of 3-bromo-8-[3-(methoxycarbonyl)benzoylamino]quinoline (356 mg) and 1N sodium hydroxide aqueous solution (1.1 ml) in methanol (5 ml) and dioxane (5 ml) was gently refluxed for 2 hours. After cooling, the mixture was neutralized with 1N hydrochloric acid. The solvent was removed in vacuo, and the residue was washed with hot 95% ethanol and collected by filtration to give 3-bromo-8-(3-carboxybenzoylamino)quinoline (397 mg) as pale tan solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[C:16]([Si:13]([CH3:15])([CH3:14])[O:12][CH2:11][CH2:10][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a stirred solution of hydroquinone (Aldrich, 11.01 g, 100 mmol) in DMF (300 mL), (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (Aldrich, 12.0 g, 50 mmol), cesium carbonate (40.7 g, 125 mol) were added and the mixture was stirred at 60° C. overnight. The mixture was poured into water (300 mL) and 6N HCl was added to adjust the “pH” to 6. The mixture was extracted with EtOAc (3×60 mL) and the extracts were combined and dried. Removal of solvent gave the crude, which was chromatographied on a ISCO machine eluting with EtOAc/hexane (0-30%) to give a light brown solid. 5.71 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[O:3]1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:17]1[CH2:22][CH2:21][CH:20]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)[CH2:19][CH2:18]1
Reactant: O=C1CCOCC1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC1(C)OB(c2ccc(NC3CCOCC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.5 g, 2.28 mmol), tetrahydropyran-4-one (0.25 ml, 2.73 mmol) and sodium triacetoxy-borohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred at room temperature for 16 hours. The crude was filtered over diatomaceous earth, washed with DCM and the filtrate was evaporated in vacuo to yield D7 (0.69 g) that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8](CC2C=CC=CC=2)CC2C=CC=CC=2)[C:5]2[N:23]=[C:24]([CH3:31])[N:25]([CH2:26][CH2:27][O:28][CH2:29][CH3:30])[C:4]=2[C:3]=1[CH3:32].Cl.C(OCC)(=O)C.CCCCCC>CO.[OH-].[OH-].[Pd+2]>[CH2:29]([O:28][CH2:27][CH2:26][N:25]1[C:4]2[C:3]([CH3:32])=[CH:2][N:7]=[C:6]([NH2:8])[C:5]=2[N:23]=[C:24]1[CH3:31])[CH3:30]
Reactant: CCOCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(Cl)c(C)c21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOCCn1c(C)nc2c(N)ncc(C)c21
Reaction time: 4 h
Yield: 49.2 %

Procedure:
6-Chloro-1-(2-ethoxyethyl)-2,7-dimethyl-N4,N4 -bis(phenylmethyl)-1H -imidazo[4,5-c]pyridin-4-amine (0.7 g, 1.56 mmole) was taken up in methanol saturated with anhydrous hydrochloric acid (100 mL), combined with palladium hydroxide on carbon and then hydrogenated on a Paar apparatus for four hours. The reaction mixture was filtered to remove the catalyst then concentrated under vacuum. The residue was partitioned between methylene chloride/water/sodium bicarbonate. The methylene chloride layer was separated, dried over magnesium sulfate then concentrated under vacuum to provide an off white solid. This material wasrecrystallized from ethyl acetate/hexane to provide 0.18 g of the desired product as a solid, m.p. 129°-130° C. Analysis: Calculated for: C12H18N4O+1/4H2O: % C, 60.35; % H, 7.81; % N,23.46; Found: % C, 60.64; % H, 7.50; % N, 23.39.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([O:29]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:10]2)[O:6][N:5]=1)[CH3:2].Cl.[OH:40][CH:41]1[CH2:44][NH:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[C:17]([F:26])[CH:16]=3)[CH2:12][N:11]([C:27]([N:43]3[CH2:44][CH:41]([OH:40])[CH2:42]3)=[O:29])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)n1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)c(F)c3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
145 mg (0.23 mmol) of the compound from Example 65A, 76 mg (0.68 mmol) of 3-hydroxyazetidine hydrochloride and 62 mg (0.45 mmol) of potassium carbonate were initially charged in 4.5 ml of DMF and reacted in the microwave at 150° C. for 15 minutes. The reaction mixture was purified by means of preparative HPLC. Yield: 41 mg (36% of theory)
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[O:11]CCCO1.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:3][CH2:4][CH2:5][C:6]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[O:11])[CH2:23][CH2:24]2)=[N:26]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: Fc1ccc(C2(CCCCl)OCCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Product: O=C(CCCN1CCN(c2nsc3ccccc23)CC1)c1ccc(F)cc1

Procedure:
Title product hydrochloride--A mixture of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane (4.31 g., 0.0176 mole), 3-(1-piperazinyl)-1,2-benzisothiazole (3.86 g., 0.0176 mole), powdered potassium carbonate (2.43 g., 0.0176 mole) and potassium iodide (0.88 g., 0.0053 mole) in 180 ml. of dry acetonitrile is refluxed for a 20 hr. period. The reaction mixture is filtered, concentrated in vacuo and residual oil dissolved in chloroform and filtered. Concentration of the filtrate affords an oily residue which is taken up in 100 ml. of ethanol containing 10 ml. of 3 N hydrochloric acid and refluxed for 15 min. period. Acetonitrile is added to the cooled mixture and the solid obtained collected, 3.3 g. m.p. 248°-250° C. Crystallization of this material from ethanol affords analytically pure 4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone hydrochloride, m.p. 251°-254° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:19]=[N:20][C:21]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[CH:12]=2)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.I[CH2:50][C:51]([NH2:53])=[O:52]>O>[NH2:53][C:51](=[O:52])[CH2:50][N:20]1[C:21](=[N:24][S:25]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][C:18]([O:17][C:13]2[CH:12]=[C:11]([NH:10][C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:9])[CH:16]=[CH:15][CH:14]=2)=[CH:19]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4ncccc4C)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of 3-methyl-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}pyridine-2-carboxamide (12.4 g, 26.2 mmol), N,N-diisopropylethylamine (6.00 mL, 34.4 mmol) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1 hr. Iodoacetamide (6.29 g, 34.0 mmol) was added, and the mixture was stirred at room temperature for 71 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (9.72 g, 70%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][C:6]=2[CH:19]=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+].[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>O1CCCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[NH:7][C:6]=2[CH:19]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCc1nc2ccc(I)cc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl ((6-iodo-1H-benzo[d]imidazol-2-yl)methyl)carbamate (G4, 216 mg), bis(triphenylphosphine)palladium(II) dichloride (40 mg) and copper(I) iodide (22 mg) in tetrahydrofuran (2 mL), triethylamine (243 μL) and trimethylsilylacetylene (96 μL) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 70 to 0% hexane in ethyl acetate) to obtain tert-butyl ((6-((trimethylsilyl)ethynyl)-1H-benzo[d]imidazol-2-yl)methyl)carbamate (G5, 82 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O.C(OCC)(=O)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[F:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: Fc1ccccc1CBr
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
After dissolving 1.70 g of 1-(tert-butoxycarbonyl)-4-mercaptopiperidine in a mixture of 8 ml ethanol/8 ml 2N sodium hydroxide, 1.05 ml of 2-fluorobenzyl bromide was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.72 g, 68% yield).
Reaction SMILES: [I:1]I.C(Cl)(Cl)Cl.[F:7][C:8]1[CH:9]=[C:10]([OH:18])[CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15]>FC(F)(F)C([O-])=O.[Ag+]>[F:7][C:8]1[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][C:11]([I:1])=[C:10]([OH:18])[CH:9]=1
Reactant: II
Reactant: Oc1ccc(C(F)(F)F)c(F)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Oc1cc(F)c(C(F)(F)F)cc1I
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A solution of iodine (0.874 g, 3.44 mmol) in chloroform (17.1 mL, 214 mmol) was added over a period of 1.5 hours dropwise via addition funnel to a mixture of 3-fluoro-4-(trifluoromethyl)phenol (Preparation 886, 620 mg, 3.4 mmol) and silver trifluoroacetate (0.760 g, 3.44 mmol) in chloroform (3.4 mL, 43 mmol). After addition was complete, the reaction mixture was stirred an additional 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was washed successively with 10% aqueous sodium thiosulfate (w/v), half-saturated aqueous sodium bicarbonate, water and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated onto diatomaceous earth. The residue was purified by automated flash chromatography (24 g SiO2, hexanes to 1:1 methylene chloride-hexanes gradient elution). The initial product-containing fraction contained predominantly diiodinated material (by mass) with some monoiododinated material. The remaining fractions were concentrated in vacuo to afford the product as a light yellow oil (579 mg, 54%). The product was not dried under vacuum due to volatility.