Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].CC1(C)C(C)(C)OB([C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][O:28][C:24]=3[CH:23]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[NH2:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][O:28][C:24]=3[CH:23]=2)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Br)cc(N)c1Cl
Reactant: CC1(C)OB(c2ccc3ncoc3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1nc(-c2ccc3ncoc3c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
0.024 g (0.03 mmol) of (PPh3)2PdCl2 is added to a solution of 0.3 g (1.13 mmol) of methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate in 20 ml of dioxane, and this mixture is stirred at RT for 30 min. In succession, 0.28 g (1.13 mmol) of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole, 0.47 g (3.4 mmol) of K2CO3 and 2 g (111 mmol) of H2O are then added to this mixture, which is then stirred under reflux for 6 h. The mixture is allowed to stand at RT for a further 12 h and then added to 40 ml of H2O. This mixture is extracted repeatedly with CH2Cl2, and the combined organic phase is dried over Na2SO4 and then concentrated. Purification by chromatography on silica gel using the mobile phase heptane/ethyl acetate (3/7) gives 0.1 g (29%) of product. 1H-NMR (CDCl3): δ 8.25 (s, 1H, benzoxazole), 8.15 (s, 1H, benzoxazole), 7.90, 7.80 (2d, 2H, benzoxazole), 7.20 (s, 1H, pyridine), 4.80 (bs, 2H, NH2), 4.00 (s, 3H, COOCH3).
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[N+:24]([C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[CH:30][NH:31]2)([O-:26])=[O:25]>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:31]2[C:32]3[C:28](=[C:27]([N+:24]([O-:26])=[O:25])[CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:30]2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCCl
Product: O=[N+]([O-])c1cccc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Cyclopropyl boronic acid (1.0 g), sodium bicarbonate (0.99 g), copper acetate (II) (1.1 g), and 2,2′-bipyridine (0.92 g) were added to a solution of 4-nitro-1H-indole (0.96 g) in 1,2-dichloroethane (60 ml). The reaction solution was stirred at room temperature for 7 days, and then further stirred at 60° C. for 2 hours. The insolubles were filtrated through celite, and then the resultant was washed successively with water and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 1-cyclopropyl-4-nitro-1H-indole as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[H-].[Na+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23]>C1COCC1.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:22]([N:21]([CH3:26])[CH3:20])(=[O:24])=[O:23])[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: CN(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 138 mg, 0.610 mmol) in a 1:1 mixture of THF-DMF (4.5 mL) was added NaH (73.0 mg, 2.50 mmol). The mixture was stirred at RT. After 10-15 min, dimethylsulfamoyl chloride (212 mL, 1.10 mmol) was added and the reaction was stirred for another 2 h. The reaction was quenched with water (50 mL) and poured into a separatory funnel containing EtOAc (100 mL). The mixture was shaken and the layers were separated. The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to give 2-amino-9-[(dimethylamino)sulfonyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (17, 24.9 mg, 12%). HCOOH standard conditions. DAD Retention time=3.68 min. M+H=334. 1H NMR (300 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.06 (s, 1H), 8.00-7.97 (m, 1H), 7.84-7.81 (m, 1H), 7.72 (br s, 2H), 7.40-7.32 (m, 3H), 3.02 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:14][CH2:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: CCN
Product: CCNc1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the method of Example 1, Step 4 starting from the product of Example 1, Step 3 and ethylamine. MS (ES+) m/e 202 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:19](O)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].CN1CCOCC1.[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41].O>CC1OCCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:26])([S:22]([CH3:25])(=[O:23])=[O:24])[C:19]([NH:41][O:40][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][O:34]3)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NOC1CCCCO1
Reactant: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)O)S(C)(=O)=O
Solvent: O
Solvent: CN1CCOCC1
Solvent: CC1CCCO1
Product: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)butanoic acid (0.360 g, 0.969 mmol) in 2-MeTHF (30 mL) was added N-methyl morpholine (0.139 g, 1.36 mmol, 1.4 eq), followed by CDMT (0.204 g, 1.16 mmol, 1.2 eq). The reaction mixture was allowed to stir for one hour. O-Tetrahydro-2H-pyran-2-yl-hydroxylamine (0.136 g, 1.16 mmol, 1.2 eq) was added, and the reaction mixture and was allowed to stir for an additional two hours. Water (20 mL) was added, and the solution was extracted with 2-MeTHF (100 mL). The aqueous layer was re-extracted with 2-MeTHF (150 mL), and the combined organic layers were washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude was purified by flash chromatography, eluting with 30%-100% ethyl acetate/heptane to yield (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (209 mg, 46% yield) as a colorless oil. LC-MS M−H 469.3.
Reaction SMILES: [NH:1]([N:18]=[N+:19]=[N-])[C@H:2]([C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].N(N=[N+]=[N-])[C@H](C(O)=O)CC(=O)OC>>[CH3:6][O:5][C:4](=[O:7])[CH2:3][C@H:2]([N:1]=[N+:18]=[N-:19])[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)NCc1ccccc1
Agent: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)O
Product: COC(=O)C[C@H](N=[N+]=[N-])C(=O)NCc1ccccc1

Procedure:
Benzyl-protected L-aspartate was used in the procedure of Lundquist and Pelletier17 to give N3(L)Asp(OMe)OH (46-L). Under these conditions, we observed transesterification to give the methyl ester product as opposed to the benzyl ester. N3(L)Asp(OMe)OH (46-L) was produced as a yellowish oil in 78% yield. N3(L)Asp(OMe)OH (46-L) was then coupled with benzylamine as above to give N3(L)Asp(OMe)NHBn (49-L) as a yellowish oil in 90% yield (70% overall, two steps). The procedure above was repeated with benzyl-protected D-aspartate to give N3(L)Asp(OMe)NHBn (49-D) as a yellowish oil in 67% overall yield. Spectral Data. The spectral data for both N3Asp(OMe)OH (D and L enantiomers) and both N3Asp(OMe)NHBn (D and L enantiomers) products are identical. N3(L)Asp(OMe)OH (46-L) 1H NMR (500 MHz, CDCl3) δ 10.24 (bs, 1 H), 4.47 (dd, J=7.4, 5.3 Hz, 1 H), 3.76 (s, 3 H), 2.91 (dd, J=16.9, 5.1 Hz, 1 H), 2.79 (dd, J=16.8, 7.6 Hz) ppm; 13C NMR (125 MHz, CDCl3) δ 174.68, 170.12, 50.09, 52.44, 35.84 ppm; MS (ESI) m/z 196.0340 (MNa+ [C5H7N3O4Na]=196.0334). N3(L)Asp(OMe)NHBn (49-L) 1H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 5 H), 6.83 (bs, 1 H), 4.54 (m, 3 H), 3.75 (s, 3 H), 3.18 (dd, J=17.1, 3.7 Hz, 1 H), 2.75 (dd, J=17.3, 8.7 Hz, 1 H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.77, 167.90, 137.35, 128.81, 127.80, 127.77, 60.32, 52.24, 43.71, 37.00 ppm; MS (ESI) m/z 285.0953 (MNa+ [C12H12N4O3Na]=285.0964).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:18][C:19]1[N:20]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:21]([C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)([CH3:26])[CH3:25])=[CH:22][N:23]=1>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([C:24]([C:21]2[N:20]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:19]([CH2:18][O:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)=[N:23][CH:22]=2)([CH3:26])[CH3:25])[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(CCl)n1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (202 mg, 1 mmol) in anhyd THF (3 mL) was added NaH (60% in mineral oil, 53 mg, 1.32 mmol). The mixture stirred at room temperature for 30 min, then a solution of 2-(chloromethyl)-5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (262 mg, 0.66 mmol) in THF (2 mL) was added. After stirring at ambient temperature overnight, the reaction was quenched by addition of MeOH and concentrated in vacuo. The residue was partitioned in water and EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (silica, 0-90% EtOAc/Hex) to give tert-butyl 4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)piperidine-1-carboxylate as a white solid (215 mg, 60%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=1>CO>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Anhydrous potassium carbonate (0.9g, 0.0065 moles) was added to a solution of chloro-4-trimethylsilylethynylbenzene (3.Og, 0.014 moles) in methanol (60 cm3) under an atmosphere of nitrogen. The reaction was stirred, under nitrogen, at room temperature for 4 hours. The solvent was removed, the solid residue was tritura&ed with ether and then dichloromethane and filtered. The organic filtrates were combined and evaporated to dryness giving chloro-4-ethynylbenzene as a brown solid. This was used in the next step without any further purification yield 1.1 g (58%). 1H NMR 67.3 (2H, d), 7.4 (2H, d), 3.1 (1H, s)ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1>>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[N:7]=1)[CH2:9]2
Reactant: FC(F)(F)c1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)cc(C(F)(F)F)n2)cc1
Yield: 86 %

Procedure:
The title compound was prepared in 86% yield from 3-(2-chloro-6-trifluoromethyl-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (63) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, using the general procedure from scheme 2 for the preparation of 6. MS (ES+): 351.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 1.4 g (2.4 mMol) of tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 15 ml of trifluoroacetic acid in 30 ml of methylene chloride is stirred for 14 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with about 30 ml of water and made alkaline with 2N sodium hydroxide solution. After extracting twice with 30 ml of diethyl ether, the aqueous phase is acidified with 20% citric acid. The crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant: methylene chloride/ethanol=96:4).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][NH:13][C:14]1[N:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1>C(#N)C>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[N:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:7]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: CC#N
Product: N#Cc1ccc(NCCNc2nc(N)cc(Cl)n2)nc1

Procedure:
10.3 g (63 mmol) of 2,6-dichloropyrimidine-4-amine and 10.22 g (63 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile are dissolved in 164 ml acetonitrile and heated under reflux conditions for 24 h. After cooling, the major amount of the precipitated product is filtered off with suction. 11.9 g (50% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[CH3:2]>[Cl-].[Cl-].[Cl-].[Ti+3]>[CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=2)[CH2:13][CH2:12]1)[CH3:2]
Reactant: CCc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1CC
Agent: [Ti+3]
Agent: [Cl-]
Product: CCc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1CC

Procedure:
In the manner given in Example 1B, 1-(2,3-diethylphenyl)-4-(p-nitrobenzyl)piperazine is reduced with aqueous titanium trichloride to give 1-(2,3-diethylphenyl)-4-[(4-aminophenyl)methyl]piperazine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[S:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][CH:39]3[CH2:40][CH2:41][S:36][CH2:37][CH2:38]3)[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: NC1CCSCC1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(NC3CCSCC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (100 mg, 0.186 mmol) and tetrahydro-2H-thiopyran-4-amine (100 mg, 0.853 mmol) the title compound was obtained as a crude yellow foam and used directly in the next step. MS (ESI): 620.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([F:21])[CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22].B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([F:21])[CH:14]=3)=[CH:9][C:10]=2[F:12])[CH:5]=[CH:4][C:3]=1[OH:22]
Reactant: COc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(F)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 1-chloro-8-fluoro-6-(3-fluoro-4-methoxyphenyl)-2-naphthol (0.13 g, 0.41 mmol) with boron tribromide (0.8 mL of 1N solution, 0.8 mmol) according to method D to yield 0.070 g (56%) of a white solid mp 198-200° C.; 1H NMR (DMSO-d6): δ 7.03-7.09 (1H, m) 7.34 (1H, d, J=8.92 Hz), 7.49-7.52 (1H, m), 7.68 (2H, d, J=15.0 Hz), 7.85-7.88 (1H, m), 8.02 (1H, d, J=0.70 Hz), 10.13 (1H, s), 10.66 (1H, s); MS (ESI) m/z 305/307 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22]([O:24]C2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55][CH:54]([N:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:53][CH2:52]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22]([N:60]3[CH2:59][CH2:58][N:57]([CH:54]4[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]4)[CH2:62][CH2:61]3)=[O:24])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[O:49])[CH2:38][CH2:39]1)=[O:36]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added 1-(N-methylpiperidin-4-yl)piperazine (68.7 mg), followed by stirring at room temperature for 12 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (30.1 mg, 63.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:46])[NH2:40])=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2cc(N(CCN(C)C)S(=O)(=O)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(N(CCN(C)C)S(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-5-[N-(2-dimethylaminoethyl)-benzenesulphonylamino]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [Na].[S:2]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.[F:14][C:15]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[C:17](F)[C:16]=1[F:24].C1OCCOCCOCCOCCOC1>C(#N)C.O>[F:21][C:19]1[C:18]([F:22])=[C:17]([N:3]2[C:4](=[O:11])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:2]2(=[O:12])=[O:13])[C:16]([F:24])=[C:15]([F:14])[N:20]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2S(=O)(=O)N1c1c(F)c(F)nc(F)c1F
Reaction time: 3.5 h
Yield: 77 %

Procedure:
A mixture of the sodium salt of 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (0.81 g, 3.95 mmol), pentafluoropyridine (0.68 g, 4.0 mmol) and 15-Crown-5 (0.88 g, 4.0 mmol) in acetonitrile (15 ml) was heated to reflux for 6 hours, cooled, and the solvent evaporated in vacuo. The oily residue thus obtained was suspended in water and stirred for 3-4 hours. The solid which percipitated was collected by filtration and dried to afford 1.01 g (77%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 164°-165° C. after recrystallization from carbon tetrachloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1.Br[C:28]1[CH:33]=[CH:32][CH:31]=C[C:29]=1[S:34]([CH3:37])(=[O:36])=[O:35]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:31]=[CH:32][CH:33]=[CH:28][C:29]=2[S:34]([CH3:37])(=[O:36])=[O:35])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:26]=[N:25][C:24]2[NH:23][CH2:22][CH2:21][O:20][C:19]=2[CH:18]=1
Reactant: CC1(C)OC(c2ccc(-c3cnc4c(c3)OCCN4)c(F)c2)OC1(C)C
Reactant: CS(=O)(=O)c1ccccc1Br
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3c(c2)OCCN3)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 444 using 7-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine and 1-bromo-2-(methylsulfonyl)benzene. MS (ESI): mass calcd. for C20H17FN2O3S, 384.09; m/z found, 385.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.27-8.24 (m, 1H), 7.99-7.93 (m, 1H), 7.71-7.65 (m, 1H), 7.63-7.57 (m, 1H), 7.47 (m, 1H), 7.41-7.38 (m, 1H), 7.33-7.27 (m, 3H), 4.32-4.24 (m, 2H), 3.67-3.59 (m, 2H), 2.76 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2].[C:18]([O-])(=[O:20])C.[Na+].C(O)(=O)C.C=O.C([O-])(O)=O.[Na+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:13]3[C:14]([CH2:18][OH:20])=[CH:15][N:16]=[C:12]3[CH2:11][CH2:10]2)=[CH:5][C:4]=1[F:17])#[N:2]
Reactant: N#Cc1ccc(C2CCc3nccn32)cc1F
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(C2CCc3ncc(CO)n32)cc1F

Procedure:
A solution of product from Step J (3.79 g, 16.7 mmol), sodium acetate (2.44 g, 29.7 mmol), acetic acid (1.82 mL, 31.9 mmol), and formaldehyde (37% in water, 15.1 mL) was heated to reflux for 96 hours. The reaction was slowly neutralized by the addition of sat. aq. NaHCO3. The aqueous layer was extracted with methylene chloride (5×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by column chromatography (1→10% MeOH/CHCl3) to provide the title compound as a white solid.