Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1>CO.CN(C=O)C.CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:20])([CH3:21])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: CC(C)(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reaction time: 64 h

Procedure:
A mixture of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)-2-methylpropanamide A37 (0.067 g, 0.20 mmol) and PtO2 (0.014 g, 0.060 mmol) in MeOH (3.0 mL) and DMF (3.0 mL) was stirred in an atmosphere of H2 for 64 hours. The mixture was diluted with EtOAc, filtered through Celite and the filtrate solvent was removed in vacuo. The residue was purified by column chromatography (Biotage Isolera, 12 g SiO2, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A38 as an off-white solid (0.042 g, 62%). LCMS-D: rt 3.37 min; m/z 338 [M+H]+.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5].[CH3:25][OH:26]>>[CH2:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([O:26][CH3:25])=[CH:21][CH:22]=2)=[C:9]([NH2:24])[N:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CO
Reactant: CCCCOc1nc(N)c2ncn(Cc3ccc(Cl)nc3)c2n1
Agent: [Na]
Product: CCCCOc1nc(N)c2ncn(Cc3ccc(OC)nc3)c2n1
Yield: 50 %

Procedure:
Sodium (415 mg, 18.0 mmol) was added and completely dissolved in methanol (18 ml). Thereafter, 2-butoxy-9-(6-chloro-3-pyridylmethyl)adenine (300 mg, 0.90 mmol) was added thereto, and the resultant was heated under reflux for 24 hours. The reaction solution was concentrated under reduced pressure, water (30 ml) was added to the residue, and the resultant was neutralized with concentrated hydrochloric acid under ice cooling. The precipitated solid was collected by filtration, and crude crystal was purified by silica gel column chromatography (methylene chloride:methanol=50:1) to obtain 148 mg of the title compound (yield: 50%).
Reaction SMILES: [N:1]([CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[C:2]=[O:3].[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[OH:32]>N1C=CC=CC=1>[OH:32][C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[C:17]([NH:16][C:2]([NH:1][CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:3])[CH:18]=2)[N:23]=[N:22][C:21]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1nnc2ccc(N)cc2c1O
Reactant: COC(=O)C(Cc1ccccc1)N=C=O
Solvent: c1ccncc1
Product: CCOC(=O)c1nnc2ccc(NC(=O)NC(Cc3ccccc3)C(=O)OC)cc2c1O
Reaction time: 8 h

Procedure:
1-Isocyanato-1-methoxycarbonyl-2-phenylethane (1.2 g.) was added to a stirred solution of ethyl 6-amino-4-hydroxycinnolin-3-yl carboxylate (1.17 g.) in pyridine (20 ml.). The mixture was stirred overnight and the solid which separated was washed successively with pyridine (10 ml.) and ether (100 ml.). The solid was dissolved in boiling ethanol (1 l.), and the solution was filtered whilst hot. The filtrate was evaporated to approximately 300 ml. After standing at 0° C. overnight, the mixture was filtered and the solid residue washed successively with ethanol (50 ml.) and ether (100 ml.) to give ethyl 4-hydroxy-6-[3-(α-methoxycarbonylphenethyl)ureido]cinnolin-3-yl carboxylate, m.p. 242°-243° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][Cl:16])[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:17]=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:12]([CH2:13][CH2:14][CH2:15][Cl:16])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Br)c(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c2nc(Nc3ccc(Cl)cc3Cl)n(CCCCl)c12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-bromo-2-[(3-chloropropyl)amino]-3-{[(2,4-dichlorophenyl)carbamothioyl]amino}benzoate (520 mg, 0.989 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (209 mg, 1.09 mmol) and triethylamine (0.152 mL, 1.09 mmol) in tetrahydrofuran (10 mL) was stirred at 50° C. for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless solid, which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]3[N:14]([C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.Cl[C:47]([O:49][CH3:50])=[O:48]>C1COCC1>[C:19]([C:16]1[N:14]2[N:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:47](=[O:48])[O:49][CH3:50])[CH:3]=3)[CH:11]=[C:12]([N:21]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]2=[N:18][CH:17]=1)#[N:20]
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Nc3ccc(F)c(N)c3)nn3c(C#N)cnc23)cc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Nc1cc(Nc2cc(N(Cc3ccc(OC)cc3)c3ccccn3)c3ncc(C#N)n3n2)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.4 %

Procedure:
A solution of 8B (82 mg, 0.17 mmol) in THF (3 mL) was treated with DIEA (0.039 mL, 0.22 mmol), followed by methyl chloroformate (0.048 mL, 0.62 mmol). The resulting solution was stirred at room temperature for 12 hours and then concentrated to dryness. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, DCM to 20% ethyl acetate/DCM, 24 g column, 40 min. gradient) to afford 8C (15 mg, 16.3%). HPLC: Rt=3.98 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=539.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH3:12].CCN(CC)CC.[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].N#N>C1(C)C=CC=CC=1.O.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>[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[C:23][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH3:12]
Reactant: CNc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 70 °C
Yield: 88.8 %

Procedure:
To a solution of (2-bromo-4-nitro-phenyl)-methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) were added Et3N (19.7 g, 195 mmol), Pd(PPh3)2Cl2 (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g, 195 mmol) successively under N2 protection. The mixture was heated at 70° C. for 3 hours and then cooled down to room temperature. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine (20.1 g, 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=2.4 Hz, 1H), 8.08 (dd, 0.1=2.8, 9.2 Hz, 1H), 6.50 (d, J=9.2 Hz, 1H), 5.30 (brs, 1H), 3.00 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[CH3:13]CN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CO>[Br:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(CCBr)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
Commercially available 4-bromoethylbenzoic acid (997.9 mg) was dissolved in methanol (30 ml). After the addition of WSCI hydrochloride (1.2527 g) and HOBt (598.5 mg), the solution was stirred for 24 hours at 60° C. After the reaction, the solvent was removed by distillation. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, 1 mol/l aqueous solution of sodium hydroxide, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified by silica gel column chromatography to obtain the title compound (829.5 mg) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4]=[CH:5][CH:6]=[CH2:7].[CH3:9][C:10]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([CH:26]=[N:27][OH:28])=[CH:24][CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>>[CH3:1][O:2][C:3](=[O:8])[CH:4]=[CH:5][CH:6]1[O:28][N:27]=[C:26]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([CH3:9])[CH:19]=3)=[CH:30][CH:29]=2)[CH2:7]1
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Reactant: C=CC=CC(=O)OC
Product: COC(=O)C=CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 73 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using penta-2,4-dienoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-acrylic acid methyl ester (2.57 g, 73%) as a white powder. MS found: (M+H)+=403.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Br)=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH2:16]([S:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=3[O:2][CH3:1])=[CH:29][CH:30]=[N:31]2)=[CH:26][N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Brc1ccnc2cc(SCc3ccccc3)ncc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1-c1ccnc2cc(SCc3ccccc3)ncc12
Temperature: 110 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
A screw capped vial was charged with 2-methoxy-4-(trifluoromethyl)phenyl boronic acid (0.096 g, 0.438 mmol), 7-(benzylthio)-4-bromo-1,6-naphthyridine (0.145 g, 0.438 mmol), and potassium phosphate tribasic (0.279 ml, 1.313 mmol). Dioxane (1.756 ml) and water (0.585 ml) were added and the vial was purged with argon, followed by addition of Pd(AmPhos)2Cl2 (0.019 g, 0.026 mmol). The vial was capped and heated to 110° C. After 3 hours, the reaction was cooled to room temperature, diluted with water (30 mL), and washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel MPLC chromatography (40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were collected and the solvent was removed under reduced pressure to provide 0.129 g of 7-(benzylthio)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1,6-naphthyridine as an off white solid. m/z (ESI) 427.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(OCC)C.O>[CH2:1]([O:8][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl alcohol (19.7 g, 182.3 mmol) was slowly added to a suspension of sodium hydride (15.9 g 55% in mineral oil, 364.5 mmol) in anhydrous diethyl ether (116 mL) and the resulting mixture was stirred at room temperature for 1 hour. It was then diluted with some diethyl ether to ensure good stirring. Ethyl 4-chloro-3-oxobutanoate (12.3 mL, 91.1 mmol) was then slowly added and the mixture was stirred at room temperature overnight. The reaction mixture was cooled with an ice bath and then diluted with cold water and diethyl ether pH was adjusted to 4 with 5 N HCl and it was extracted three times with diethyl ether containing some ethyl acetate. The combined organic phases were dried over Na2SO4 and it was concentrated to dryness, thus obtaining the title compound with quantitative yield as a crude product that was used as such in the following step.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38]>CO.C(Cl)Cl>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[N:9][CH:10]=1
Reactant: NCCOCCO
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: OCCOCCNc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Temperature: 25 °C
Yield: 35 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (210 mg, 0.504 mmol) obtained in Example 54 and 2-(2-aminoethoxy)ethanol (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. Water was added to the residue thus obtained, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the 30% methanol/methylene chloride eluate was concentrated under reduced pressure to give the title compound (85 mg, 0.175 mmol, 35%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:4]=[C:3]1[C:29]([O:31]CC)=[O:30].O.[OH-].[Li+]>CS(C)=O.CO.O.C(#N)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:4]=[C:3]1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccc(C(F)(F)F)cc2)c2cccnc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2-c2ccc(C(F)(F)F)cc2)c2cccnc2c1=O
Reaction time: 15 h
Yield: 43.2 %

Procedure:
To a solution of ethyl 4-oxo-1-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylate (37) (11 mg, 0.024 mmol) in dimethyl sulfoxide (1 mL) and methanol (5 mL) was added the solid lithium hydroxide monohydrate (51.0 mg, 1.22 mmol) at room temperature under a nitrogen atmosphere. It gave a clear solution within 30 minutes and this light yellow solution was stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, the mixture was diluted with water and the methanol was removed under vacuum. The basic aqueous layer was diluted with water and then neutralized with 1.0N HCl. The resulting acid was extracted with ethyl acetate (2×30 mL) and the combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave a brown residue which was dissolved in acetonitrile and water. It was frozen and then lyophilized under high vacuum to obtain 4-oxo-1-((4′-(trifluoromethyl)biphenyl-2-yl)methyl)-1,4-dihydro-1,5-naphthyridine-3-carboxylic acid (38) (4.4 mg, 42.6% yield) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Reactant: BrCc1ccccn1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)oc1C
Yield: 27 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(bromomethyl)pyridine hydrobromide. Yield 27%. 1H NMR (500 MHz, dMSO): δ 1.98 (s, 3H), 2.28 (s, 3H), 4.37 (s, 2H), 6.76 (s, 1H), 7.3 (m, 1H), 7.45 (d, 1H), 7.75 (t, 1H), 8.6 (s, 1H). MS (M+H, 287).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][CH3:19])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7]2=[O:17].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:66][N:67]1[CH2:73][CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[O:10][C:11]2[C:6]([C:7](=[O:17])[CH:8]=1)=[CH:5][C:4]([O:18][CH3:19])=[CH:3][C:2]=2[N:70]1[CH2:71][CH2:72][CH2:73][N:67]([CH3:66])[CH2:68][CH2:69]1)=[O:13])[CH3:16]
Reactant: CN1CCCNCC1
Reactant: CCOC(=O)c1cc(=O)c2cc(OC)cc(Br)c2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(=O)c2cc(OC)cc(N3CCCN(C)CC3)c2o1
Temperature: 80 °C
Yield: 60 %

Procedure:
Into a 250 mL 3 neck round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5 g (4.59 mmol, 1.0 equiv.) of 8-Bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (Reference Example 2c), 84 mg (0.092 mmol, 0.02 equiv.) of tris dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.) of racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl and 2 g of 4 A molecular sieves. To this in suspension is added 150 mL of dry toluene. To the stirred suspension is then added 628 mg, 684 μL, (5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05 g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then heated to 80° C. for 3 days. At the end of this time completion was monitored by LC/MS analysis of an aliquot. When the reaction was determined to be complete it was cooled to room temperature then filtered through a plug of diatomaceous earth with toluene washing to remove solid by products. Purification by flash chromatography, using a gradient of 5 to 20% methanol in methylene chloride as eluent, yielded 1.0 g, (60%) of the desired product.
Reaction SMILES: N1([C:6](=[S:31])[O:7][CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])C=CN=C1.CO.[O:34]1CCOC[CH2:35]1>C(Cl)(Cl)Cl>[CH3:35][O:34][C:6]([O:7][CH:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[S:31]
Reactant: C1COCCO1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(OC(=S)n1ccnc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=S)OC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
4.3 g. (10mM) of α[(1H-imidazol-1-yl)thioxomethoxy]-benzeneacetic acid, diphenylmethyl ester together with 0.35 g. of methanol in 30 ml. of dioxane and one drop of a 10% sodium imidazole-dioxane solution, are held at 40° for 5 hours. After drawing off the solvent, the oily residue is dissolved in chloroform and washed three times, each time with 30 ml. of water. After drawing off the solvent, 2.3 g. of α-[(methoxycarbonothioyl)oxy] benzeneacetic acid, diphenylmethyl ester are obtained from the dried chloroform solution in the form of a pale yellow oil which crystallizes after 24 hours. Recrystallization from cyclohexane/petroleum ether yields 1.6 g. of white crystals, m.p. 74°.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:43])[NH:33][CH2:34][CH:35]([NH:42][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NC(CNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (120 mg, 0.32 mmol) and (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (305 mg, 1.29 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 20:1) to afford crude (2-{4-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester (Yield 44 mg).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].C[O:16][C:17]1[C:21](OC)=[N:20][S:19](=[O:24])[N:18]=1.[OH-].[Na+].Cl>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:21]2[C:17]([OH:16])=[N:18][S:19](=[O:24])[N:20]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COC1=NS(=O)N=C1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (4.15 g; 17.9 mmoles) in 50 ml of methanol was added dropwise over a 30 minute period to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.91 g; 17.9 mmoles) in 350 ml of methanol that had been cooled in an ice-water bath. The reaction mixture was treated with a solution of sodium hydroxide pellets (3.58 g; 89.5 mmoles) in methanol. After stirring overnight at ambient temperature, the mixture was neutralized with 14.9 ml (89.5 mmoles) of aqueous 6.0N HCl and after 10 minutes was evaporated under reduced pressure. The solid residue was triturated for 2 hours with 70 ml of water at ambient temperature and filtered to give product. Recrystallization from water yielded the title compound, mp 148°-151°.