Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.N12[CH2:23][CH2:22][CH2:21][N:20]=[C:19]1[CH2:18][CH2:17][CH2:16][CH2:15]C2.[CH3:24][N:25]([CH3:30])[S:26](N)(=[O:28])=[O:27]>O1CCCC1>[CH3:24][N:25]([CH3:30])[S:26]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:23][CH:22]=2)(=[O:28])=[O:27]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CN(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To 1.0 g of carboxylic acid 1 in a 100 mL round bottom flask equipped with a septa under nitrogen, was added 20 mL of dry dichloroethane (DCE). To this solution was then added 1.2 equivalents of Diphenylphosphorylazide (DPPA) in one portion followed by 3 equivalents of triethylamine. The solution was stirred overnight at room temperature. The reaction progress was followed by an analytical Shimadzu LC/MS. The crude mixture was passed through a 24 g SiliCycle/Isco silica gel cartridge with DCE to give acyl azide 2 as a light yellow foam after solvent evacuation (50-65% yield). The acyl azide was found to be stable at room temperature in a vacuum desiccator for up to one month. To 0.3 mmol of acyl azide 2 in 2 mL of dry toluene was added 1.2 equivalents of amine in a Biotage/Personal Chemistry microwave vial. The vial was capped and heated to 100° C. in a Biotage/Personal Chemistry Emrys Optomizer microwave for 25 minutes. The crude reaction mixture was then evacuated to near dryness, taken up in a 1:1 ethyl acetate/hexane mixture and purified by flash chromatography to yield urea 3 (50-55% yield). To 0.15 mmol of intermediate 3 was added 10 equivalents of potassium trimethylsilanolate (TMSOK) and 3 mL of dry tetrahydrofuran. The mixture was stirred at room temperature overnight. After the overnight treatment, the crude product was evacuated to near dryness, taken up in ethyl acetate, and neutralized with 0.5 M HCl. After extraction the solvent was removed to give a near quantitative yield of carboxylic acid 4 (purity >90%) which was used without further purification. To 0.14 mmol of carboxylic acid 4 in 1 mL of dry tetrahydrofuran was added 3 equivalents of carbonyldiimidazole. The solution was heated for 2-3 hours at 70° C. in a one dram vial equipped with a screw cap. At this point, 1.4 equivalents of neat 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) was dripped into the mixture followed by the addition of N,N-Dimethylsulfamide (as a solid). The vial was returned to the heating bath and shaken overnight. The crude reaction mixture was then evacuated to dryness and purified using a Shimadzu preparative HPLC to give dimethylamino sulfamide 5 as a yellow amorphous solid (35-50% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:26]([CH3:28])[CH3:27])[CH:13]([O:18][Si](C(C)(C)C)(C)C)[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5][CH:4]=[C:3]1[NH:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:37]>CO.ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:26]([CH3:28])[CH3:27])[CH:13]([OH:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5][CH:4]=[C:3]1[NH:35][C:36]([NH:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[O:37]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2cccnc2)c1=O)C(O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(3-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide was subjected to a method similar to that described in Example 2.d. Chromatography, with methanol:dichloromethane (5:95) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(3-pyridyl)methylureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid; MS: m/z=533(M+1).
Reaction SMILES: N[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.N(OCCC(C)C)=O.[I:39]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[I:39][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: CCCn1c(N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: II
Agent: CC(C)CCON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(I)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 2-Amino-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (prepared as given in Example 13) (0.169 g, 0.41 mmol), isoamyl nitrite (0.2 ml, 1.5 mmol), iodine (83 mg, 0.32 mmol) was taken in THF (5 ml) and stirred for 2 hours at 80° C. Reaction mixture was cooled and saturated solution of Na2S2O3 was added and extracted with ethyl acetate (3×5 ml). The organic layer was washed with brine (10 ml), dried over Na2SO4 and evaporated to obtain 2-Iodo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (93 mg, 44%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=3[CH:23]=[C:15]2[C:14]2[N:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=O)=O.[C-:26]#[N:27].[K+]>CN(C=O)C.O>[Cl:25][C:12]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:6][C:26]#[N:27])[N:16]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=4[CH:23]=[C:15]3[C:14]=2[N:13]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 80 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
A mixture of (2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)methyl methanesulfonate (1 g, 2.52 mmol) and KCN (491 mg, 7.55 mmol) in DMF (15 mL) was stirred at 80° C. for 15 hours. The mixture was diluted with water (30 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column (PE:EA=1:1) to afford the desired product of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetonitrile (600 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 7.49 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.18 (d, J=8.0 Hz 2H), 7.09 (d, J=8.4 Hz, 1H), 6.77˜6.79 (m, 1H), 5.00˜5.06 (m, 1H), 3.48˜3.54 (m, 1H), 3.27 (d, J=16.4 Hz, 1H), 2.54˜2.59 (m, 1H), 2.37˜2.44 (m, 1H). MS (M+H)+: 312/314.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:27]=[C:28]2[O:36][CH2:35][O:34][C:29]2=[C:30]([CH:33]=1)[CH:31]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:31][C:30]1[CH:33]=[C:26]([Br:25])[CH:27]=[C:28]2[O:36][CH2:35][O:34][C:29]=12
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1cc(Br)cc2c1OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1cc(Br)cc2c1OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Carbon tetrabromide (44.3 g, 0.134 mol) was added portionwise to a solution of triphenylphosphine (70.1 g, 0.267 mol) in methylene chloride (200 ml) under ice cooling. A solution of 5-bromo-2,3-methylenedioxybenzaldehyde (27.65 g, 0.121 mol) in methylene chloride (100 ml) was then added dropwise to the mixture over 20 minutes. The reaction mixture was stirred at room temperature for 2 hours, washed with water and with saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was added with ethyl acetate (200 ml), and the mixture was heated to 60° C. and then added with hexane (50 ml). The mixture was cooled to room temperature, and the deposited triphenylphosphine oxide was removed by filtration and the filtrate was concentrated. Triphenylphosphine oxide was removed again in a similar manner by using 100 ml of ethyl acetate and 100 ml of hexane, and the filtrate was concentrated. The residue was purified by silica gel chromatography (Wako Gell C-300: 200 g, eluent: hexane/ethyl acetate=1/10) to give β,β-dibromo-5-bromo-2,3-methylenedioxystyrene (42.36 g).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[N:14]=[C:13]2[CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:8][C:9]1[N:14]=[C:13]2[CH:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:12]2=[CH:11][CH:10]=1
Reactant: CC(=O)NCCC1CCc2ccc(N(Cc3ccccc3)Cc3ccccc3)nc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NCCC1CCc2ccc(N)nc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.4 %

Procedure:
(N-{2-[2-(Dibenzylamino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]ethyl}acetamide (870 mg, 2.18 mmol) was dissolved in acetic acid (22 mL), 20% palladium hydroxide-carbon powder (220 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. This was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (35.3 mg, yield 7%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@@H:4]([C:15]([OH:17])=[O:16])[CH2:3]1.[CH3:18]O.Cl>>[O:1]=[C:2]1[N:6]([C@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][C@@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C(=O)O)CC1=O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1

Procedure:
(S)-5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylic acid (1.16 g, 5 mmol) was treated with CH3OH/HCl (10 mL, 1 M) for 3 h. The excess CH3OH/HCl was removed under reduced pressure. The residue was basified with saturated aqueous NaHCO3 to pH 8. The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organics were washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give (S)-methyl 5-oxo-1-((S)-1-phenylethyl)pyrrolidine-3-carboxylate, which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.24-7.37 (m, 5H), 5.48 (q, J=7.2 Hz, 1H), 3.72 (s, 3H), 3.51-3.56 (m, 1H), 3.03-3.21 (m, 2H), 2.62-2.79 (m, 2H), 1.53 (d, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8](Cl)=[N:7][C:6]=12.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[NH:16]1)([CH3:14])[CH3:13].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:16]3[C@@H:15]([CH:12]([CH3:14])[CH3:13])[CH2:19][O:18][C:17]3=[O:20])=[N:7][C:6]=12
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: Clc1ccn2ncc(Br)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(Br)c2n1
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To a solution of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine (5.30 g, 22.8 mmol) and (S)-4-isopropyloxazolidin-2-one (4.42 g, 34.2 mmol) in dry DMF (100 mL) at ambient temperature was added sodium hydride (0.821 g, 34.2 mmol) and the solution stirred for 12 hours. Saturated aqueous NH4Cl solution was added and the solids were collected by filtration. Purification of the crude material by column chromatography, eluting with 1% MeOH/dichloromethane afforded 5.30 g (71%) of (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one as a yellow solid. LCMS (APCI+) m/z 325, 327 [M+H]+.
Reaction SMILES: C([O:8][CH2:9][N:10]1[C:21](=[O:22])[C:20]2[C:12](=[C:13]3[C:17](=[C:18]4[N:25]([C@@H:26]5[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]5[O:28][C:29](=[O:31])[CH3:30])[C:24]5[N:49]=[CH:50][CH:51]=[CH:52][C:23]=5[C:19]4=2)[NH:16][C:15]2[N:53]=[CH:54][CH:55]=[CH:56][C:14]3=2)[C:11]1=[O:57])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][N:10]1[C:21](=[O:22])[C:20]2[C:12](=[C:13]3[C:17](=[C:18]4[N:25]([C@@H:26]5[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:48])[CH3:47])[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:27]5[O:28][C:29](=[O:31])[CH3:30])[C:24]5[N:49]=[CH:50][CH:51]=[CH:52][C:23]=5[C:19]4=2)[NH:16][C:15]2[N:53]=[CH:54][CH:55]=[CH:56][C:14]3=2)[C:11]1=[O:57]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c3ncccc3c3c4c(c5c6cccnc6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c3ncccc3c3c4c(c5c6cccnc6[nH]c5c32)C(=O)N(CO)C4=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of Example 10c (0.090 mmol) in 4.5 ml of dry methanol and 1.5 ml of dry ethyl acetate there is added 10% palladium-on-carbon (84.0 mg). The reaction mixture is degassed twice and is then stirred at ambient temperature under a hydrogen atmosphere (1 bar) for 24 hours. After 24 hours, more 10% palladium-on-carbon (42.0 mg) is added. The reaction mixture is degassed again and is then held under a hydrogen atmosphere for 24 hours. The mixture is filtered over Celite, and the solid is washed with methanol and with chloroform. After evaporating off the solvents and purifying the residue by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:36]2[N:40](COCC[Si](C)(C)C)[N:39]=[CH:38][CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1COCC1.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.CCO>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:36]2[NH:40][N:39]=[CH:38][CH:37]=2)[CH2:23]1
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
A suspension of (R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.225 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (146 mg, 0.45 mmol), Pd(PPh3)2Cl2 (17.34 mg, 0.025 mmol) and Na2CO3 (119 mg, 1.123 mmol) in a mixture of water (272 μL), DME (953 μL) and EtOH (136 μL) was subjected to MW irradiation at 125° C. for 20 min. The RM was diluted with THF (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 94 mg, 0.135 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 40% to 100% EtOAc) to yield the title compound as a yellow oil. UPLC-MS (Condition 1) tR=3.28 min, m/z=563.2 [M+H]+, m/z=561.2 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].[C:10](=O)(OC)OC>>[CH3:10][O:7][C:6]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: COC(=O)OC
Reactant: Cc1cc(O)cc(O)c1
Product: COc1cc(C)cc(O)c1
Yield: 98 %

Procedure:
The reaction is carried out as described in Example 1, with 22.8 parts of 5-methylresorcinol and 9 parts of dimethyl carbonate. 9 parts (98% of theory) of 5-methylresorcinol monomethyl ether of boiling point 63°-65° C./0.4 mbar are obtained. The conversion is 36 percent.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[F:21][C:3]1[C:2]([N:32]2[CH2:33][CH2:34][N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:30][CH2:31]2)=[CH:20][C:6]2=[N:7][C:8]3[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Solvent: c1ccncc1
Product: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(Cc5ccccc5)CC4)cc3nc21
Yield: 48.1 %

Procedure:
7-Fluoro-8-[4-benzylpiperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 2 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 4.6 g of N-benzylpiperazine in 20 cm3 of pyridine. After recrystallizing twice from 25 cm3 of dimethylformamide on each occasion, 1.4 g of 7-fluoro-8-[4-benzylpiperazin-1-yl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid were obtained in the form of a yellow solid melting at about 311° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:34][CH:35]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Product: CN1CCN(Cc2ccc(Nc3nc4cccc(-c5cccc(S(C)(=O)=O)c5)n4n3)cc2)CC1
Yield: 44.4 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (125 mg, 0.43 mmol) and 1-(4-bromobenzyl)-4-methylpiperzine (129 mg, 0.48 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine (91 mg, 44%) as an off-white powder following purification on a 4 g Isco silica gel column using methanol in dichloromethane (0-20%) as eluent. MP=232-234° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.62 (br s, 1H), 8.78 (s, 1H), 8.36 (d, J=7.50 Hz, 1H), 8.11 (d, J=7.50 Hz, 1H), 7.87 (t, J=17.1 Hz, 8.5 Hz, 1H), 7.70 (m, 1H), 7.62 (m, 3H), 7.35 (d, J=7.5 Hz, 1H), 7.16 (d, 9.63 Hz, 2H), 3.37-3.30 (m, 5H), 2.31 (br s, 8H), 2.15 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[F:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.[H+].[F-].[K+].[Cl-].[NH4+]>O1CCCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:42]3[CH:43]=[N:44][C:39]([F:38])=[CH:40][CH:41]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OB(O)c1ccc(F)nc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 19.8 %

Procedure:
A solution of the above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 (200 mg), 6-fluoropyridine-3-boronic acid 58 (117 mg), tri-tert-butylphosphine•tetrafluoroboric acid adduct (24 mg), potassium fluoride (80 mg) and tris(dibenzylideneacetone) dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 2 days under argon atmosphere. Added thereto was a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-70:30) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4 ml), and added thereto was 2N sodium hydroxide (2 ml). The mixture was stirred at room temperature for one hour. The mixture was made acidic by addition of an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH4).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[S:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:12][C:7]1[S:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:2][CH3:1]
Reactant: CSc1csc(S(N)(=O)=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CSc1cc(S(N)(=O)=O)sc1Br
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.4 %

Procedure:
To a solution of 4-methylsulfanylthiophene-2-sulfonamide (210 mg, 1.00 mmol) in CHCl3 (10 mL) and AcOH (10 mL) is added N-bromosuccinimide (231 mg, 1.30 mmol). The reaction mixture is stirred at room temperature for 7 hr. After 7 hr, the reaction mixture is neutralized with 1 M NaOH and the solution is extracted with EtOAc (200 mL). The organic layer is washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The crude product is chromatographed on silica gel, eluting with Hex:EtOAc (3:1) to afford the title compound (200 mg, 70%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C@@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([OH:11])=O)[CH2:4]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][NH2:42])=[N:39][CH:40]=1>C(Cl)Cl>[F:34][C:35]1[CH:36]=[CH:37][C:38]([NH:41][NH:42][C:9]([C@@H:5]2[CH2:4][C@H:3]([N:2]([CH3:1])[CH3:12])[CH2:7][N:6]2[CH3:8])=[O:11])=[N:39][CH:40]=1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)O)N(C)C1
Reactant: NNc1ccc(F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)[C@H]1C[C@@H](C(=O)NNc2ccc(F)cn2)N(C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
A solution of Intermediate 38a (5.95 g, 34.2 mmol) in DCM (60 mL) was treated with EDCI (7.87 g, 34.2 mmol), HOBt (0.462 g, 41.0 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (4.35g g, 34.2 mmol) and the solution was stirred at RT for 16 hours. The reaction mixture was partitioned between H2O (50 mL) and DCM (40 mL) and the phases were separated. The organic phase was washed with sat. bicarbonate solution and the brine. The volatiles were concentrated in vacuo and the resultant residue was purified by FCC using 0-10% MeOH in DCM to afford the title compound (1.74 g, 20%). LCMS (Method 3): Rt 0.44 min, m/z 282 [MH+].