Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:11]([C@@H:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH3:10])=[O:12]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of tert-butyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (300 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (64.4 mL) and a solution of sulfur trioxide pyridine complex (80.7 g) in dimethyl sulfoxide (300 mL) were successively added. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr, 1 mol/L aqueous citric acid solution (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a white powder (yield: 24.3 g, 85%).
Reaction SMILES: [OH-].[Na+:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:19][CH:20]([CH2:24][S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH2:19][CH:20]([CH2:24][S:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:21]([O-:23])=[O:22])(=[O:17])=[O:18])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1.[Na+:2]
Reactant: O=C(O)C(CSc1ccccc1)CS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(CSc1ccccc1)CS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Sodium hydroxide (1 M, 48 mL) was added to a solution in methanol (75 mL) of 3-[(4′-chloro[1,1′-biphenyl]-4-yl)sulfonyl]-2(RS)-[(phenylsulfanyl)-methyl]propanoic acid (20 g, obtained as described in Example 1). Charcoal was added and the mixture was filtered. Concentration of the filtrate to 1/3 of the original volume furnished a shiny precipitate, which was collected by filtration and sequentially washed with cold water, ethanol and diethyl ether. Drying to a constant weight provided 19 g of the title compound as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4].[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([CH3:21])[NH:16]1>>[CH3:14][C@H:15]1[NH:16][C@@H:17]([CH3:21])[CH2:18][N:19]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=2[CH3:13])=[O:4])[CH2:20]1
Reactant: Cc1c(F)cccc1NC(=O)CCl
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1

Procedure:
The subtitle compound was prepared from the product of Example 36 step (i) (14.5 g) and cis-2,6-dimethylpiperazine (9.0 g) by the method of Example 58 step (i) as cream solid. Yield: 11.48 g
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5]([CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C:28]4[C:23](=[C:24]([O:29][CH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21]3)[CH:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6]>O.CC(O)C>[CH3:36][S:33]([CH2:32][CH2:31][CH2:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[CH:22]=[CH:21][N:20]2[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][CH:10]2[CH2:11][CH2:12][CH:7]([C:5]([O-:6])=[O:4])[CH2:8][CH2:9]2)[N:19]=1)(=[O:35])=[O:34].[Na+:2]
Reactant: COC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)[O-])CC2)n1
Temperature: 82 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
A 50% (w/w) aqueous solution of NaOH in H2O (198.95 g) was added to 4-{4-[4-(3-Methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid methyl ester (830.0 g) in IPA (7.5 L) and the mixture allowed to stir at 82° C. for 1 h and then stirred overnight at room temperature. The mixture was then filtered, and the solid rinsed with IPA, and dried in vacuo at 60° C. for 3 days to yield sodium 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylate (96.9%).
Reaction SMILES: NCCCCN.[S:7](S(Cl)(=O)=O)([C:10]1[CH:26]=[CH:25][C:13]([N:14]=[N:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[NH2:31][CH:32]([CH3:36])[CH:33]([NH2:35])[CH3:34]>C(#N)C>[S:7]([CH2:34][CH:33]([NH2:35])[CH:32]([NH2:31])[CH3:36])([C:10]1[CH:26]=[CH:25][C:13]([N:14]=[N:15][C:16]2[CH:24]=[CH:23][C:19]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CC(N)C(C)N
Reactant: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)S(=O)(=O)Cl)cc2)cc1
Agent: NCCCCN
Solvent: CC#N
Product: CC(N)C(N)CS(=O)(=O)c1ccc(N=Nc2ccc(N(C)C)cc2)cc1

Procedure:
1,4-diaminobutane was dissolved in acetonitrile. Dabsyl sulfonyl chloride was slurred in acetonitrile. The Dabsyl sulfonyl chloride slurry was added to the diaminobutane solution and reacted for 15 minutes. The reaction was quenched with water, diluted to 40% water and filtered. The filtrate was diluted to 60% water and re-filtered. The resulting filter cake was dried under high vacuum. The dry filter cake was dissolved in acetonitrile and dried in a rotoevaporator. The dried material was subject to further characterization. Calculated mass 375.49. Observed m+1 376.3. Elemental analysis—Calculated: % C, 57.57; % H, 6.71; % N, 18.65. Observed: % C, 57.48; % H, 6.35; % N, 18.33.
Reaction SMILES: C(C1NC(=S)NC=1C(=O)C1C=CN=CC=1)CC.[CH2:18]([C:20]1[NH:21][C:22](=[S:36])[NH:23][C:24]=1[C:25](=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]2OCO[C:27]=12)C>>[CH3:18][C:20]1[NH:21][C:22](=[S:36])[NH:23][C:24]=1[C:25](=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCc1[nH]c(=S)[nH]c1C(=O)c1cccc2c1OCO2
Agent: CCCc1[nH]c(=S)[nH]c1C(=O)c1ccncc1
Product: Cc1[nH]c(=S)[nH]c1C(=O)c1ccccc1

Procedure:
In a like manner, but substituting 2-amino-1-(2,3-methylenedioxyphenyl)-1,3-pentadione; 2-amino-4-methyl-1-[2-(1H-pyrryl)]-1,3-pentadione; or 2-amino-1-(4-pyridyl)-1,3-hexadione for 2-amino-1-phenyl-1-3-butadione in the above example, results in 1,3-dihydro-4-ethyl-5-(2,3-methylenedioxybenzoyl)-2H-imidazole-2-thione; 1,3-dihydro-4-isopropyl-5-[2-(1H-pyrrolyl]-2H-imidazole-2-thione; or 1,3-dihydro-4-propyl-5-isonicotinoyl-2H-imidazole-2-thione, respectively.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][F:14])[CH:12]=1)[CH2:8][OH:9])=[N+:2]=[N-:3].[C:15](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1)[C:16]1[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=1.CN(C=O)C>N1C=CC=CC=1>[CH3:29][O:28][C:27]1[CH:26]=[CH:25][C:24]([C:15]([O:9][CH2:8][C:7]2[CH:6]=[C:5]([CH:12]=[C:11]([CH2:13][F:14])[CH:10]=2)[CH2:4][N:1]=[N+:2]=[N-:3])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]2[CH:23]=[CH:22][C:19]([O:20][CH3:21])=[CH:18][CH:17]=2)=[CH:31][CH:30]=1
Reactant: [N-]=[N+]=NCc1cc(CO)cc(CF)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1ccc(C(OCc2cc(CF)cc(CN=[N+]=[N-])c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
From a reaction system containing 3-Azidomethyl-5-fluoromethylbenzylalcohol (36) (142 mg, 0.73 mmol), the air was evacuated and then Ar was charged therein. To this were added DMTrCl (323 mg, 0.95 mmol), DMF (2.0 mL), and pyridine (2.0 mL), and stirred for 22 hours at a room temperature. TLC was used to confirm the progress of the reaction. Then, the solvent was removed in vacuo. The residue was subjected to extraction with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=20:1 to 5:1) to isolate
Reaction SMILES: [OH:1][CH:2]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]3[N:34]=[CH:35][N:36]=[C:10]23)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl>CS(C)=O>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]4[N:34]=[CH:35][N:36]=[C:10]34)[CH2:7][CH2:8]2)=[O:1])=[CH:42][CH:41]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(O)c3ccc(OC)cc3)CC2)c2ncnn12
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](C(=O)c3ccc(OC)cc3)CC2)c2ncnn12
Reaction time: 2 h

Procedure:
To a mixture of 4′-[(4-{trans-4-[hydroxy(4-methoxyphenyl)methyl]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (2.2 g), triethylamine (2.6 mL) and dimethyl sulfoxide (10 mL) was added a solution (10 mL) of sulfur trioxide-pyridine complex (1.8 g) in dimethyl sulfoxide at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.7 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:13]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:12]2=[O:30])=[C:4]([F:32])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:39]1[S:44](=[O:46])(=[O:45])[O:43][CH2:42][CH2:41][CH2:40]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:31])[CH2:9][CH2:10][CH:11]2[C:12](=[O:30])[N:13]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:42][CH2:41][CH2:40][CH2:39][S:44]([OH:46])(=[O:45])=[O:43])=[CH:27][CH:28]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[C:4]([F:32])[CH:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3F)C(=O)N2c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3F)C(=O)N2c2ccc(OCCCCS(=O)(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11) were dissolved in 4 ml of absolute dimethylformamide. 210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under oil pump vacuum, taken up in dichloromethane and washed 1× with water. The aqueous phase was acidified with 2N hydrochloric acid and extracted 2× with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was chromatographed on a 10 g SiO2 cartridge (dichloromethane/methanol=5/1). The product (72 mg) was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]([C:23]#[N:24])([CH3:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:20]#[N:21])([CH3:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1.CO>[CH3:18][C:17]([CH3:19])([CH2:20][NH2:21])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][C:2]([CH3:1])([CH3:22])[CH2:23][NH2:24])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(C#N)Cc1ccc(-c2ccc(CC(C)(C)C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(CN)Cc1ccc(-c2ccc(CC(C)(C)CN)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 1-liter flask, equipped as described in Example 2(b), was put 6.54 g of 4,4'-bis(2-methyl-2-cyanopropyl)biphenyl and 400 ml of reagent grade toluene which had been passed through acid alumina under nitrogen directly into the reaction vessel. With stirring at room temperature, 71 ml of a 25% solution of diisobutylaluminum hydride in toluene was added in 30 minutes. The mixture was then refluxed for 17 hrs 40 min. After the mixture had been cooled in an ice-water bath, a solution of 5 ml of water in 22 ml of methanol was added dropwise with stirring in 1 hr. This was followed by the dropwise addition of a solution of 20 ml of water in 40 ml of methanol in 1 hr. The mixture was stirred for 1 hr while being cooled in the ice bath and for 1 hr at room temperature. It then stood at room temperature for one day. The mixture was filtered under nitrogen, the solid was washed thoroughly with toluene on the filter, and the combined filtrate and rinsings were distilled on the water pump. The resulting solid, after drying in vacuo, weighed 5.5 g and melted at 97° to 99°. Sublimation at 185° to 200°/0.10 mm gave 4,4'-bis(2,2-dimethyl-3-aminopropyl)biphenyl as a colorless crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([I:17])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)C>O>[I:17][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:7][C:2]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:3][CH:4]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)ncc2I)cn1
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2nc(N3CCCCC3)ncc2I)cn1
Temperature: 140 °C
Yield: 92.2 %

Procedure:
A glass microwave reaction vessel was charged with 2-chloro-5-iodo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (181 mg, 0.499 mmol), piperidine (0.099 mL, 0.998 mmol) and ethanol (2 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as orange oil. The crude product was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 5-iodo-N-(6-methoxypyridin-3-yl)-2-(piperidin-1-yl)pyrimidin-4-amine (189 mg, 0.460 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ 8.24 (s, 1H); 8.17 (s, 1H); 7.79 (dd, J=8.84, 2.56 Hz, 1H); 6.75 (d, J=8.77 Hz, 1H); 6.63 (s, 1H); 3.94 (s, 3H); 3.57-3.73 (m, 4H); 1.47-1.69 (m, J=4.68 Hz, 6H). m/z (ESI, +ve ion) 412.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: C1CSCCN1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCSCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in thiomorpholine (1 ml) was heated at 110° C. for 36 h in a sealed tube. The reaction was concentrated under vacuum, the residue triturated with water and purified by preparative HPLC. The solvent was evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-thiomorpholin-4-ylisonicotinamide (25 mg). NMR; δH [2H6]—DMSO 10.30,(1H, s), 8.62,(1H, t), 8.25,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.64,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.22,(1H, s), 7.03,(1H, d), 3.96,(4H, m), 3.16,(2H, t), 2.62,(4H, m), 2.20,(3H, s), 1.05,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.57 min, MH+487.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1.[N:16]1[O:20][N:19]=[C:18]2[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:17]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:4]([CH2:5][N:6]2[CH:10]=[N:9][CH:8]=[N:7]2)=[CH:3][C:2]=1[C:22]1[CH:23]=[CH:24][C:17]2[C:18]([CH:21]=1)=[N:19][O:20][N:16]=2
Reactant: OB(O)c1ccc2nonc2c1
Reactant: COc1ccc(Cn2cncn2)cc1Br
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cncn2)cc1-c1ccc2nonc2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A suspension of 1-(3-Bromo-4-methoxy-benzyl)-1H-[1,2,4]triazole (I-104, 402 mg, 1.50 mmol), benzo[1,2,5]oxadiazole-5-boronic acid (I-105, 246 mg, 1.50 mmol), palladium(0) bis(dibenzylideneacetone) (43 mg, 0.075 mmol), and triphenyl phosphine (39.3 mg, 0.15 mmol) in dimethylformamide (15 mL) and 1 M aqueous cesium carbonate (4.5 mL, 4.5 mmol) was heated to 85° C. with stirring overnight. The solvent was removed under vacuum and the residue suspended in ethyl acetate (15 mL). The organic suspension was washed with water (3×15 mL) and brine, dried over sodium sulfate, decolorized over activated carbon, filtered, and the solvent removed under vacuum to give crude material. The residue was purified by recyrstalization from dichloromethane (2 mL) and hexanes (10 mL) to give P-481 (180 mg, 39% yield). 1H NMR (400 MHz, CDCl3) δ ppm 3.88 (s, 4H) 5.51 (s, 2H) 7.06 (d, J=7.8 Hz, 1H) 7.41-7.54 (m, 3H) 7.59 (d, J=9.3 Hz, 1H) 7.71-8.03 (m, 3H) 8.25 (s, 1H) 9.34 (br. s., 1H), LCMS=95.7% purity.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].ClCCl>>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained from step A was dissolved in 50% trifluoroacetic acid/dichloromethane and the mixture was stirred at room temperature for 30 minutes. The excess acid was removed under reduced pressure and the residue was triturated with ether to give a white powder, 1.51 g, 90% for two steps. MS(ES) (M+H)+=193.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:41])[N:29]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:30]=[CH:31][C:32]=2I)=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:10]=12.CC(O)C.[CH3:46][NH2:47]>O>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([C:27]2[C:28](=[O:41])[N:29]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:30]=[CH:31][C:32]=2[NH:47][CH3:46])=[O:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:17][C:10]=12
Reactant: CN
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Solvent: O
Solvent: CC(C)O
Product: CNc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)c(F)c1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
To a 2 mL microwave tube with stirbar was added 1-(4-fluoro-phenyl)-4-iodo-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [3-fluoro-4-(2-phenyl-furo[3,2-b]pyridin-7-yloxy)-phenyl]-amide (45.00 mg; 0.07 mmol; 1.00 eq.) and iPrOH (1.00 ml) and the vial was sealed and flushed with N2. To the reaction mixture was added a solution of methylamine (0.05 ml; 0.54 mmol; 8.00 eq.) 40% in water. The reaction mixture was heated to 100° C. in a microwave reactor for 1 h. The reaction mixture was cooled to room temperature and the white precipitate was filtered, washed methanol, and dried under vacuo to afford the title compound as a white solid (19 mg, 49%). (HPLC (method F): 94%, RT: 4.96 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.46 (d, J=5.1, 1H), 8.36 (d, J=5.6, 1H), 8.02 (dd, J=13.3, 2.4, 1H), 7.96-7.89 (m, 2H), 7.75 (d, J=7.8, 1H), 7.71 (s, 1H), 7.56-7.44 (m, 6H), 7.42-7.32 (m, 3H), 6.74 (d, J=5.0, 1H), 6.27 (d, J=7.9, 1H), 3.03 (d, J=5.1, 3H); MS (m/z) 565 [M+H]+, RT: 4.3 min.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(C)(C)C>C(C(O)=O)(F)(F)F.C1(C)C=CC=CC=1>[Cl:35][C:25]1[C:24]2[C:29](=[CH:30][C:21]([S:18]([N:8]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[CH2:7][C:6]([OH:36])=[O:5])(=[O:19])=[O:20])=[CH:22][CH:23]=2)[C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[N:27][CH:26]=1
Reactant: COc1ccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 18.9 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine t-butyl ester (65 mg, 0.122 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 40 min. The mixture was diluted with PhMe, concentrated in vacuo, and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (83:15:3) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine (11 mg, 0.023 mmol) as a white solid.
Reaction SMILES: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].Cl.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 127 mg (4.71 mmol) of aluminum (foil) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for 30 min. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 763 mg (4.10 mmol) of diphenylphosphine in 87% yield.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.O.[NH2:28][NH2:29]>CN(C=O)C>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:29][N:28]=1
Reactant: O=C(Cc1cccs1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccs3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 76.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2-thienyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (30 mg, 0.08 mmol, prepared in Synthetic Example 17) in DMF (1.5 ml) was added hydrazine monohydrate (80%, 30 μl, 0.75 mmol, 9.4 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(2-thienylmethyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (22 mg, 72%).