Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+:6](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]2[CH:37]=[CH:36][C:35]([S:38](C)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH:23]=[CH:24][C:25]=1[F:26].CC([O-])=O.[Na+].NOS(O)(=O)=O>C(OCC)(=O)C.O.C1COCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2[CH2:31][CH2:30][CH2:29][C:28]=2[C:32]2[CH:37]=[CH:36][C:35]([S:38]([NH2:6])(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)c(Cl)c3)CCC2)cc1
Agent: CC(=O)[O-]
Agent: NOS(=O)(=O)O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C2=C(c3ccc(F)c(Cl)c3)CCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
Tetrabutylammonium fluoride (0.83 mL, 0.83 mmol, 1M in THF) was added to the silane from Step 1 (0.121 g, 0.277 mmol) and dry THF (0.5 mL). The resulting mixture was refluxed for 1 hour then cooled to room temperature. To the reaction mixture was added sequentially NaOAc (0.103 g, 1.26 mmol), water (1.5 mL), and H2NOSO3H (0.157 g, 1.38 mmol) and the reaction was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (5.0 mL) and water (5.0 mL). The layers were separated, and the organic layer was washed with saturated NaHCO3 (5.0 mL), water (5.0 mL), and brine (5.0 mL) then dried over MgSO4. The solution was filtered, the solids washed with ethyl acetate, and the solvents removed under reduced pressure. The crude product was purified by silica gel chromatography to afford 0.087 g (97%) of product as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[S:32][C:31]([S:33]([NH2:36])(=[O:35])=[O:34])=[N:30][N:29]=1>>[S:33]([C:31]1[S:32][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:29][N:30]=1)(=[O:35])(=[O:34])[NH2:36]
Reactant: Nc1nnc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1nnc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide [commercially available, CAS 14949-00-9] according to general procedure II.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([NH2:19])=[C:14]([NH2:20])[CH:13]=1>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.O>[CH3:18][C:17]1[CH:16]=[C:15]2[C:14](=[CH:13][C:12]=1[CH3:11])[NH:20][C:1](=[O:8])[C:2](=[O:4])[NH:19]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(N)c(N)cc1C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Diethyl oxalate (4.0 mL, 29 mmol) and ytterbium trifluoromethanesulfonate (226 mg, 0.37 mmol) were added to 4,5-dimethyl-1,2-phenylenediamine (1.0 g, 7.3 mmol) and the mixture was stirred at 80° C. for 2 hours. After water was added to the reaction mixture, the precipitate was washed with ethanol. Thus, 6,7-dimethylquinoxaline-2,3(1H,4H)-dione (1.2 g, yield: 87%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14](=[O:22])[C@H:13]2[CH2:23][C:24](OC)=[O:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14](=[O:22])[C@H:13]2[CH2:23][CH2:24][OH:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)C[C@@H]1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2N(S(=O)(=O)c2ccc(Cl)c(Cl)c2)[C@@H]1CCO
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a solution of methyl {(2R)-1-[(3,4-dichlorophenyl)sulfonyl]-3oxo-1,2,3,4-tetrahydroquinoxalin-2-yl}acetate (Example 1, Step 3, 371 mg, 0.86 mmol) in THF (2 mL) was added LiAlH(tBuO)3 (3 mL, 3 mmol). The reaction mixture was stirred at room temperature for approximately two weeks and was then poured into 1N HCl (30 mL) and extracted with EtOAc (3×20 mL). The combined organics were washed with brine (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was subjected to silica gel chromatography eluting with 2%-7% MeOH in CH2Cl2 to give (3R)-4-[(3,4-dichlorophenyl)sulfonyl]-3-(2-hydroxyethyl)-3,4-dihydroquinoxalin-2(1H)-one (211 mg, 61%). LCMS (ES) 400.8.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2=[CH:14][S:15][CH:16]=[C:3]12.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:17]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([CH:8]=2)[C:2](=[O:1])[C:3]2[C:4](=[CH:14][S:15][CH:16]=2)[N:5]=3)=[N:13][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc3cscc3c(=O)n2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cscc2nc2ccc(-c3nnn[nH]3)cn12

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carbonitrile (0.058 g., 0.0003 mol), sodium azide (0.074 g., 0.0011 mol) and ammonium chloride (0.061 g., 0.0011 mol) in dimethylformamide (15 ml) is heated at 95°-100° C. under nitrogen for 46 hours. The solvent is evaporated. The residue is triturated with 1 N hydrochloric acid, filtered and sucked dry to give the product, mp 300° C. (dec).
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].CSC.[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[C:23](OS(C(F)(F)F)(=O)=O)=[C:22]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[C:21]1=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[C:23]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:22]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[C:21]1=[O:45])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CSC
Product: Cc1cc(-c2c(C3CCCCC3)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of cyclohexylmagnesium chloride (250 ul, 0.50 mmol, 2M in THF) was added to a suspension of cupper (I) bromide-dimethylsulfide (51 mg, 0.25 mmol) in 2 ml of THF at −78° C. under N2. The mixture was warmed to rt until a dark color homogenous solution was observed (ca. 15 min), then re-cooled to −78° C. A solution of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (80 mg, 0.16 mmol) in 2 ml of THF was added to the mixture. The resulting mixture was stirred at −78° C. for 2 h and warmed to rt. Treated with 2 ml of sat. NH4Cl followed by 20 ml H2O, the mixture was extracted with EtOAc (2×20 ml). The combined organic layers were washed with H2O (10 ml), brine (10 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-30% EtOAc/hexanes) gave 61 mg (88%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ8.08 (br s, 1H), 7.40 (dd, 1H, J=9.2, 2.2 Hz), 7.20-7.34 (m, 6H), 6.42 (s, 1H), 5.53 (s, 2H), 2.98 (br s, 1H), 2.41 (s, 3H), 1.67-1.93 (m, 7H), 1.22-1.40 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H25ClN2O2, 433.2 (M+H), found 433.1.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([NH:5][C:6]([C:8]1[C:12]([NH:13][CH2:14][C:15]2[O:19][N:18]=[C:17]([C:20](OC)=[O:21])[CH:16]=2)=[C:11]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([OH:31])=[CH:26][C:25]=2[OH:32])[O:10][N:9]=1)=[O:7])[CH3:4].Cl>CCO.O>[OH:21][CH2:20][C:17]1[CH:16]=[C:15]([CH2:14][NH:13][C:12]2[C:8]([C:6]([NH:5][CH2:3][CH3:4])=[O:7])=[N:9][O:10][C:11]=2[C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([OH:31])=[CH:26][C:25]=2[OH:32])[O:19][N:18]=1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1NCc1cc(C(=O)OC)no1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCNC(=O)c1noc(-c2cc(Cl)c(O)cc2O)c1NCc1cc(CO)no1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (2 eq) was added portionwise at 0° C. to a solution of methyl 5-((3-(ethylcarbamoyl)-5-(5-chloro-2,4-dihydroxyphenyl) isoxazol-4-ylamino)methyl)isoxazole-3-carboxylate (0.34 mmol, 150 mg) in EtOH 95% (5 ml). After 30 min, few drops of a 5% HCl solution were added to the mixture and the solvent was evaporated under vacuo. The crude reaction mixture was diluted with H2O (10 ml) and extracted with AcOEt (2×10 ml). The combined organic phases were washed with brine, dried and filtered. Solvent was removed under vacuo and the crude product was purified by flash chromatography on silica gel (AcOEt/light petroleum).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[CH:15][CH:14]=3)=[CH:11][S:10][C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([O:28][CH3:29])[CH:3]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:11][S:10][C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COCOc1ccc(-c2csc(CCC(=O)O)c2-c2ccc(Cl)cc2OC)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)ccc1-c1c(-c2ccc(O)cc2)csc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 3-(3-(4-chloro-2-methoxyphenyl)-4-(4-(methoxymethoxy)phenyl)thiophen-2-yl)propanoic acid (190 mg, 0.44 mmol) in THF (5 mL) was added HCl (1 mL, 12 M) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc, and concentrated to give the crude compound, which was purified by preparative HPLC (Column: YMC ODS-AQ 150×30 cm, 5 μm; Retention Time: 15 min; Mobile phase: from 38% MeCN in water (0.05% TFA) to 68% MeCN in water (0.05% TFA); Wavelength: 220 nm, 254 nm; sample dissolved in DMSO) to give 3-(3-(4-chloro-2-methoxyphenyl)-4-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid (47.5 mg, yield 28%). 1H NMR (CD3OD 400 MHz): δ 7.11 (s, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.97-6.92 (m, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.58 (d, J=8.8 Hz, 2H), 3.58 (s, 3H), 2.90 (t, J=8.0 Hz, 2H), 2.50 (t, J=8.0 Hz, 2H); MS (ESI): m/z [M+1]+=389.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:30]CC>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH:16]=[O:30]
Reactant: COc1ccccc1C1CCCCC1CC#N
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: COc1ccccc1C1CCCCC1CC=O
Yield: 96 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetonitrile (0.346 g, 1.51 mmol), diisobutylaluminum hydride (2.7 mL, 2.72 mmol), and ether (8.0 mL) at −10° C. After 1 hour quenched reaction at 0° C. with 1N HCl and added ethyl acetate. Separate layers, wash with brine, and dry over anhydrous sodium sulfate. Concentrate to yield the titled compound (0.336 g, 96%). TLC Rf=0.08 in 5% ethyl acetate/hexanes. 1H NMR (CDCl3): 9.3 (s, 1H), 7.2 (m, 1H), 7.0 (m, 1H), 6.9 (m, 2H), 3.8 (s, 3H), 3.3 (m, 1H), 2.8 (m, 1H), 2.3 (m, 1H), 2.2 (m, 2H), 1.6 (m, 7H).
Reaction SMILES: [C:1]([OH:8])(=O)[C:2]#[C:3][CH2:4][CH2:5][CH3:6].[CH:9]1([NH2:12])[CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH:9]1([NH:12][C:1](=[O:8])[C:2]#[C:3][CH2:4][CH2:5][CH3:6])[CH2:11][CH2:10]1
Reactant: CCCC#CC(=O)O
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCCC#CC(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A solution of 2-hexynoic acid (5.03 g) and cyclopropylamine (2.70 g) in dichloromethane (75 ml), and a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.00 g) and 1-hydroxybenzotriazole hydrate (7.19 g) in dichloromethane (75 ml) were mixed, and the mixture was stirred at room temperature for 18 hr. 1N Hydrochloric acid (200 ml) was added, and the mixture was extracted with dichloromethane. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and purified by silica gel column to give the title compound (6.04 g, 89%).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([NH:51][C:52]([N:56]([CH3:58])[CH3:57])=[N:53][C:54]#[N:55])[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Cl>C(O)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([NH:51][C:52]([N:56]([CH3:58])[CH3:57])=[N:53][C:54]#[N:55])[CH:48]=[C:49]([Cl:50])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: CCCc1nc2c(Cl)cc(NC(=NC#N)N(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
225 mg (0.29 mMol) of 4'-[[2-n-propyl-4-chloro-6-(2-cyano-3,3-dimethyl-guanidino)-1H-benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in 10 ml of absolute ethanol, mixed with 2.5 ml of methanolic hydrochloric acid and stirred for 90 minutes at ambient temperature. The solvent is then removed in vacuo and the residue is taken up in methylene chloride/ethanol (4:1) and adjusted to pH 8 with methanolic ammonia. After the addition of 5 g of silica gel the mixture is evaporated to dryness. The residue is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant first methylene chloride and then methylene chloride/ethanol (50:1, 25:1, 19:1 and 9:1). The uniform fractions are combined and evaporated down.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 87.3 %

Procedure:
A solution of diethyl 2-benzyloxycarbonylaminomalonate (50 g) in anhydrous DMF (300 mL) was added portionwise with sodium hydride (60%, 6.47 g) with ice cooling and stirring, then the mixture was stirred at room temperature for 30 minutes, and subsequently added with ethyl 2-bromoacetate (22.6 g), and the mixture was stirred overnight. The reaction mixture was poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (5:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (46.7 g, yield: 83%) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].Br[CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1>CN(C)C=O>[CH3:7][O:8][C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1OCCCC/C=C/c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
651 mg of cesium carbonate is added to a solution of 180 mg of 3-(2-hydroxyphenyl)-propionic acid methyl ester and 272 mg of (1E)-6-bromo-1-(4-methoxyphenyl)-1-hexene in 2 ml of dimethylformamide and the suspension is stirred for 16 hours at room temperature. The reaction mixture is filtered, the filtration residue is washed with dichloromethane, the filtrate concentrated by evaporation and the residue chromatographed on silica gel with hexane. 255 mg of 3-[2-[6-(4-methoxyphenyl)(5E)-5-hexenyloxy]-phenyl]-propionic acid methyl ester is obtained as oil.
Reaction SMILES: [OH:1][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])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](O)=[O:28])=[CH:21][CH:20]=1>O>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:27](=[O:28])[CH2:26][CH2:25][C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCc1ccncc1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Solvent: O
Product: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 150 °C
Yield: 51 %

Procedure:
A mixture of 4-hydroxy-1-phenyl-1,8-naphthyridin-2 (1H)-one (2.0 g, 8.4 mmol; synthesized according to JP, A, 61-246183 (1986)), 3-(pyridin-4-yl)propionic acid (19.03 g, 126 mmol, 15 eq.) and polyphosphoric acid (about 100 ml) was heated overnight at 150° C. while stirring. The mixture was poured into water with stirring to form a solution while it was occasionally cooled. The operation including 3 times washing of the aqueous layer with chloroform, then addition of saturated aqueous sodium hydrogen carbonate followed by occasional extraction with chloroform was repeated until the aqueous layer was made pH3 to 3.5. The organic layers which were collected during neutralizing were pooled, dried over anhydrous magnesium sulfate, and then evaporated to give a residue which was purified by flash column chromatography to afford 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (1.59 g, 51%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][CH2:41]B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([CH2:41][CH2:40][C:39]3[CH:51]=[CH:52][C:36]([Cl:35])=[CH:37][CH:38]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)OB(CCc2ccc(Cl)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(CCc2ccc(Cl)cc2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
In a 30 mL sealed cap glass vial, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (150 mg, 0.299 mmol), 2-(4-chlorophenethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.329 mmol) and PdCl2(PPh3)2 (63.1 mg, 0.090 mmol) were dissolved in dioxane (5 mL). To the reaction mixture was added 2N aqueous sodium carbonate solution (2 mL). The cap was sealed and the reaction mixture was heated at 85° C. for 2 hours. The reaction mixture was subsequently diluted with water (5 mL) and extracted with EtOAc (2×30 mL). The combined organic phase was dried over sodium sulfate and evaporated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(4-chlorophenethyl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in dichloromethane (3 mL) and treated with TFA (3 mL) at room temperature for 1 hour to remove the protecting groups. The volatiles were subsequently evaporated from the reaction mixture and the residual material was dissolved in DMSO (8 mL) and purified by preparative HPLC, eluting with a gradient of 20-65% ACN (0.035% TFA) and water (0.05% TFA). The pure product fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (43 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (d, J=9.60 Hz, 1H), 1.90-2.15 (m, 1H), 2.86-3.02 (m, 2H), 3.19-3.38 (m, 2H), 3.47-3.61 (m, 1H), 3.61-3.75 (m, 2H), 3.81-4.03 (m, 2H), 4.13-4.41 (m, 3H), 6.99 (d, J=5.31 Hz, 1H), 7.22 (m, J=8.34 Hz, 2H), 7.32 (m, J=8.34 Hz, 2H), 7.91 (br s, 3H), 8.33 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H22ClFN4O2, 405. found, 405.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[OH:19])[C:5]([O:7][CH3:8])=[O:6].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[F:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1ccccc1CCl
Reactant: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1OCc1ccccc1F
Temperature: 25 °C
Yield: 71.6 %

Procedure:
5 g (19 mmol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyloxime, 2.7 g (19 mmol) of 2-fluorobenzyl chloride and 2.6 g (19 mmol) of potassium carbonate in 65 ml of methanol are stirred under reflux for 8 h. The mixture is cooled to room temperature and the solids are removed by filtration. The filtrate is concentrated, and dilute sodium hydroxide solution is added. The mixture is then extracted by shaking several times with ether; the combined ether phases are washed with H2O, dried over sodium sulfate and concentrated. 5 g (13.6 mmol) of methyl 1-(2-fluorobenzyloxy)-2-naphthylglyoxylate O-methyloxime (yield 71%) are obtained (compound no. 2, Table 1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[C:5]([F:21])[CH:4]=1.O1CCCC1.C(N(CC)CC)C.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O.ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:10](=[O:20])[NH:11][N:12]=[C:13]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:37]([NH:36][CH2:34][CH3:35])=[O:38])[CH2:16]2)=[C:5]([F:21])[CH:4]=1
Reactant: CCN=C=O
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 4 mL vial was placed 4-(4-bromo-2-fluorophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.212 mmol) and tetrahydrofuran (2 mL). In succession was added triethylamine (0.717 mmol) and ethyl isocyanate (0.253 mmol). The vial was capped and the solution stirred at room temperature for 1 h. The solution was poured into a 10 mL solution of 1:1 dichloromethane:water. The solution was shaken and allowed to settle. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. No further purification was performed on the title compound (74 mg, 68%). MS(ES)+ m/e 412.2, 414.1 [M+H]′.