Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:15]=3[CH:16]=2)[O:8][C:7](=[O:25])[C:6]=1[CH3:26])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[C:21]([C:19]1[CH:18]=[CH:17][C:15]2[CH:16]=[C:12]([C:9]3[O:8][C:7](=[O:25])[C:6]([CH3:26])=[C:5]([OH:4])[C:10]=3[CH3:11])[O:13][C:14]=2[CH:20]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1ccc2cc(-c3oc(=O)c(C)c(OC(C)=O)c3C)oc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2cc3ccc(C(=O)O)cc3o2)oc(=O)c(C)c1O

Procedure:
A mixed solution of 4-acetyloxy-3,5-dimethyl-6-(6-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one (85 mg) and K2CO3 (45 mg) in MeOH (5 ml) and H2O (1 ml) was stirred at room temperature for one hour, and then the reaction solution was rendered acidic with a 1 N hydrochloric acid aqueous solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/MeOH=5/1) to obtain 6-(6-carboxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: [C:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:19])[CH:16]([CH:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[CH2:6])[OH:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCC1=CCCC1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 53 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (cyclopent-1-enyl)methylbromide (3.8 g) in tetrahydrofuran was added to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (3.5 g) and zinc powder(1.6 g) in tetrahydrofuran at 20° C. under an inert atmosphere. The temperature increased to 53° C. slowly and after 2 hours, ethyl acetate and hydrochloric acid (1N) were added and the organic phase washed with brine, dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (2:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.66 g), NMR: 1.46(s,3H), 1.61(s,3H), 1.88(s,3H), 1.5-1.9(4H), 2.24(2H), 2.50(1H), 3.24(d,1H), 3.80(s,1H), 4.93(s,1H), 5.06(s,1H), 5.19(d,1H), 5.26(d,1H), 7.22-7.38(5H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([S:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])=[N:5]2.[OH-].[Na+].Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([S:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])=[N:5]2
Reactant: COC(=O)c1ccccc1Sc1ccc2nccn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1Sc1ccc2nccn2n1
Temperature: 70 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of methyl 2-(imidazo[1,2-b]pyridazin-6-ylthio)benzoate (619 mg, 2.17 mmol) in methanol (20 mL) was added 8N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at 70° C. for 18 hr. After the reaction mixture was allowed to cool to room temperature, 6N hydrochloric acid (1.33 mL) was added to the reaction mixture, and the precipitated precipitate was collected by filtration, and washed with water. The precipitate was suspended in methanol (10 mL), and the suspension was stirred with heating under reflux for 10 min. After the suspension was allowed to cool to room temperature, the precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to give the title compound (496 mg, 1.83 mmol, yield 84%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH2:29][CH3:30])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: CCn1cc(Br)cn1
Reactant: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCn1cc(-n2c(C)c(Sc3cc(C(=O)OC)ccn3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-isonicotinic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:31](=[O:33])[CH3:32])[CH:9]=1)[C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cccc(NC(C)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 735 (435.0 mg, 1.06 mmol) in pyridine (3.0 ml) was added acetic anhydride (50 μL, 1.59 mmol) and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to dryness to provide 480 mg of 742. ##STR121##
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1.O.I([O-])(=O)(=O)=[O:30].[Na+]>CC(C)=O.CC(O)(C)C.[Os]>[Cl:1][C:2]1[C:7]([CH:8]=[O:30])=[CH:6][C:5]([C:10]#[N:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]=[C:17]([NH:19][CH:20]2[CH2:22][CH2:21]2)[C:16]2=[N:23][CH:24]=[C:25]([C:26]#[N:27])[N:15]2[N:14]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(C#N)cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1Cl
Agent: [Os]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: N#Cc1cc(C=O)c(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
A suspension of 2-((2-chloro-5-cyano-3-vinylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (210 mg, 0.557 mmol) in acetone (50 mL) was heated to give a cloudy solution. After cooling to RT, water (5 mL), osmium tertroxide (0.350 mL, 2.5 wt % in t-BuOH, 0.028 mmol) and sodium periodate (262 mg, 1.23 mmol) were added. This was stirred overnight. Additional water (20 mL) was added and the reaction was left stirring for 1 day. Most of the acetone was removed and the suspended solid was collected by filtration, washed with water, and air dried to leave 2-((2-chloro-5-cyano-3-formylphenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (188 mg) as a light yellow solid.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=O)[CH3:10].N1C=CC=CC=1>O>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)=[N:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[CH3:10]
Reactant: NN1CCCC1=O
Reactant: CCOC(=O)CC(=O)c1cccc(C)n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969, 9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanical stirrer and nitrogen inlet. Add 3-[6-methyl-(pyridin-2-yl)]-3-oxo-propionic acid ethyl ester (154 g, 0.66 mol), and pyridine (280 mL). Stir the reaction mixture at room temperature for 20 h. Dilute the mixture with water (200 mL) and extract with toluene (2×250 mL). Combine the organic layers, filter, and concentrate in vacuo to yield the subtitled product (201 g) as a dark oil. MS ES+ m/e 290 (M+1).
Reaction SMILES: C(OC)(OC)OC.CN(C)C(N(C)C)=N.[CH2:16]=[C:17]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[PH2:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][PH:36]([CH2:16][CH:17]([CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])=[O:37]
Reactant: C=C(CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CO[PH2]=O
Agent: CN(C)C(=N)N(C)C
Solvent: COC(OC)OC
Product: CO[PH](=O)CC(CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Trimethyl orthoformate (11.0 mL, 10.7 g, 101 mmol) was added to anhydrous hypophosphorous acid3 (4.0 mL, 6.0 g. 90 mmol) and the solution was stirred for 1.5 h at room temperature. In a separate flask, N,N,N',N'-tetramethylguanidine (1.50 mL, 1.38 g, 12.0 mmol) was added to benzyl 2-methylene-4-phenyl-butanoate (3.99 g, 15.0 mmol) and the solution was cooled to 0° C. by an ice bath. An portion of the methyl hypophosphite solution (12.0 mL, d=1.04 g/mL, approx. 68 mmol) was added over 1 h. The ice bath was removed and the solution was stirred an additional 1.25 h. The reaction was diluted with ethyl acetate (150 mL) and washed with 2N aqueous hydrochloric acid (50 mL), water (50 mL), and saturated aqueous sodium chloride (50 mL). The aqueous layers were extracted in succession with ethyl acetate (50 mL). The organic layers were dried (sodium sulfate), decanted, and evaporated. After drying overnight under vacuum, the crude product was 5.19 g (100% yield) of viscous colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[N:18]2[CH:19]=[CH:20][N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1)(=[O:5])=[O:4].[CH2:24]=O>C(O)(=O)C>[F:23][C:2]([F:1])([F:22])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:12][C:13]2[N:18]3[C:19](=[CH:20][N:21]=[C:17]3[CH:16]=[CH:15][CH:14]=2)[CH2:24]1)(=[O:5])=[O:4]
Reactant: C=O
Reactant: O=S(=O)(NCCCCNCc1cccc2nccn12)C(F)(F)F
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 6.91 g (19.72 mmol) of 5-[N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 20 ml of acetic acid was added 22.1 ml (295.8 mmol) of a 37% aqueous solution of formaldehyde. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure, and the residue was dissolved in 100 ml of a saturated aqueous solution of potassium hydrogencarbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was subjected to extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel chromatography (eluent: chloroform/methanol=20:1) to give 4.86 g (68.0%, pale yellow liquid product).
Reaction SMILES: [OH:1][C:2]12[CH2:8][N:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[Li+].CC([N-]C(C)C)C.[CH2:17]([N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[N:5]12[CH2:8][C:2]([O:1][C:25](=[O:26])[N:24]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: OC12CCN(CC1)C2
Reactant: O=C(Cl)N(Cc1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(OC12CCN(CC1)C2)N(Cc1ccccc1)c1ccccc1
Temperature: -60 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
In a two necked flask under nitrogen, 3 ml of THF and 150 mg (1.33 mmoles) of 4-hydroxy-1-azabicyclo[2.2.1]heptane were placed. The suspension was cooled to −60° C. and 0.7 ml (1.46 mmoles) of LDA was added dropwise. After the addition the temperature was allowed to rise to 0° C. and was kept during two hours. A solution of 295 mg (1.20 mmoles) of benzylphenylcarbamyl chloride in 2 ml of THF was added in 30 minutes. The reaction mixture was allowed to slowly warm to room temperature and stirred for 18 hours. The suspension was filtered and the filtrate concentrated under reduced pressure. The residue was extracted with dichloromethane and water. The organic layer was extracted with 2N HCl and the aqueous layer basified with 8N NaOH and extracted with dichloromethane. The organic layers were dried over Na2SO4 anhydre and evaporated. The oil obtained (162 mg) was purified by HPLC-MS to obtain 4.86 mg (0.015 mmoles) 1.3% of a pure product as formiate, structure confirmed by 1H-NMR 300 MHz, (DMSO-d6): δ 1.86 (m, 4H), 2.65 (s, 2H), 2.77 (bs, 2H), 3.03 (bs, 2H), 4.84 (s, 2H), 7.14-7.32 (m, 10H). 8.19 (s, 1H); MS [M-HCOO]+: 323.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-cyanophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 212.5-215.7° C. 1H NMR (acetone-d6/300 MHz) 7.96 (s, 1H), 7.90 (d, 2H, J=8.9 Hz), 7.81 (s, 1H), 7.27 (d, 2H, J=8.9 Hz), 6.96 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)−79.4 (d, J=7.2 Hz). FABLRMS m/z 396 (M+H). ESHRMS m/z 413.0544 (M+NH4, Calc'd 413.0516). Anal. Calc'd for C18H9ClF3NO4: C, 54.63; H, 2.29; N, 3.54; Cl, 8.96. Found: C, 54.40; H, 2.18; N 3.30; Cl, 9.20.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:18](O)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH:46]1[O:51][NH2:52]>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[C:18]([NH:52][O:51][CH:46]2[CH2:47][CH2:48][CH2:49][CH2:50][O:45]2)=[O:19])[C:11](=[O:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)O)S(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(CCn1ccc(OCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (670 mg, 1.77 mmol) in methylene chloride (18 mL) at ambient temperature was added 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (474 mg, 2.47 mmol), 1-hydroxy benzotriazole monohydrate (487 mg, 3.18 mmol), triethylamine (443 uL, 3.18 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (310 mg, 2.65 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and water. The phases were separated and the aqueous layer was extracted with methylene chloride two times. The organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing desired product were combined and concentrated to afford 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as an oil. 536.3 mg
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:15]([N+:22]([O-:24])=[O:23])=[C:16]([O:21][CH2:28][CH2:27][O:26][CH3:25])[N:17]=[C:18]([CH3:20])[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCC(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1nc(C)nc(N2CCC(c3ccc(F)cc3)CC2)c1[N+](=O)[O-]

Procedure:
In analogy to the procedure described in example 8, the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 7) was treated with 2-bromoethyl methyl ether and potassium carbonate in N,N-dimethylformamide at 50° C. to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-methoxy-ethoxy)-2-methyl-5-nitro-pyrimidine as a yellow oil; MS: [M+H]30 =391; and the 6-[4-(4-fluoro-phenyl)-piperidin-1-yl]-3-(2-methoxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as a yellow solid; m.p. 45-48° C.; MS: [M+H]+=391.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][CH2:32][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: C1CCNC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCN3CCCC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(4-chloro-butane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 255) and pyrrolidine (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N6O4SF [(M+H)+] 535.2500, observed 535.2498.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][S:7][C@@H:6]([C:9]([SH:12])([CH3:11])[CH3:10])[CH2:5]1)([OH:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([S:12][C:9]([C@H:6]1[CH2:5][C@H:4]([C:1]([OH:3])=[O:2])[CH2:8][S:7]1)([CH3:10])[CH3:11])(=[O:15])[CH3:14]
Reactant: CC(C)(S)[C@H]1C[C@H](C(=O)O)CS1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)SC(C)(C)[C@H]1C[C@H](C(=O)O)CS1
Temperature: 25 °C
Yield: 72 %

Procedure:
trans-4-carboxy-2-(1-mercapto-1-methylethyl)tetrahydrothiophene (compound No. 8-1, 50 mg) was dissolved in a mixture of acetic anhydride (1 ml) and pyridine (1 ml) and the mixture was stirred over night at room temperature. The reaction mixture was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 43 mg (72%) of the titled compound (compound No. 13-1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[NH2:21][C:22]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:30][C:28]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([NH2:21])[CH:29]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Reactant: N#Cc1ccc(CBr)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C#N)c(N)c2)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1 g, 5 mmol) is dissolved in THF (100 mL) under nitrogen, and cooled to 0° C. Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added in one portion to the vigorously stirring solution, followed by 18-crown-6 (10 mg, 0.038 mmol), and the reaction mixture allowed to warm to room temperature and stirred for 1 hour. The solution is cooled to 0° C. and 2-amino-4-(bromomethyl)benzonitrile (1.16 g, 5.5 mmol) added dropwise as a solution in THF (10 mL), before leaving the reaction mixture to warm to room temperature and stir overnight. The reaction is quenched with 0.25M HCl (20 mL), then neutralized with saturated aqueous NaHCO3, and brine added. The solution is extracted with ethyl acetate, and the organic phase dried over MgSO4, concentrated, and purified by column chromatograph on silica with 0.5-5% methanol/dichloromethane. The product fractions are combined, concentrated, and the semi-solid oily residue triturated with hexanes/dichloromethane=100/1 (25 mL). The product is isolated as a pale yellow powder (1.24 g, 3.75 mmol).
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[C:17]([C:19]1[C:20](=[O:48])[N:21]([CH2:25][C@H:26]2[C@H:32]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[O:31][CH2:30][CH2:29][N:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]2)[CH:22]=[CH:23][CH:24]=1)#[N:18]>C1(C)C=CC=CC=1>[Cl:40][C:35]1[CH:34]=[C:33]([C@@H:32]2[O:31][CH2:30][CH2:29][N:28]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:27][C@H:26]2[CH2:25][N:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]3[NH:16][N:15]=[N:14][N:18]=3)[C:20]2=[O:48])[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(-c3nnn[nH]3)c2=O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Tributyltin azide (0.340 mL, 1.24 mmol) was added to a solution of tert-butyl (6R,7R)-6-[(3-cyano-2-oxopyridin-1(2H)-yl)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (198 mg, 0.41 mmol) in toluene (5 mL). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (148 mg, 0.284 mmol, 68.6%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](CO)=[C:5]([C:18]([O:20][CH2:21]C)=[O:19])[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[CH2:21][O:20][C:18](=[O:19])[C:5]=2[CH:6]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1cccs1
Reaction time: 2 h
Yield: 58.5 %

Procedure:
A solution of diethyl 2-methyl-4-(2-thienyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (400 mg) and p-toluenesulfonic acid (catalytic amount) in 99% ethanol (10 ml) was refluxed with stirring for 2 hours. After the resultant solution was concentrated, the residue was pulverized. The powder was recrystallized from ethyl acetate to give colorless prisms (203.2 mg) of ethyl 2-methyl-4-(2-thienyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylate, m.p. 232° C.
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:21]([O:24][CH2:25][CH2:26][CH2:27]Br)(=[O:23])[CH3:22]>>[CH2:1]([O:7][C:8]1[C:9](=[O:20])[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:27][CH2:26][CH2:25][O:24][C:21](=[O:23])[CH3:22])[C:12]=2[C:13]=1[OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(O)c2c(O)cccc2oc1=O
Reactant: CC(=O)OCCCBr
Product: CCCCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-hexyloxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.