Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCCCCC.C(OCC)(=O)C>CCOCC>[OH:26][C:20]1([C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[O:4][CH2:3][O:2][CH3:1])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: COCOc1cccc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCOc1c(C2(O)CCCCC2)ccc2ccccc12
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
A solution of 1-methoxymethoxy-naphthalene (3.76 g, 0.020 mole) in dry ether (40 mL) was treated with n-butyllithium (1.6M in hexane; 25.0 mL, 0.040 mole) at room temperature over a period of 15 minutes. After stirring for an additional 1.5 hours, a solution of cyclohexanone (4.90 g, 0.050 mole) in ether (15 mL) was added and the resulting mixture was stirred at room temperature for 2 hours. It was then quenched with saturated aqueous ammonium chloride and the crude product was isolated by extraction with ether. Chromatography with 9:1 hexane/ethyl acetate provided the title compound as a colorless oil (3.30 g, 58%).
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:2]([C:12]([OH:14])=O)[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[NH2:25][C@H:26]([C:30]([NH:32][C@H:33]([C:46]([O:48][CH3:49])=[O:47])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:37][CH:36]=1)=[O:31])[CH:27]([CH3:29])[CH3:28].Cl>CN(C)C=O>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@@H:2]([C:12]([NH:25][C@H:26]([C:30]([NH:32][C@H:33]([C:46]([O:48][CH3:49])=[O:47])[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[CH:39][CH:40]=1)=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:14])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)C

Procedure:
4.04 g (12 mmoles) of Z-D-Glu(OBut)-OH are subjected to a condensation reaction with 4.64 g (12 mmoles) of H-Val-Tyr(But)-OMe.HCl in 25 ml of dimethylformamide analogously to Example 38 A. Yield 6.72 g. The substance is purified further by chromatography on silica gel. The eluting agent is a mixture of methylene chloride and acetone in proportions such as 9:1. Yield 6.63 g (70%), melting point 100°-104°, [α]D27 =-8.4° (c=1, methanol).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].C(O)=O.C(NC[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)C.CO>O1CCCC1>[CH:1]([N:8]([CH2:9][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH2:12][CH3:11])=[O:2]
Reactant: CCNCCc1ccc(O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=CO
Solvent: CO
Product: CCN(C=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a suspension of 1,1'-carbonyldiimidazole (326 mmole, 52.81 g) in tetrahydrofuran (164 ml) cooled to 0° C., was added dropwise 96% formic acid (326 mmole, 14.99 g) over a 26 minute period. Reaction stirred at 0° C. for 30 minutes then a light suspension of N-ethyl-p-hydroxyphenethylamine (102 mmole, 16.88 g) in tetrahydrofuran (66 ml) was added over a 10 minute period. Reaction then stirred at 22° C. for 170 minutes before being treated with methanol (10 ml). After stirring for 90 minutes, reaction was concentrated in vacuo to an oil containing crystals. The mixture was taken up into methylene chloride and subjected to preparatory chromatography eluting with a gradient of 0 to 5% methanol methylene chloride over a thirty-minute period. The fractions containing the title compound were combined, concentrated in vacuo to afford 13.46 g of an oil that slowly crystallizes out. Fractions containing title compound and impurities were resubjected to preparatory column chromatography under the same conditions described above to afford an additional 2.61 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12](Br)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1.[CH:29]1([CH2:32][O-:33])[CH2:31][CH2:30]1>CS(C)=O>[CH:1]1([C:4]([OH:28])([CH3:27])[CH2:5][NH:6][C:7]([C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[N:13][C:12]([O:33][CH2:32][CH:29]3[CH2:31][CH2:30]3)=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F)C1CC1
Reactant: [O-]CC1CC1
Solvent: CS(C)=O
Product: CC(O)(CNC(=O)c1nc(-c2ccc(Cl)cc2)c(OCC2CC2)nc1C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.048 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid (2-cyclopropyl-2-hydroxy-propyl)-amide in 0.3 ml dimethylsulfoxide was added 0.2 ml of a 1M solution of cyclopropylmethoxide in dimethylsulfoxide and the mixture was stirred at room temperature for 30 min. The orange reaction mixture was partitioned between 10% citric acid and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane: ethyl acetate=9:1 to 1:1 to yield 0.015 g of the title compound as white solid. MS (M+H) at 468.3.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(OC1C=CC=CC=1)=O.[NH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of phenyl dichlorophosphate (1.72 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[N:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[N:11]=1.CC1(C)C(C)(C)OB([C:34]2[CH:51]=[CH:50][C:37]([CH2:38][NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:36][CH:35]=2)O1.O>O1CCOCC1.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.Cl[Pd]Cl.[Fe]>[F:23][C:22]([F:25])([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:13]=[N:14][C:10]([C:34]3[CH:51]=[CH:50][C:37]([CH2:38][NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:36][CH:35]=3)=[N:11]2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2ccc(CNC(=O)OCc3ccccc3)cc2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)OCc1ccccc1
Temperature: 75 °C
Yield: 84.1 %

Procedure:
To a 5.0 mL vial, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.011 mg, 0.017 mmol), and potassium phosphate (0.14 g, 0.65 mmol) were charged as solids. The vial was sealed with a septum and placed under nitrogen. A solution of 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (WO 2013/009791) (0.10 g, 0.33 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (0.13 g, 0.36 mmol) in dioxane (1.8 mL) was added followed by water (0.45 mL). The reaction mixture was evacuated with vacuum and purged with nitrogen and placed in a pre-heated heating block that at 75° C. for 18 hours. The reaction mixture was then poured into brine solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified via flash chromatography using 15-80% ethyl acetate/hexanes as eluent to afford the title compound as a white solid (0.13 g, 87%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.16-8.01 (m, 4H), 7.91 (t, J=6.2 Hz, 1H), 7.67-7.58 (m, 2H), 7.48-7.15 (m, 7H), 5.07 (s, 2H), 4.28 (d, J=6.2 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 469 ([M+H]+).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[CH3:25][CH2:26][C:27](Cl)=[S:28].[OH-].[Na+]>C(=O)(O)[O-].[Na+].CC(C)=O>[CH3:25][CH2:26][C:27]([NH:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:20]([OH:22])=[O:21])=[C:6]([CH2:9][S:10][C:11]3[O:12][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[S:28]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reactant: CCC(=S)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCC(=S)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CC(=O)O)o3)CS[C@H]12
Reaction time: 0.33 h

Procedure:
To a stirred, cooled (-20°) solution of 8.8 g (0.026 mol) of 7-amino-3-(5-carboxymethyl-1,3,4-oxadiazol-2-ylthiomethyl)3-cephem-4-carboxylic acid in 220 ml of 3% sodium bicarbonate and 220 ml of acetone is added dropwise a solution of 3.66 g (0.029 mol) of methylthioacetyl chloride in 52 ml of acetone, during which time the pH of the reaction mixture is maintained at 8.0 by addition of 10% sodium hydroxide. After addition the reaction mixture is stirred an additional 20 minutes at -15°, then is warmed to 25° and extracted with ether. The remaining aqueous phase is cooled, 250 ml of ethyl acetate is added and the slurry is acidified with 3n hydrochloric acid. The layers are separated and the aqueous phase is extracted twice more with ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to dryness to yield the title compound.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[C:17]([OH:41])=[C:18]([C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].O[CH2:43][CH:44]1[CH:48]=[CH:47][CH2:46][N:45]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[C:17]([O:41][CH2:43][CH:44]2[CH:48]=[CH:47][CH2:46][N:45]2[C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC1CO
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OCC1C=CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.8 %

Procedure:
Diisopropylazodicarboxylate (1.4 g) was added to a suspension of methyl 3-bromo-6-[bis-(tert-butoxycarbonyl)amino]-2-hydroxybenzoate (Intermediate 13, 2.58 g), tert-butyl 2-hydroxymethyl-2,5-dihydropyrrole-1-carboxylate (Prepared according to Morriello et al, Bioorg. Med. Chem, 2008, 16(5), 2156; 1.27 g) and triphenylphosphine (1.82 g) in anhydrous THF (20 mL) and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-25% to give tert-butyl 2-(6-bromo-3-[bis-(tert-butoxycarbonyl)amino]-2-methoxycarbonylphenoxymethyl)-2,5-dihydropyrrole-1-carboxylate (4.13 g) as a light brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][S:13][CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:16][CH2:15][CH2:14][S:13][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: CSCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCCNc1ccc(S(C)(=O)=O)cc1
Temperature: 65 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
To 8.28 g (47.52 mmol) of 4-fluorophenyl methyl sulfone dissloved in 20 mL DMF was added 5.20 g (57.03 mmol) of 2-(methylthio)ethyl amine (1.2 eq.), followed by 13.13 g (95.04 mmol, 2 eq.) potassium carbonate. The mixture was heated to 65° C. and stirred for 12 h. Upon cooling to room temperature, the mixture was partitioned between EtOAc and brine, dried over MgSO4 and concentrated. Column chromatography, eluting with ethyl acetate/hexane, provided 5.53 g of 4-[2-(methylthio)ethylamino]phenyl methyl sulfone, pure by 1H NMR.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:27])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([O:21]C(=O)C)=[C:17]([O:25][CH3:26])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:27])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:25][CH3:26])[CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(/C=C/C(=O)Oc2ccc(NC(C)=O)cc2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(/C=C/C(=O)Oc2ccc(NC(C)=O)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid 4-(acetylamino)phenyl ester (4.2 g, 11.37 mmoles) in methanol (650 ml) and tetrahydrofuran (850 ml), potassium carbonate (9.11 g, 65.95 mmoles) dissolved in water (50 ml) is added and it is left under stirring at room temperature for 2 hours. The precipitate is filtered and the solution is brought to pH 6 with HCl 5% (15 ml). One extracts with ethyl acetate and the organic phase is anhydrified and removed from the solvent at reduced pressure. The raw product is purified by chromatography on silica gel eluting with chloroform/methanol (9/0.5 v/v). Trans-3-[4-hydroxy-3-methoxyphenyl]-2-propenoic acid 4-(acetylamino)phenyl ester (2.1 g) is obtained as a white solid. M.p. 185-195° C. Yield 56%.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14](I)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH:30]=[CH2:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:31]=[CH:30][CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: C=CCc1ccccc1
Reactant: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2c(C=CCc3ccccc3)cccc2c(=O)[nH]1
Yield: 63.9 %

Procedure:
The title compound is prepared analogously to the method of Example 1, starting with the compound from Example III and 3-phenyl-1-propene.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[N+](C1C=CC([O:18][C:19]([O:21][CH:22]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:26][C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:24][CH2:23]2)=O)=CC=1)([O-])=O>CN(C)C1C=CN=CC=1.C(#N)C>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:19]([O:21][CH:22]3[CH:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:26][C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[N:24][CH2:23]3)=[O:18])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc2c(c1)OCO2)OC1CN=C(c2ccccc2)OC1c1ccccc1
Yield: 48.1 %

Procedure:
3,4-Methylenedioxyaniline (1.1 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-5-(4-nitrophenoxycarbonyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1.67 g) and 4-(dimethylamino)pyridine (0.2 g) in anhydrous acetonitrile (50 cc). The solution obtained is heated to reflux for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate/triethylamine (65:30:5 by volume)], collecting 15-cc fractions. Fractions 3 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(3,4-methylenedioxyphenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (0.8 g), m.p. 138° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[NH:24][CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1.[O:26]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC([N+]([O-])=O)=CC=2)=[N:27]1.C(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:24]([C:32]([NH:31][C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:33])[CH2:23][CH2:22][O:21][C:20]=2[CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc4c(c3)OCCN4)c2cc1OC
Reactant: O=C(Nc1ccon1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(c3)OCCN4C(=O)Nc3ccon3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.2955 mmol) and 4-nitrophenyl isoxazol-3-ylcarbamate (294 mg, 1.182 mmol) in CH2Cl2 (3 mL) DIPEA (269 μL, 2.069 mmol) was added at RT. The reaction mixture was stirred at 35° C. for 15 h before the solution was concentrated in vacuo and purified with column chromatography using 100% EtOAc→10%→30%→50% 19:1 EtOAc:MeOH to yield the title compound. MS (ESI, pos. ion) m/z: 449 (M+1). Mass calc'd for C23H20N4O6: 448.44.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:7]1)=[O:5].[CH2:22]([Mg]Cl)[CH2:23][CH3:24]>C1COCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][CH:6]([C:4](=[O:5])[CH2:22][CH2:23][CH3:24])[CH2:7]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CN2CCCC(C(=O)N(C)OC)C2)cc1
Reactant: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Yield: 94.4 %

Procedure:
Combine 1-(4-Methoxy-benzyl)-piperidine-3-carboxylic acid methoxy-methyl-amide (401.0 mg, 1.37 mmol) and THF (10 mL) at 0° C. under a Nitrogen atmosphere. By dropwise addition, add Propylmagnesium chloride (4.0 mL, 8.22 mmol). Reflux the reaction for 5 hours then cool the reaction to room temperature and quench the reaction mixture with sat NH4Cl (aq) and extract product from the water using Ethyl acetate. Wash the organic layer with brine and then dry over Na2SO4. Concentrate under reduced pressure and add to an SCX (5 g) column pre-treated with 5% AcOH/MeOH. Wash with MeOH and elute product using 1N NH3 MeOH to give 356.0 mg (94% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.8 (3H, t), 1.3 (1H, qd), 1.4-1.5 (3H, m), 1.6-1.8 (1H, m), 1.9 (1H, dd), 2.0 (1H, td), 2.1 (1H, t), 2.4 (2H, t), 2.5-2.6 (1H, m), 2.7 (1H, d), 2.9 (1H, d), 3.4 (2H, dd), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); TLC 4% 1N NH3 MeOH:CH2Cl2 Rf=0.42.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([O:33][C:34]([F:37])([F:36])[F:35])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[O:33][C:34]([F:37])([F:35])[F:36])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CP(C)(=O)c1ccc(N)c(OC(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2OC(F)(F)F)nnc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-(trifluoromethoxy)aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12](=[O:17])C(F)(F)F)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[OH-:20].[Na+].Cl>C(OCC)(=O)C>[O:1]1[C:5]2[C:6]([C:10]([CH3:19])([CH3:18])[CH2:11][C:12]([OH:17])=[O:20])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(CC(=O)O)c1cccc2c1OCC2
Temperature: 80 °C
Yield: 99 %

Procedure:
4-(2,3-Dihydrobenzofur-7-yl)-1,1,1-trifluoro-4-methyl-2-pentanone (1.00 g) was treated with NaOH (3.6 mL, 4 M in ethanol-water (2:1)) at room temperature. The mixture was heated to 80° C. for 1 hour. After the mixture had been cooled to room temperature, 20 mL of ethyl acetate, and approximately 15 mL of 2 M HCl were added. The organic phase was separated and the aqueous layer was extracted with three 20 mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed to yield 800 mg (99%) of 3-(2,3-dihydrobenzofur-7-yl)-3-methylbutanoic acid as an orange-brown solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl[CH2:10][CH:11]=O.S(=O)(=O)(O)O.COC1C=CC(OC)=CC=1>C(OCC)(=O)C.O>[O:7]=[C:3]1[C:2]2[CH:10]=[CH:11][O:8][C:1]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=CCCl
Reactant: O=C1CCCC(=O)C1
Agent: COc1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 ml of water were added 1.12 g (10 mmoles) of 1,3-cyclohexanedione and the each base shown in Table 1, and then 2 ml of 40% aqueous solution of chloroacetaldehyde was added thereto. The resulting mixture was stirred at a room temperature for 2 hours. To the reaction mixture was added about 10 ml of ethyl acetate, and then the reaction mixture was acidified with 0.5 to 1 ml of sulfuric acid and stirred for 30 minutes. The resulting ethyl acetate layer was analyzed by gas-liquid chromatography (hereinafter referred to as "GLC") (SE30 10%, 1.2 m×3 mmφ glass column, 130° C.) using p-dimethoxybenzene as an internal standard. The obtained each result is shown in Table 1. It was proved from the results of the GLC that 4-oxo-4,5,6,7-tetrahydrobenzofuran was produced in a yield shown in Table 1, in each Example. Comparative Example 1 was carried out in the absence of a base.