Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: OCc1cc2ccoc2cn1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(C)=O
Product: O=Cc1cc2ccoc2cn1
Reaction time: 0.08 h
Yield: 95 %

Procedure:
Furo[2,3-c]pyridin-5-yl methanol (521 mg, 3.49 mmol) was dissolved in acetone (17 mL), added 2,2,6,6-tetramethylpiperidine 1-oxyl (27 mg, 170 μmol) at room temperature. Then, the reaction solution was added 1,3,5-trichloro-2,4,6-triazinetrione (892 mg, 3.84 mmol) under ice-cold conditions, and stirred at the same temperature for 5 minutes. The reaction solution was concentrated in vacuo, added water and a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (488 mg (yield 95%)) was obtained as a yellow solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:30]COCCOC)=[C:8]([CH:29]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25](=[O:27])[CH3:26])[CH2:20][CH2:19]2)=[C:14]([F:28])[CH:13]=1)=[O:10].Cl>CO>[ClH:3].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([OH:30])=[C:8]([CH:29]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH:25]([OH:27])[CH3:26])[CH2:22][CH2:23]2)=[C:14]([F:28])[CH:13]=1)=[O:10]
Reactant: COCCOCOc1ccc(Cl)cc1C(=O)Nc1ccc(N2CCN(CC(C)=O)CC2)c(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CN1CCN(c2ccc(NC(=O)c3cc(Cl)ccc3O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187 %

Procedure:
Sodium borohydride (0.038 g, 1.00 mmol) was added to a solution of 5-chloro-N-{3-fluoro-4-[4-(2-oxopropan-1-yl)piperazin-1-yl]phenyl}-2-(2-methoxyethoxy methoxy)benzamide (compound of Reference Example 144; 0.134 g, 0.272 mmol) in methanol (1 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 0.5N Hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with water. 2N Hydrochloric acid was added to the obtained solid, and the mixture was refluxed for 1 hour. The reaction mixture was cooled to room temperature, and the precipitated solid was collected by filtration and washed with acetone to give the title compound (0.113 g, 93%) as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1>>[CH3:7][C:6]1[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=[CH:3][C:2]=1[B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(I)c2C)CC1
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-5-methyl-1H-pyrazol-1-yl)cyclohexanecarboxylate (100.0 mg, 0.2761 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5522 mL, 1.104 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2262 mL, 1.380 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil. The material was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: C1COCCN1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCOCC1
Yield: 13.2 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and morpholine (0.099 mL, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (29 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.02 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m, 5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:13](OCC)(=[O:18])[CH2:14][C:15]([CH3:17])=O>C(O)C>[CH3:17][C:15]1[CH2:14][C:13](=[O:18])[N:11]([C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:12]=1
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: CC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1

Procedure:
1.63 g of p-nitrophenylhydrazine hydrochloride and 1.26 g of ethyl acetoacetate are heated under reflux in 30 ml of ethanol for 45 min. The mixture is concentrated somewhat in vacuo. The crystals which have separated out are then filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:11]([NH:4][C:3]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:2]=1[F:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(F)c(N)c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.3 %

Procedure:
This procedure was patterned after that of Tietze and Grote, Chem Ber. 126(12), 2733 (1993). A solution of 2.73 g of 2-fluoro-5-methoxyaniline and 2.67 g of benzaldehyde in 48 ml of methanol was treated with 3.43 g of zinc chloride and then cooled in an ice bath. Sodium cyanoborohydride (1.58 g) was added in small poroom temperature ions over 30 minutes and the reaction was stirred for five hours at room temperature. After evaporation of the solvent, the residue was slurried in 40 ml of 1 N sodium hydroxide solution and then extracted twice with ether. The extracts were washed with water and then with brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from hexane to afford 2.61 g and the mother liquors were chromatographed on silica gel using 20:1 hexane/ether to afford another 1.4 g of the subtitle compound (90%). mp. 56-58° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:18]1([CH2:24][CH2:25][CH:26]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[C:18]1([CH2:24][CH2:25][CH2:26][N:2]2[CH2:3][CH2:4][CH:5]([O:8][C:9]3[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC(=O)c1ccc(OC2CCNCC2)cc1
Reactant: O=CCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: NC(=O)c1ccc(OC2CCN(CCCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
Combine 4-(piperidin-4-yloxy)-benzamide hydrochloride (102 mg, 0.397 mmol), 3-phenyl-propionaldehyde (106 μL, 0.796 mmol) and triacetoxy-borohydride (127 mg, 0.597 mmol) in CH2Cl2 (3 mL). Stir the reaction mixture at room temperature overnight. Dilute the reaction mixture with CH2Cl2 (3 mL) and wash with sodium hydroxide (1N, aq. 5 mL). Separate the organic layer and placed onto an SCX column directly eluting with ammonia (2.0 in methanol). The resulting residue was triturated with CH2Cl2 and diethyl ether to provide the title compound (63 mg, 47%) as a white solid. mass spectrum (ion spray): m/z=339.1 (M+1); 1H NMR (CDCl3): 7.79 (ad, J=9.0 Hz, 3H), 7.28–7.12 (m, 6H), 6.95 (d, J=9.0 Hz, 2H), 4.74–4.40 (m, 1H), 2.70–2.63 (bm, 2H), 2.56 (t, J=7.6 Hz, 2H), 2.31–2.25 (bm, 2H), 2.22–2.15 (bm, 2H), 1.96–1.89 (bm, 2H), 1.71 (pentet, J=7.3 Hz, 2H), 1.63–1.56 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24])[NH:8][C:7](=[O:25])[CH:6]=[CH:5]2.Br[CH2:27][CH:28]=[CH2:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=2)[CH:5]=[CH:6][C:7]1=[O:25])[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc3[nH]c(=O)ccc3cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 75.9 %

Procedure:
These compounds were prepared in a manner analogous to that of Step I of Example 1, using 0.5 gram (0.001 mole) of 3-(6-fluoroquinolin-2-on-7-yl)-1-methyl-6-trifluoromethyluracil (prepared in Step H of Example 1), 0.5 gram (0.003 mole) of 3-bromopropene, and 0.4 gram (0.003 mole) potassium carbonate in 40 mL of N,N-dimethylformamide. The crude reaction product was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 ethyl acetate-heptane and ethyl acetate. The appropriate, product-containing fractions were combined and concentrated under reduced pressure, yielding 0.3 gram of 3-[1-(2-propen-1-yl)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 26), mp 178°-179° C. Other product-containing fractions were combined and concentrated under reduced pressure, yielding 0.2 gram of the O-alkylated product, 3-[2-(2-propen-1-yloxy)-6-fluoroquinolin-2-on-7-yl]-1-methyl-6-trifluoromethyluracil (Compound 20A). The NMR spectra were consistent with the proposed structures.
Reaction SMILES: C[Al](C)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].[Si:12]([O:29][CH2:30][CH2:31][O:32][CH2:33][C@H:34]([OH:39])[C:35](OC)=[O:36])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Si:12]([O:29][CH2:30][CH2:31][O:32][CH2:33][C@H:34]([OH:39])[C:35]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1)=[O:36])([C:25]([CH3:28])([CH3:26])[CH3:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@@H](O)COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Nc1ccccn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](O)C(=O)Nc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
Trimethylaluminium (3.73 mL, 7.45 mmol) was added to pyridin-2-amine (0.701 g, 7.45 mmol) in toluene (6 ml) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-hydroxypropanoate (1.5 g, 3.73 mmol) (Intermediate AB3) in toluene (6 ml) was added and the reaction was allowed to warm to room temperature and then heated to 110 for 5 hours in a microwave. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organics were washed with brine (20 ml), then dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 30 to 50% EtOAc in isohexane to afford the product (1.085 g, 62.7%). 1H NMR: (400 MHz, CDCl3) δ 1.05 (9H, t), 3.60-3.66 (2H, m), 3.67 (1H, d), 3.82-3.84 (2H d, m), 3.80-3.85 (2H, m), 4.33-4.35 (1H, m), 7.03-7.06 (1H, m), 7.35-7.68 (10H, m), 7.70 (1H, d), 8.22 (1H, d), 8.29-8.30 (1H, m),9.15 (1H, s); m/z (ES+) (M+H)+=465.42; HPLC tR=3.13 min.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([CH:40]=[N:41][N:42]=2)[C:7]([CH2:31][C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[F:30])(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([Cl:38])[C:32]=1[CH2:31][C:7]1[N:6]2[CH:40]=[N:41][N:42]=[C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[F:30])[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3nc(Cc4c(Cl)cccc4Cl)n4cnnc4c3C(N)=O)c(F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Nc2ccc(N3CCNCC3)cc2F)nc(Cc2c(Cl)cccc2Cl)n2cnnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28F (220 mg, 0.36 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL) dropwise and the mixture was stirred at ambient temperature for 4 hours. After concentration, the residue was washed with ethanol and dried under vacuum to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 12.11 (s, 1H), 9.68 (s, 1H), 8.94-8.91 (m, 3H), 8.07 (s, 1H), 7.64-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.19-7.12 (t, J=9.3 Hz, 1H), 6.87(dd, J=2.4 Hz, J=14.4 Hz, 1H), 6.29 (dd, J=9.0, 1.8 Hz, 1H), 4.96 (s, 2H), 3.27 (m, 8H). MS: 515 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[C:18]([C:19](Cl)=[O:20])=[C:17]([Cl:22])[N:16]([CH3:23])[N:15]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[C:1]1([C:7](=[C:19]([C:18]2[C:14]([Cl:13])=[N:15][N:16]([CH3:23])[C:17]=2[Cl:22])[OH:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=C(O)c1c(Cl)nn(C)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
8.2 g (50 mmols) of ethyl phenylacetate and 10.7 g (50 mmols) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride were dissolved in 100 ml of dry tetrahydrofuran, and 14 g (125 mmols) of potassium tert-butoxide at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and 300 ml of water was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 17 g of the intended ethyl 2-phenyl-3-(3,5-dichloro-1-methylpyrazol-4-yl)-3-hydroxyacrylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([O:15][Si](C(C)(C)C)(C)C)[C@@H:9]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH3:14])[CH2:11][C@H:10]([OH:15])[C@@H:9]1[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H]1C[C@H](O)[C@H](Cc2ccccc2)N1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of (2S,3S,5R)-2-benzyl-3-(tert-butyl-dimethyl-silanyloxy)-5-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.243 mmol; 102 mg) in THF is added 1.0 M THF solution (0.36 mL) of tetra-n-butylammonium fluoride under nitrogen at room temperature. After 3 hours, The reaction mixture is quenched with saturated aqueous ammonium chloride solution, extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; n-hexane/EtOAc) to give (2S,3S,5R)-2-benzyl-5-ethyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (74.4 mg, 99%); ESI-MS m/z: 250 [M+−tBu+2], Retention time 2.34 min (condition A).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:6]([CH3:14])([CH2:7][O:8][C:9](=[O:13])[C:10]([CH3:12])=[CH2:11])[O:5][C:3]1=[O:4].B(F)(F)F.COC1C=CC(O)=CC=1>C(OCC)(=O)C>[CH3:12][C:10]1([CH3:11])[C:6]([CH3:14])([O:5][C:3](=[O:4])[C:2]([CH3:1])=[CH2:15])[CH2:7][O:8][C:9]1=[O:13]
Reactant: C=C(C)C(=O)OCC1(C)OC(=O)C1(C)C
Agent: COc1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)OC1(C)COC(=O)C1(C)C

Procedure:
In a 50 mL four-necked flask, 0.5 g of α,α,β-trimethyl-β-methacryloyloxymethyl-β-propiolactone was put, and dissolved in 10 g of ethyl acetate, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. Further, 5 mol % of diethyl ether complex of boron trifluoride was added thereto based on the substrate, and 5 mg of p-methoxyphenol was added thereto, and while solution temperature was kept at 30° C., the resulting mixture was stirred. After the mixture was stirred for 2 hours, the resulting reaction mixture was washed with a 10% sodium carbonate aqueous solution and saturated brine, and dried over magnesium sulfate. After separation by filtration, the solvent was distilled off using an evaporator. A quantitative isomerization reaction to crude α,α,β-trimethyl-β-methacryloyloxy-γ-butyrolactone represented by formula (9) was confirmed. FIG. 2 shows an NMR measurement chart.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C.[C:36]([O:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([CH3:68])=[C:47]([C:49]2[CH:50]=[C:51]3[C:57]([C:58](O)=[O:59])=[C:56]([C:61]4[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=4)[O:55][C:52]3=[N:53][CH:54]=2)[CH:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.CCOC(C)=O>[F:67][C:64]1[CH:65]=[CH:66][C:61]([C:56]2[O:55][C:52]3=[N:53][CH:54]=[C:49]([C:47]4[CH:48]=[C:43]([CH:44]=[CH:45][C:46]=4[CH3:68])[C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH:50]=[C:51]3[C:57]=2[C:58](=[O:59])[NH:2][CH3:1])=[CH:62][CH:63]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Reaction time: 1 h
Yield: 90.2 %

Procedure:
HATU (209 mg, 0.550 mmol) was added to a stirring solution of methanamine (1.2 mL, 2.4 mmol, 2M in THF), DIEA (240 μL, 1.37 mmol) and 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (205 mg, 0.458 mmol) in DMF (4.5 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (190 mg, 0.413 mmol, 90% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, MeOD) δ ppm 8.28 (1H, d, J=2.26 Hz), 8.08 (1H, d, J=2.01 Hz), 7.99-8.06 (2H, m), 7.92 (1H, dd, J=8.03, 1.76 Hz), 7.86 (1H, d, J=1.51 Hz), 7.45 (1H, d, J=8.03 Hz), 7.30 (2H, t, J=8.78 Hz), 2.95 (3H, s), 2.34 (3H, s), 1.60 (9H, s). LC-MS retention time: 2.70 min; m/z (MH+): 461. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: N1C=CN=C1.CO[C:8](=[O:20])[C@H:9]([CH2:18][OH:19])[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Si:21](Cl)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C)C=O.O1CCCC1.O>[C:14]([O:13][C:11]([NH:10][CH:9]([CH2:8][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][OH:19])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 39 h

Procedure:
At room temperature, imidazole (6.43 g) was added to a solution of N-(t-butoxycarbonyl)-L-serine methyl ester (13.8 g) in N,N-dimethylformamide (140 ml), followed by the addition of t-butyldiphenylsilyl chloride (19.7 ml) at 0° C. The resulting mixture was stirred at room temperature for 39 hours. Ethyl acetate (200 ml) and water (600 ml) were added to the reaction mixture to cause separation. The water layer was extracted with ethyl acetate (100 ml). The organic layers were combined, washed with saturated aqueous NaCl solution (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was dissolved in tetrahydrofuran (100 ml) and methanol (100 ml) without purification, followed by the addition of sodium borohydride (7.20 g) in portions at 0° C. After stirring at 0° C. for 2 hours and then at room temperature for 1 hour, ethyl acetate (100 ml), an aqueous saturated solution of ammonium chloride (300 ml) and water (300 ml) were added to the reaction mixture to cause separation. The water layer was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column (500 g of silica gel, hexane:ethyl acetate=10:1˜1:1), whereby the title compound (24.9 g) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH:8]([C:11]1[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][C:16]=1[O:17][CH3:18])([CH3:10])[CH3:9].P([O-])([O-])(O)=O.[Na+].[Na+]>C1C=CC=CC=1>[OH:4][CH:3]=[C:13]1[C:12](=[O:19])[C:11]([CH:8]([CH3:10])[CH3:9])=[C:16]([O:17][CH3:18])[CH2:15][CH2:14]1
Reactant: CCOC=O
Reactant: COC1=C(C(C)C)C(=O)CCC1
Agent: O=P([O-])([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1=C(C(C)C)C(=O)C(=CO)CC1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a suspension of sodium hydride (3.6 g, 60% suspension, 90 mmol) in benzene (100 mL), a mixture of ethyl formate (12.5 g) and 2-isopropyl-3-methoxy-cyclohex-2-enone (5g, 29.7 mmol) in benzene was added dropwise at 5° C. The reaction mixture was stirred at ice temperature for 1 hour, and at room temperature for 18 hours. The reaction mixture was cooled in an ice bath, and 10% sodium hydrogen phosphate solution (200 mL) was added dropwise. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the resulting product was purified on a column of silica gel (Hex:EtOAc) to give the title compound as a thick viscous liquid (3.5 g, 60%). 1H NMR (CDCl3): δ 1.15 (d, 6H, 2×CH3), 2.35–2.6 (m, 4H, 2×CH2), 3.15 (m, 1H, CH), 3.8 (s, 3H, OCH3), 7.17 (d, 1H, ═CHOH).