Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:27]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28])[C:3]([NH:5][C@@H:6]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([O:15]CC)=[O:14])=[O:8])=[O:4].O[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[OH:1][C@H:2]([C:27]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:28])[C:3]([NH:5][C@H:6]([C:7]([N:9]([CH3:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])/[CH:11]=[C:12](\[CH3:18])/[C:13]([OH:15])=[O:14])=[O:8])[C:23]([CH3:24])([CH3:25])[CH3:26])=[O:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](O)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (0.34 g, 0.70 mmol, from Reference Example 41) is dissolved in methanol (3.2 mL) and tetrahydrofuran (3.2 mL). To this solution is added water (1.6 mL) and lithium hydroxide monohydrate (64 mg, 1.5 mmol), and the resulting mixture is stirred at 65° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (200 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2R)-2-hydroxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a white foam, which is crushed to a powder (50 mg). MS (ES+): (M+H)=461.0
Reaction SMILES: [CH:1]1([C@H:4]2[C@@H:10]([N:11](CC3C=CC=CC=3)CC3C=CC=CC=3)[C:9](=[O:26])[NH:8][C:7]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:6]=3[O:5]2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:11][C@H:10]1[C:9](=[O:26])[NH:8][C:7]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:6]=2[O:5][C@H:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(F)ccc2O[C@@H](C2CC2)[C@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1C(=O)Nc2cc(F)ccc2O[C@H]1C1CC1

Procedure:
The title compound was prepared by hydrogenation of (+)-(6S,7R)-6-cyclopropyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 235.1 (M−H, 100).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[NH2:15][C:16]1([CH3:31])[C:20]2([CH2:22][CH2:21]2)[C:19](=O)[N:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:15][C:16]1([CH3:31])[C:20]2([CH2:22][CH2:21]2)[CH2:19][N:18]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17]1
Reactant: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(N)CN(Cc2ccccc2)CC12CC2
Temperature: 60 °C
Reaction time: 1 h
Yield: 105006.6 %

Procedure:
A solution (65% toluene solution) of sodium bis(2-methoxyethoxy)aluminum hydride (1.65 kg, 3.5 eq.) in toluene (870 mL) was added to a solution of 7-amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane (348 g, 1.51 mmol) in toluene (2.62 L), and the mixture was stirred at an internal temperature of 60° C. for 1 hour. The reaction mixture was cooled with ice. Aqueous sodium hydroxide solution (5N) was added to the cooled mixture, and the aqueous layer was extracted with toluene. The thus-obtained organic layers were combined, and the solvent of the combined organic layer was evaporated under reduced pressure, to thereby yield the title product as brown oil (343 g, purity: 81.3%, yield: 100%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[CH2:17])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:20][C:21]1[C:26](I)=[CH:25][CH:24]=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].C(N(CC)CC)C.O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:16]=[CH:17]/[C:26]3[C:21]([OH:20])=[C:22]([C:28](=[O:30])[CH3:29])[CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)c1cccc(I)c1O
Reactant: C=Cc1ccc(OCCCCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)c1cccc(/C=C/c2ccc(OCCCCc3ccccc3)cc2)c1O
Temperature: 100 °C
Reaction time: 24 h
Yield: 70293.9 %

Procedure:
A mixture of 4-(4-phenylbutoxy)styrene (742 mg, 2.92 mmol), 2'-hydroxy-3'-iodoacetophenone (612 mg, 2.33 mmol), triethylamine (0.408 ml, 3.01 mmol), palladium (II) acetate (14 mg, 0.06 mmol) in acetonitrile (15 ml) was left under stirring at 100° C. for 24 h. Then the mixture was added with water (15 ml), extracted with ethyl ether (4×30 ml), dried and the solvents were evaporated off under reduced pressure. The resulting residue was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 9:1, recovering 633 g of the title compound (70% yield).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=3[C:33]([O:35]C)=[O:34])[CH2:16][CH2:15]2)=[CH:12][C:11](=[O:37])[N:10]([CH3:38])[C:9]1=[O:39].[OH-].[Na+].Cl>CO>[CH3:7][N:8]1[C:13]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=3[C:33]([OH:35])=[O:34])[CH2:16][CH2:15]2)=[CH:12][C:11](=[O:37])[N:10]([CH3:38])[C:9]1=[O:39]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CO
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3C(=O)O)CC2)cc(=O)n(C)c1=O
Yield: 103.6 %

Procedure:
1.38 g of 1,3-dimethyl-6-{4-[3-(2-methoxycarbonyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 151--free form) were dissolved in 200 ml of methanol, followed by the addition of 100 ml of a 1.5 N aqueous solution of sodium hydroxide. The resultant mixture was stirred at 60° C. for 30 minutes. The reaction mixture was allowed to cool down, neutralized with dilute hydrochloric acid, and then concentrated to a total volume of 50 ml under reduced pressure. The concentrate was ice-cooled and precipitated crystals were collected by filtration, thereby obtaining 1.16 g of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[C:17]([CH3:19])=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl.CO>[CH2:22]([O:21][C:16](=[O:20])/[C:17](=[N:12]/[C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)/[CH3:19])[CH3:23]
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CO
Product: CCOC(=O)/C(C)=N/c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-imidazol-1-yl-phenyl amine (637 mg) was dissolved in 2 M hydrochloric acid/MeOH (3 ml), and this was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (1 ml), and an aqueous solution of sodium nitrite (304 mg, 2.5 ml) was added dropwise thereto over 30 minutes at 0° C. on ice. The reaction mixture was slowly added dropwise to an aqueous solution prepared in advance from aqueous solutions of sodium hydrosulfite (2.3 g, 13 ml) and 5 M sodium hydroxide (400 μl), while keeping the temperature of the reaction mixture at 5° C. or lower. Then, the mixture was stirred at 25° C. for one hour. An ethanol solution (5 ml) of ethyl pyruvate (465 μl) was added dropwise to the reaction mixture. After stirring at 50° C. for 30 minutes, the mixture was further stirred at 25° C. for 10 hours. The pH of the mixture was adjusted to 11 using an aqueous solution (about 10 ml) of 20% potassium phosphate. The resulting precipitate was collected by filtration, and dried. Thus, 2-[(E)-4-imidazol-1-yl-phenylimino]-propionic acid ethyl ester was obtained as a pale yellow powder (1.1 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)(O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCCCCC(O)(c1ccc(C(=O)OC)cc1)c1ccc(OC)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCCC=C(c1ccc(C(=O)OC)cc1)c1ccc(OC)c(Br)c1
Yield: 69.5 %

Procedure:
To a solution of 4-[1-(3-bromo-4-methoxy-phenyl)-1-hydroxy-heptyl]-benzoic acid methyl ester (572 mg, 1.31 mmol) in dichloromethane (10 mL) is added TFA (749 mg, 6.57 mmol). 5 min later, triethylsilane (763 mg, 6.57 mmol) is added dropwise. 5 h later, the reaction mixture is diluted with ethyl acetate, washed with 1N NaOH, water, brine, dried over sodium sulfate, concentrated and purified by column chromatography to give 4-[1-(3-bromo-4-methoxy-phenyl)-hept-1-enyl]-benzoic acid methyl ester (380 mg), which is hydrolyzed by 5N NaOH (1 mL) to afford the titled compound (380 mg).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[C:8](OC)=[O:9])=[N+:2]=[N-:3].[BH4-].[Na+].CO>C1COCC1>[N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([CH2:15][F:16])[CH:14]=1)[CH2:8][OH:9])=[N+:2]=[N-:3]
Reactant: COC(=O)c1cc(CF)cc(CN=[N+]=[N-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cc(CO)cc(CF)c1
Yield: 36.3 %

Procedure:
Methyl 3-azidomethyl-5-fluoromethylbenzoate (35) (468 mg, 2.10 mmol) was dissolved in THF (1.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (97.5 mg, 2.58 mmol), and then a mixed solution of THF:MeOH (1.3 mL:0.4 mL) slowly dropwise. The reaction mixture was refluxed for 20 hour. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with 1N hydrochloric acid (2.5 mL). The mixture was extracted 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=5:1, then EtOAc) to isolate 3-azidomethyl-5-fluoromethylbenzylalcohol (36) (149 mg, 36%) as a colorless oil. In addition, the aqueous layer of the extraction was basified with a saturated sodium hydrogen carbonate aqueous solution and extracted 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 give methyl 3-aminomethyl-5-fluoromethylbenzoate (37) (33.1 mg, 8%) as a yellow clear oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)C)[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(-c2nc(-c3ccccc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
A mixture of N-{4-[4-phenyl-5-(4H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (250 mg, 0.70 mmol) produced in Example 1-B (vi), 1N aqueous sodium hydroxide solution (3.5 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was stirred at 60° C. for 3 hr. To the reaction mixture was added 1N aqueous sodium hydroxide solution (3.5 mL), and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (130 mg, 58%) as a yellow solid.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 23.8 %

Procedure:
In a reactor equipped with a water trap (Dean-Stark trap), a mixture of benzhydrol (5.0 g), 1-(2-hydroxyethyl)piperazine (3.5 g), camphor-10-sulfonic acid (14 g), and toluene (80 mL) was refluxed for 6 hours. Then, 1N-hydrochloric acid was added and the mixture was separated into two phases. The aqueous layer was made basic with 5 N aqueous sodium hydroxide, saturated with sodium chloride, and extracted with chloroform. The extract was washed with a small amount of saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to provide 1.9 g of the title compound. Yield 24%. This compound was not further purified but directly submitted to the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[I-].[Na+].O1CCCC1.[CH2:23]([NH2:25])[CH3:24]>CC(C)=O.C(Cl)Cl>[CH2:23]([NH:25][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1])[CH3:24]
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCNCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (500 mg, 1.47 mmol) in acetone (7.3 ml) was treated with sodium iodide (242 mg, 1.6 mmol). The resulting mixture was stirred at ambient temperature. After 1.5 hours, the sodium bromide was removed by filtration, and the filtrate concentrated. The residue was treated with a tetrahydrofuran solution of ethylamine (11 ml, 22.0 mmol). The resulting mixture was stirred for about 17 hours at ambient temperature. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was diluted with methylene chloride, and washed with 25 mM phosphate buffer and brine. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][N:8]=1)(=[O:26])=[O:25]
Reactant: OCCCCSc1nccc2nccn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCSc1nccc2nccn12

Procedure:
Using 2.23 g (10 mmol) of 5-(4-hydroxybutylthio) imidazo[1,2-c]pyrimidine, 1.53 ml (11 mmol) of triethylamine and 0.85 ml (11 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(4-methanesulfonyloxybutylthio)-imidazo[1,2-c]pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10](I)[N:9]=1)=[O:7].[C:35]([NH2:38])(=[O:37])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(OCC)(=O)C.O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]2[C:11]([CH:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH:14]=[N:15]2)=[C:10]([NH:38][C:35](=[O:37])[CH3:36])[N:9]=1)=[O:7]
Reactant: CC(N)=O
Reactant: COCCNC(=O)c1nc(I)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1nc(NC(C)=O)c2cc(Cc3ccc(F)cc3)cnc2c1OCc1ccccc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To Compound 10 (571 mg, 1 mmol) and acetic acid amide (89 mg, 1.5 mmol) was added and solved dioxane (12 ml), and were added cesium carbonate (48.8 mg, 1.5 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxancene (88 mg, 0.152 mmol), and palladium acetate (24 mg, 0.107 mmol) under stirring at room temperature in nitrogen gas flow, and then the solution was stirred for 5 hours under heating in an oil bath at 70° C. The mixture was added with ethyl acetate, water and ammonium chloride aqueous solution for extraction, washed with sodium chloride aqueous solution, dried over sodium sulfate and the subjected to distillation. The obtained residue was subjected to silica gel chromatography and recrystallized from acetone-diisopropyl ether, to give 5-acetylamino-8-benzyloxy-3-(4-fluorobenzyl)[1,6]naphthyridine-7-carboxylic acid (2-methoxyethyl) amide 12 (245 mg, 80.9%) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].Cl[C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=1.[H-].[Na+]>O1CCCC1>[O:20]1[C:16]2([CH2:21][CH2:22][CH:13]([O:12][C:10]3[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=[C:6]([O:3][CH2:2][CH2:1][OH:4])[CH:11]=3)[CH2:14][CH2:15]2)[O:17][CH2:18][CH2:19]1
Reactant: FC(F)(F)c1nc(Cl)cc(OC2CCC3(CC2)OCCO3)n1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
1,2-Ethanediol (60 μL, 1.1 mmol) and 4-chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (91 mg, 0.27 mmol) were dissolved in tetrahydrofuran (1.4 mL) and cooled to 0° C. Sodium hydride (60%/mineral oil, 22 mg, 0.56 mmol) was added and stirred for 30 minutes at 0° C., then at 22° C. for 20 hours. LCMS analysis showed no remaining starting material, and as the main component, formation of the product, M+H 365. The reaction was quenched with aqueous bicarbonate. The aqueous solution was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (Na2SO4) and the solvent removed in vacuo. The product was purified by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 38% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 56%; 60 mL/min; detector set at M+H 365; retention time, 5.7 min. HPLC found the UVmax as 240 nm. The solvent was removed by rotary evaporation to give 56 mg of product (57% yield). The compound of Example 56 was then obtained by following the steps described for Example 45.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[Mg].[CH2:11]([CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]=[CH:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].Cl>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: CCCCCC1C=CC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC1=CCC(O)(c2ccc(F)c(F)c2)CC1

Procedure:
A solution of 7.1 g of 3,4-difluorobromobenzene in 25 ml of anhydrous diethyl ether was added dropwise under stirring at 15°-20° C. to 1 g of magnesium metal powder, followed by reaction at room temperature for 1 hour so that a Grignard reagent was formed. After 5 g of 4-pentylcyclohexenone were added under stirring at -10° to 0° C. to the thus-formed Grignard reagent, they were reacted at room temperature for additional 1 hour. After the completion of the reaction, diluted hydrochloric acid was added dropwise to the reaction mixture, followed by the extraction of the reaction mixture with diethyl ether. After the extract was washed with saturated NaCl, anhydrous sodium sulfate was added to dry the extract. The diethyl ether was distilled off under reduced pressure, whereby 4-(3,4-difluorophenyl)-4-hydroxy-l-pentylcyclohexene was obtained as a crude reaction product.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[C:21]([O:25][C:26](=[O:29])[CH2:27]Br)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:29])[CH2:27][N:16]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:19])[O:3][C:2]([CH3:20])([CH3:1])[C:7]=3[CH:8]=2)=[CH:13][CH:14]=[C:15]1[C:17]#[N:18])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: CC(C)(C)OC(=O)Cn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (5.4 g, 20 mmol) and tert-butylbromoacetate (4.64 g, 22 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 188-190° C. (3 g, 40%). 1H-NMR (DMSO-d6) δ 1.35 (s, 9H), 1.62 (s, 6H), 4.8 (s, 2H), 6.35 (d, J=4.3 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.09 (d, J=4.3 Hz, 1H), 7.26 (m, 2H), 10.42 (s, 1H), MS (APCI (−)) m/z 380 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](B3OC(C)(C)C(C)(C)O3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1.[OH:28]OS([O-])=O.[K+]>CO.ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:28])=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[N:8]=[CH:9]2)=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2c(-c3ccccc3Cl)ncc3cc(Cl)ncc23)OC1(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: Oc1c(-c2ccccc2Cl)ncc2cc(Cl)ncc12

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-naphthyridine (60 mg, 0.1 mmol) and Oxone® (370 mg, 0.6 mmol) in wet methanol (0.6 mL) and dichloromethane (0.2 mL) was stirred at 35° C. for 3 hours. The cooled reaction mixture was diluted with dichloromethane (50 mL) and washed with 1.0M citric acid in water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford an orange/red residue that was used in the next step without further purification (50 mg, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared from the product of Example 1 as described in Example 6 with the exception that 4-methoxybenzeneboronic acid was used instead of 2-methoxybenzeneboronic acid.