Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[CH:10][NH:9][C:8]=2[CH:12]=1)([O-])=O.[ClH:13]>[Rh]>[ClH:13].[ClH:13].[N:11]1[C:7]2[CH2:6][CH2:5][CH:4]([NH2:1])[CH2:12][C:8]=2[NH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Rh]
Agent: Cl
Product: NC1CCc2nc[nH]c2C1
Temperature: 80 °C

Procedure:
Add 5% Rh/C (5.215 g) to a 500 ml glass Parr bottle. Purge the bottle with nitrogen and wet the 5% Rh/C with 3 N HCl (50 ml). Then add 6-nitro-1H-benzoimidazole (10.354 g, 0.0635 mol) and 3N HCl (100 ml) to the purged bottle. Seal the Parr bottle and purge the reaction vessel with nitrogen (3×) and with hydrogen (3×). Then pressurize the reaction mixture with hydrogen (60 psig), seal the vessel but add hydrogen as needed to maintain 60 psig, agitate the reaction and heat to 80° C. Continue the reaction for 24 hours then turn off the heat and allow the reaction mixture to cool to ambient temperature. Vent the excess hydrogen from the vessel, purge the vessel with nitrogen (3×) and filter the reaction mixture to remove the 5% Rh/C catalyst. The filtrate is concentrated to dryness on a rotary evaporator and then under high vacuum. Dissolve the solid residue in 20 mL of methanol, heat to approximately 60° C. and add additional methanol (approximately up to 10 mL or as needed) to dissolve the residue completely. Cool the solution to room temperature and add ether (40 mL). A white solid separates, filter and dry under high vacuum to give the product (8.gm).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([C:20](=[O:30])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[C:28]#[N:29])[C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].C1C[O:34]CC1.CO.[Li+].[OH-].CC(O)=O>[Cl-].[Na+].O>[NH2:29][C:28]([C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:20]([C:11]1[C:12]2[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=2[N:9]2[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=12)=[O:30])=[O:34]
Reactant: CC(C(=O)[O-])C1CCn2c1c(C(=O)c1ccc(Cl)cc1C#N)c1c(Br)cc(F)cc12
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1cc(Cl)ccc1C(=O)c1c2n(c3cc(F)cc(Br)c13)CCC2CC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the compound of Step 1 (30 mg) in a 3/1 mixture of THF/MeOH (3 mL) was added 1N LiOH (1 mL, aqueous solution). The reaction mixture was stirred at r.t. for 16 h and AcOH (0.5 mL) and brine (5 mL) were added. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was swished in EtOAc to give 18 mg of the title compound as a white solid.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39]>CC#N>[Cl:43][C:42]([Cl:45])([Cl:44])[CH2:41][O:40][C:38]([N:8]1[CH2:9][CH:10]([N:21]([C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)[CH3:36])[CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12]1)=[O:39]
Reactant: COc1ccc(C(=O)N(C)[C@@H]2CN(Cc3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)OCC(Cl)(Cl)Cl)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a stirred solution of rac-N-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (1.10 g, 2.05 mmol) in CH3CN (15 ml) at RT was added 2,2,2-trichloroethyl chloroformate (0.56 ml, 4.10 mmol) in two portions (within 30 min.). The reaction mixture was stirred an additional 2 hours, concentrated under vacuo, and then filtrated on silica gel (CH2Cl2 as solvent) to afford the intermediate rac-(3R,4S)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carboxylic acid 2,2,2-trichloro-ethyl ester. This intermediate was then dissolved in AcOH (10 ml) and zinc powder (300 mg) was added in 4 portions over 3 hours. The reaction mixture was then filtered on celite, concentrated under vacuo, taken up in CH2Cl2, and washed with aq. NaHCO3. The organic phases were dried over Na2SO4, and purification by flash chromatography (SiO2, CH2Cl2/MeOH, 90:10) yielded 0.45 g (50%) of the title product as colorless oil. ES-MS m/e: 447.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]Br)[CH3:27]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:26][O:28][CH2:29][CH2:30][O:31][CH2:32][CH3:33])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: CCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOCCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (470 mg, 1.7 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (350 mg, 2.5 mmol) and 1-ethoxy-2-(2-bromoethoxy)ethane (505 mg, 2.6 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (147 mg, yield 22%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12.O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C[CH2:39][N:40](CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[C-]#N.[Zn+2]>[C:39]([C:2]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:3]=1[CH2:4][CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]12)#[N:40]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(Br)cccc3C21
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)CC2Cc3c(C#N)cccc3C21
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 5-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate F9 (1.5 g, 4.25 mmol) in DMF (30 mL) was added Pd(PPh3)4 (751 mg, 0.63 mmol) and Zn(CN)2 (1.00 g, 8.51 mmol). The solution was stirred at 100° C. for 16 h. After cooling, water was added and the solution was extracted with ethyl acetate. The organic layer was washed with brine three times, dried and concentrated. The crude material was dissolved in 50 ml acetonitrile in which were added Boc2O (5.5 g, 25.2 mmol), NEt3 (6 ml), and DMAP (520 mg, 4.26 mmol). The resulting mixture was stirred for 16 h. The dark brown solution was concentrated under vacuum, and the residue was dissolved in ethyl acetate. The organic layer was washed twice with HCl (1N), brine, dried and concentrated under vacuum. The residue was purified by flash chromatography eluting with ethyl acetate and cyclohexane (10/90 to 30/70 over 30 min.) to give 880 mg of the desired compound F11 as a beige gum (69%). LCMS (method E): 0.87 min; ES+: 619 [2M+Na].
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([O:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[C:9](=[N+]=[N-])[C:10](=[O:12])[CH3:11])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)=[O:23].CC1(C)OO1>CC(C)=O>[C:1]([O:6][CH2:7][CH:8]([O:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[C:9](=[O:23])[C:10](=[O:12])[CH3:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC(OC(=O)CCC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)=O
Agent: CC1(C)OO1
Product: CCCC(=O)OCC(OC(=O)CCC)C(=O)C(C)=O
Reaction time: 1 h

Procedure:
To a solution of methyl diazo dibutyrate 8 (23 mg, 0.081 mmol) in acetone (1 mL) was added dimethyldioxirane acetone solution (2.5 mL, ca. 0.07-0.09 M). The resulting mixture was stirred for 1 h and solvent and excess reagents were removed under reduced pressure to obtain 20 as bright yellow oil (yield=22 mg, quantitative).
Reaction SMILES: Cl.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl[CH2:21][CH2:22][C:23]1[N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[C:26]([S:36][CH2:37][CH2:38][CH3:39])=[N:25][CH:24]=1>CCOCC.CN(C)C=O>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][N:27]1[C:23]([CH2:22][CH2:21][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[CH:24][N:25]=[C:26]1[S:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCSc1ncc(CCCl)n1Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCSc1ncc(CCC(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
The above hydrochloride was converted to the free base in ether with 5% sodium bicarbonate solution. To a suspension of sodium hydride (57 mg, 2.38 mmol) in dimethylformamide (3 mL) held at 0° C. under argon was added a solution of diethyl malonate (0.4 g, 2.5 mmol) in dimethylformamide (3 mL). The mixture was stirred at ambient temperature for 0.5 hour or until a clear solution resulted. Then, 5-(2-chloroethyl)-1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazole (0.61 g, 1.85 mmol) in dimethylformamide (5 mL) was added, and the mixture was heated at 95° C.-100° C. for 24 hours. The reaction was partitioned between water and ethyl acetate, and the organic layer was washed with water, dried, concentrated and the residue chromatographed to provide 0.6 q (71%) of diethyl 2-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]ethylmalonate as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:32]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:32][CH2:10][C:9]([C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1)=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1ncc(C)nc1C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cnc(C(=O)CBr)c(C)n1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a chloroform (2.0 mL) solution of 1-(3,5-dimethylpyrazin-2-yl)ethanone (41 mg), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (54 μL) and trimethylsilyl trifluoromethanesulfonate (59 μL) were added, and the resultant was stirred for 1 hour. Then, N-bromosuccinimide (53 mg) was added thereto, and the resultant was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→67/33) to obtain the title compound (35 mg) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:14])([F:13])[F:12])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([O:26]CC)=[O:25])[CH:3]=1.C1COCC1.[OH-].[Na+]>O>[Cl:1][C:2]1[N:7]2[C:8]([CH2:15][CH:16]3[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18][CH2:17]3)=[C:9]([C:11]([F:12])([F:13])[F:14])[N:10]=[C:6]2[CH:5]=[C:4]([C:24]([OH:26])=[O:25])[CH:3]=1
Reactant: CCOC(=O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)n2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
Ethyl 5-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylate (62 mg, 0.146 mmol) obtained in step 2 was suspended in a mixed solvent of THF (2.0 mL) and water (2.0 mL), and the suspension was stirred under heat and reflux for 3 hours after adding sodium hydroxide (29 mg, 0.730 mmol). The reaction mixture was allowed to cool to room temperature, and the solvent was then evaporated under reduced pressure. The residue was extracted with water after adding chloroform. Following neutralization with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. After adding a mixed solution of chloroform/methanol=4/1 to the residue, the insoluble matter was removed by filtration. The filtrate solvent was evaporated under reduced pressure to give a crude product of 5-chloro-3-(4,4-difluorocyclohexylmethyl)-2-trifluoromethylimidazo[1,2-a]pyridine-7-carboxylic acid (66 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccnc(N)c1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 150 °C
Yield: 29 %

Procedure:
A mixture of 2,4-diamino-pyridine (1.26 g, 11.5 mmol), copper (I) bromide (82.8 mg, 0.57 mmol), 1,10-phenanthroline monohydrate (114.0 mg, 0.57 mmol) and benzonitrile (13 mL) was heated in a 50 mL 3-necked flask to 150° C. During 41 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (conversion 42%, HPLC method see below). The reaction mixture was then filtered. The resulting clear brown solution was evaporated to dryness and the crude was product purified by silica gel chromatography (hexane/EtOAc 2:8) to yield 7-amino-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (0.72 g, 29%) as a light yellow solid with 99.0% purity (HPLC area-%, HPLC method: X-Bridge C18 column, 150×4.6 mm; mobile phase, A: water/NCMe (95:5), B: NCMe, C: NBu4HSO4 buffer pH 3-4; flow: 1.5 ml/min; gradient from 90/0/10 (A/B/C) to 5/85/10 (A/B/C) within 6 min, isocratic 5/85/10 (A/B/C) for 4 min. Retention time: 0.95 min (2,4-diamino-pyridine), 4.08 min (7-amino-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine)).
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:20][CH2:21][CH2:22][NH2:23].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:23][CH2:22][CH2:21][CH2:20][N:14]1[CH2:13][CH2:12][C:11]2([N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][NH:9][C:10]2=[O:17])[CH2:16][CH2:15]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: NCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Yield: 4 %

Procedure:
1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one (5.00 g, 21.6 mmol, 1.00 equiv), 3-bromopropylamine hydrobromide (4.73 g, 21.6 mmol, 1.00 equiv) and potassium carbonate (2.99 g, 21.6 mmol, 1.00 equiv) were stirred in refluxing dioxane (0 mL) for 24 hours. After removal of the solvent, water (50 mL) was added and the pH was adjusted to 11-12 by addition of 1 N aqueous NaOH. The mixture was extracted with CH2Cl2 (200 mL+3×100 mL) . The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, CHCl3—MeOH—NH3 (2 M in MeOH) 100:20:10 to 100:24:12) to give 250 mg (4%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:19]=2)[CH:14]=1)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1.O1CCCC1.[OH-].[Na+]>O>[CH2:2]([C:1]1[S:43][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:19]=3)[CH:14]=2)=[N:10][N:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)NNC(=O)CCCCCC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(-c3nnc(CCCCCC)s3)ccc2c1
Yield: 45.2 %

Procedure:
In a 50 ml-round-bottomed flask, 1.20 g (2.64 mM) of N-heptanoyl-N'-(6-decyloxy-2-naphthoyl)-hydrazine, 1.20 g (2.97 mM) of Lawesson's reagent and 15 ml of tetrahydrofuran were placed, followed by refluxing for 45 minutes under stirring. After the reaction, the reaction mixture was poured into a solution of 0.95 g of sodium hydroxide in 100 ml of iced water to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and purified by silica gel column chromatography (eluent: toluene). The resultant crystal was recrystallized from a mixture solvent (toluene-methanol) two times and further recrystallized from ethyl acetate and from toluene each once to obtain 0.54 g of 2-hexyl-5-(6-decyloxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 45.2%). ##STR29##
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[N:31]=[C:32]([C:37]4[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][C:38]=4[CH3:47])[S:33][C:34]=3[CH2:35][CH3:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-].Cl>O1CCOCC1.O>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][C:21]=3[C:30]3[N:31]=[C:32]([C:37]4[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][C:38]=4[CH3:47])[S:33][C:34]=3[CH2:35][CH3:36])[C@H:14]2[CH3:48])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCc1sc(-c2ccc(C(=O)OC)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1sc(-c2ccc(C(=O)O)cc2C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoate (11 mg, 0.015 mmol) in 1,4-dioxane (0.4 mL) and water (0.4 mL), was added 1N LiOH (0.151 mL, 0.151 mmol). The mixture was stirred at room temperature for 2 h. The mixture was acidified with 1N HCl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC reverse phase (C-18), eluting with MeCN/water containing 0.1% TFA. The fractions were collected and lyophilized to give 4-{4-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)phenyl]-5-ethyl-1,3-thiazol-2-yl}-3-methylbenzoic acid. LCMS calc.=717.1; found=717.0 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H); 7.99 (d, J=8.1 Hz, 1H); 7.89 (d, J=8.1 Hz, 1H); 7.87 (s, 1H); 7.78 (s, 1H); 7.74 (d, J=8.0 Hz, 1H); 7.71 (s, 2H); 7.57 (d, J=7.9 Hz, 1H); 5.61 (d, J=8.0 Hz, 1H); 4.94 (d, J=15.7 Hz, 1H); 4.25 (d, J=15.7 Hz, 1H); 4.04-3.98 (m, 1H); 2.89-2.76 (m, 2H); 2.69 (s, 3H); 1.37 (t, J=7.5 Hz, 3H); 0.60 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2OC(=O)[S:9][N:8]=2)[CH:2]=1.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17]>ClC1C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[S:9][N:8]=2)[CH:2]=1
Reactant: Cc1cccc(-c2nsc(=O)o2)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2cccc(C)c2)c1C(=O)OC
Yield: 52.2 %

Procedure:
5-m-Tolyl-1,3,4-oxathiazol-2-one (19.32 g, 0.1 mol) and dimethyl acetylenedicarboxylate (28.42 g, 0.2 mol) were heated at reflux in 60 ml of chlorobenzene as given above. After the initial crystallization from cold methanol, three recrystallizations from diethyl ether/petroleum ether gave 15.18 g (0.0522 mol, 52.2%) of white solid, m.p. 53°-54.5°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([N:26]([CH2:42][CH3:43])[C:27]1[CH:28]=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1)[CH3:25]>>[CH2:42]([N:26]([CH2:24][CH3:25])[C:27]1[CH:32]=[C:31]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:30]=[N:29][CH:28]=1)[CH3:43]
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCN(CC)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: CCN(CC)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and diethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 95.1.1) to give the title compound as a white solid. (HPLC: tR 2.31 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.13-8.09 (m, 2H), 8.07-8.05 (m, 1H), 7.96-7.91 (m, 2H), 7.60-7.58 (m, 1H), 6.95-6.92 (m, 1H), 3.87 (s, 3H), 3.58 (s, 3H), 3.46-3.39 (m, 4H), 1.97 (s, 3H), 1.13 (t, 6H))
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:14]1[N:19]=[C:18]([Cl:20])[C:17]([CH3:21])=[C:16](Cl)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH2:25][CH2:24]1.N1C2C(=CC=CN=2)C=CC=1.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CC(N(C)C)=O>[C:10]([C:14]1[N:15]=[C:16]([N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:27][CH2:28]2)[C:17]([CH3:21])=[C:18]([Cl:20])[N:19]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: c1cnc2nc(C3CCNCC3)ccc2c1
Reactant: Cc1c(Cl)nc(C(C)(C)C)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cnc2ncccc2c1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)nc(C(C)(C)C)nc1N1CCC(c2ccc3cccnc3n2)CC1
Temperature: 100 °C
Yield: 65.4 %

Procedure:
20 ml of dimethylacetamide and 5 ml (17.8 mmoles) of diisopropylethylamine are added into a single-necked flask containing 1.5 g (6.84 mmoles) of 2-tert-butyl-4,6-dichloro-5-methyl-pyrimidine and 1.46 g (6.84 mmoles) of 2-piperidin-4-yl-[1,8]naphthyridine. This mixture is heated at 100° C. overnight. The next day 0.2 equivalent of naphthyridine is added and the mixture is heated for another 6 hours. The reaction mixture is returned to ambient temperature before concentrating to dryness. The residue obtained is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The collected organic phases are dried over magnesium sulphate then the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silica gel eluting with a gradient of heptane-ethyl acetate (70-30) to heptane-ethyl acetate (50-50). 1.77 g of expected product is obtained.