Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Cl[CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>>[CH2:22]([N:23]([CH2:26][CH3:27])[CH2:24][CH2:25][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: CCN(CC)CCCl
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)CCOC1c2ccccc2C(=O)N1c1ccccc1
Yield: 105.3 %

Procedure:
Following the procedure of Example 6 but starting with 3-hydroxy-2-phenyl-isoindolin-1-one (22.5 g.), sodium hydride (50% dispersion in mineral oil) (5.3 g.) and 1-chloro-2-diethylaminoethane (13.5 g.), 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one (34 g.) is obtained in the form of an 85% pure oil. On treating this oil (28 g.) with fumaric acid (8.5 g.) in ethanol, 3-(2-diethylaminoethoxy)-2-phenyl-isoindolin-1-one hydrogen fumarate (27.6 g.), which melts at 146°-147°C., is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:33])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.O1CCCC1CO.C[O-].[Na+:45]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13]([C:15]3[CH:35]=[CH:34][C:18]([O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]([C:30]([O-:32])=[O:31])[CH2:25][CH2:26][O:27]5)=[CH:22][C:21]=4[Cl:33])=[CH:17][CH:16]=3)=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[Na+:45]
Reactant: O=C(NCCc1ccc2c(c1)OCO2)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: OCC1CCCO1
Product: O=C(NCCc1ccc2c(c1)OCO2)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylic acid (60 mg, 0.12 mmol), 0.1 molar in 4:1 tetrahydrofuran-methanol, was treated with sodium methanolate (242 μl, 0.12 mmol) at ambient temperature. After 15 minutes, the solvent was removed in vacuo. The resulting solid was taken up in ethyl acetate and concentrated in vacuo. The solid was then taken up in 4:1 dichloromethane-hexanes and concentrated in vacuo and dried under high vacuum to provide sodium 7-(4-(2-(benzo[d][1,3]dioxol-5-yl)ethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (63 mg, 0.12 mmol, 101% yield) as a solid. MS (apci) m/z=495.9 (M+2H-Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[F:17][CH2:18][CH2:19]CS([O-])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:19][CH2:18][F:17])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)([O-])CCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(OCCF)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 3-chloro-5-hydroxybenzaldehyde (8.2 g, 52.5 mmol; see Example 1(ii) above) and potassium carbonate (9.4 g, 68.2 mmol) in DMF (10 mL) under nitrogen was added a solution of (2-monofluoroethyl)methanesulfonate (9.7 g, 68.2 mmol; see step (i) above) in DMF (120 mL) dropwise at room temperature. The mixture was heated to 100° C. for 5 h and then stirred overnight at room temperature. The reaction was cooled to 0° C., poured into ice-cold 2N HCl and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The brown oil was chromatographed on silica gel eluting with Hex:EtOAc (4:1) to afford the sub-title compound (7.6 g, 71%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][C:10](=[O:11])[CH:9]2[CH2:14]OS(C)(=O)=O)=[CH:4][CH:3]=1.C(O)(=O)C.[SH-:24].[Na+]>C(O)C.C(OCC)(=O)C>[SH:24][CH2:14][CH:9]1[CH:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[CH2:13][O:12][C:10]1=[O:11]
Reactant: [SH-]
Reactant: CS(=O)(=O)OCC1C(=O)OCC1c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1OCC(c2ccccc2)C1CS
Yield: 52 %

Procedure:
To a solution of 1.0 g of α-methanesulfonyloxymethyl-β-phenyl-γ-butyrolactone (III) in 20 ml of ethanol were added 1.5 ml of acetic acid and then 1.2 g of commercially available 70% sodium hydrosulfide and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was diluted with 150 ml of ethyl acetate, washed with water in a conventional manner, dried over magnesium sulfate and the solvent was distilled off. The crude product thus obtained was purified by a column chromatography to give 400 mg (yield 52%) of the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]([C:10]([NH:12][C:13]2[C:14]([SH:23])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=2)=O)=[CH:8][N:7]=[CH:6][CH:5]=1)[CH3:2].CN(C=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:9]=1[C:10]1[S:23][C:14]2[C:13]([N:12]=1)=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)[CH3:2]
Reactant: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCSc1ccncc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 150 °C
Reaction time: 10 h
Yield: 31.1 %

Procedure:
A mixture of 494 mg of 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide, 1.05 g of p-toluenesolufonic acid-hydrate, 3 ml of DMF and 1 ml of toluene was heated and stirred at 150° C. for 10 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was applied to a silica gel column chromatography to obtain 146 mg of 2-(4-ethylsulfanylpyridin-3-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as Compound of Present Invention 42).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].O.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1(=O)CCCC1.C(O)(=O)C>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:15]3([CH2:16][CH2:17][CH2:12][CH2:22]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NC(=O)c1sc(Br)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C1CCCC1
Solvent: CC(=O)O
Product: O=C1NC2(CCCC2)Nc2cc(Br)sc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 918 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.072 g, 0.33 mmol) and p-toluenesulfonic acid monohydrate (0.013 g, 0.066 mmol) in cyclopentanone (2 mL) and acetic acid (1 mL) was stirred at 70° C. for 2 h. Then, the reaction mixture was cooled, carefully poured into sat. NaHCO3 (50 mL), and extracted with 2:1 ethyl acetate/tetrahydrofuran (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a brown gum (0.174 g), which was used without further purification. A mixture of the crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.172 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.349 g, 1.80 mmol), 2 M sodium carbonate (1.2 mL, 2.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.073 g, 0.090 mmol) in 1,4-dioxane (3 mL) was microwave-irradiated at 140° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), and purified again by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.045 g, 2 step yield 50%) as a yellow solid:
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH:2]1[C:14]([O:16][CH3:17])=[O:15]>CO.[Pd]>[N:4]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][CH2:6][NH:1][CH:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
10% Pd—C (0.2 eq) was added to a stirred RT 0.1 M solution of A2 in MeOH and the mixture was stirred under an H2 atmosphere at RT for 3 h. The mixture was filtered, washing with MeOH, and the filtrate was evaporated under reduced pressure to give the title compound in 95% yield. 1H NMR (400 MHz, CDCl3, 300K) δ 4.02 (1H, m), 3.74 (3H, s), 3.70 (1H, m), 3.43 (1H, m), 3.20 (1H, m), 3.04 (2H, m), 2.75 (1H, m), 2.14 (1H, m), 1.47 (9H, s). MS (ES+) C11H20N2O4 requires 244, found: 267 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:32]5[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=5[CH3:34])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccccc1C[Zn+]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3C)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.29 min; Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: [OH-].[NH4+:2].[C:3]([C:5]1[CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]>Cl>[C:3]([C:5]1[CH:6]=[C:7]([S:12]([NH2:2])(=[O:14])=[O:13])[CH:8]=[CH:9][C:10]=1[F:11])#[N:4]
Reactant: [NH4+]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [OH-]
Product: N#Cc1cc(S(N)(=O)=O)ccc1F

Procedure:
Concentrated ammonium hydroxide (28% solution in water, 3.17 mL) was cooled to 0° C. and 3-cyano-4-fluorobenzene-1-sulfonyl chloride (1.00 g) was added. The solution was mixed at 0° C. for four minutes. 4M HCl (10 mL) was added slowly and the solution was extracted with ethyl acetate. The extract was dried on brine and anhydrous sodium sulfate and the solvent removed under vacuum.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N-]=C=O.[C:21](Cl)(Cl)=[O:22].[CH3:25][NH:26][OH:27]>C1(C)C=CC=CC=1>[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:21]([N:26]([OH:27])[CH3:25])=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCCCCCCOCc1ccccc1
Reactant: O=C(Cl)Cl
Reactant: CNO
Agent: Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: CN(O)C(=O)NCCCCCCCOCc1ccccc1

Procedure:
By the method of Example 32 above, 7-(benzyloxy)heptylamine hydrochloride was converted to the isocyanate by treatment with phosgene in toluene, and then treated with N-methylhydroxylamine. Chromatography on silica gel, and recrystallization from ethyl acetate-hexane, provided the title compound as a white solid, mp 69°-70.5° C.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[O-:2].[NH4+:6].C1(=[N:13][OH:14])CCCCC1.C1(=O)CCCCC1>>[OH:14][NH3+:13].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:6].[NH4+:13]
Reactant: O=S(=O)([O-])O
Reactant: ON=C1CCCCC1
Agent: [NH4+]
Solvent: O=C1CCCCC1
Product: O=S(=O)([O-])[O-]
Product: [NH3+]O

Procedure:
The aqueous ammonium bisulfate phase freed from organic products such as cyclohexanone oxime and cyclohexanone may be used directly or, for example, after treatment with carbon for the removal of the final traces of organic components, in the catalytic hydroxylamine synthesis in place of sulfuric acid. Here again there is produced a hydroxylammonium/ammonium sulfate solution which may then be used for the oximation process. The aqueous ammonium bisulfate solution formed during oximation may, of course, be passed to the hydroxylamine synthesis as formed or, if desired, in a diluted or concentrated form. The oxime phase produced by the oximation reaction may be used directly, without post-oximation or purification, to particular advantage for catalytic rearrangement to caprolactam in the gas phase, the catalyst being, say, boron oxide/aluminum oxide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1(O)[C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[C:10]2[CH:11]=[C:12]([NH:17][C:18](=[O:24])[CH2:19][C:20]([CH3:22])([CH3:21])[CH3:23])[C:13]([CH3:16])=[C:14]([CH3:15])[C:9]=2[O:8][C:7]1([CH3:26])[CH3:25]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1ccco1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccco1
Yield: 67 %

Procedure:
Using N-(3-(2-furyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 252, the title compound was synthesized in the same manner as in Example 271. Yield: 67%. Melting point: 126-127° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@@H:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:19]([CH3:27])([CH2:20][CH2:21][C:22]=32)[C@@H:11]([C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10][CH:9]=4)[C:3]1([CH3:29])[CH3:28].B(F)(F)F.CCO[CH2:37][CH3:38]>C1(O)CCCCC1>[CH:38]1([O:16][C:15](=[O:17])[CH2:14][CH2:13][C@H:12]([C@@H:11]2[C@:19]3([CH3:27])[C:8]([C:7]4[CH2:6][CH2:5][C@@H:4]5[C@:23]([C:22]=4[CH2:21][CH2:20]3)([CH3:26])[CH2:24][CH2:25][C@H:2]([OH:1])[C:3]5([CH3:28])[CH3:29])=[CH:9][CH2:10]2)[CH3:18])[CH2:37][CH2:4][CH2:3][CH2:2][CH2:25]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reactant: CCOCC
Agent: FB(F)F
Solvent: OC1CCCCC1
Product: C[C@H](CCC(=O)OC1CCCCC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Temperature: 57.5 °C
Reaction time: 20 h

Procedure:
3β-Hydroxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (0.2 g) is suspended in 10 ml of cyclohexanol, 0.1 ml of boron trifluoride diethyl etherate is added and the mixture is stirred at 55-60° C. for 20 hours. After evaporation to dryness under reduced pressure, the remanens is purified by column chromatography and crystallized from methanol to give the title compound (49 mg). Melting point: 130-132° C. 1H-NMR (CDCl3): δ=5.35 (1H, s); 4.75 (1H, m); 3.24 (1H, m). MS: Calculated: 482.8. Found 482.4.
Reaction SMILES: O1CCCC1.[OH-].[Na+].[NH2:8][C:9]1[C:14]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:17]3[CH:16]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[O:19][N:18]=3)=[CH:22][CH:23]=2)=[N:31][CH:32]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: Fc1ccc(CCl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccc(F)cn3)cc2)no1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Tetrahydrofuran (10 mL) and 5 N aqueous sodium hydroxide solution (448 μL, 2.24 mmol) were added to 4-(5-(2-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (600 mg, 2.24 mmol) described in Manufacturing Example 5-1-1, which was irradiated by ultrasonic wave for 1 minute. The reaction solution was then concentrated under a reduced pressure to obtain a white solid. 2-Chloromethyl-5-fluoro-pyridine (359 mg, 2.46 mol) described in Manufacturing Example 41-2 and N,N-dimethylformamide (10 mL) were added to the resulting white solid and stirred for 1 hour at 60° C. After being cooled to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (650 mg, 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 13 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using morpholine instead of 2,2,2-trifluoroethylamine, to the title compound (16 mg, 13%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.O.[CH3:19]O>>[CH3:19][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-carboxyphenylboronic acid (2.0g) and sulfuric acid (0.1 ml) in methanol (50 ml) was refluxed overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over MgSO4. The solvent was evaporated in vacuo to give 4-methoxycarbonylphenylboronic acid (1.7 g) as colorless prisms.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH2:13][CH:14]=[CH2:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)CCCCCCCCCCCCCCC.C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[O:16][C@@H:11]([O:12][CH:13]=[CH:14][CH3:15])[C@@H:10]1[NH:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC=CO[C@@H]1O[C@H](COC(=O)CCCCCCCCCCCCCCC)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1NC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 6' (6 g., 11.0 mmol) was dissolved in dry pyridine (120 ml.), and the solution was cooled at -10°. Palmitoyl chloride (4.7 ml., 16.8 mmol) was added dropwise while the reaction mixture was stirred at -10°. After an additional 30 min. the mixture was allowed to warm up to room temperature and then stirred for 2 h. The product was isolated by conventional chloroform extraction. After purification on a column of silica gel, the yield of 7 was 7.6 g (88%).
Reaction SMILES: [CH2:1]([N:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[C:9]([C:15]#N)[C:8]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)[OH:19].[OH-:23].[Na+]>O>[CH2:1]([N:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[C:9]([C:15]([OH:19])=[O:23])[C:8]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(C)cc(C)c(C#N)c1=O
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCCCn1c(C)cc(C)c(C(=O)O)c1=O
Yield: 100 %

Procedure:
To a stirred mixture of 1-(n-hexyl)-3-cyano-4,6-dimethyl-pyrid-2-one (222.3 g., 0.957 mole) and water (100 ml.) is added dropwise concentrated sulfuric acid (300 g.). When the addition is completed the stirred solution is heated on a steam bath for 24 hours. The solution is poured onto ice and basified with a sodium hydroxide solution and filtered. The alkaline filtrate is acidified with acetic acid and extracted with 400 ml. of toluene. The toluene layer is then extracted with 2 × 350 ml. of 5% NaOH. The aqueous layer is acidified with hydrochloric acid and cooled in an ice bath. The semi-solid precipitate is recrystallized from methanol/water to give 1-(n-hexyl)-3-carboxy-4,6-dimethylpyrid-2-one, 24 g. (100% yield), mp. 79-82.5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:29])[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.C[OH:36]>CN(C=O)C>[C:28]([OH:27])(=[O:29])/[CH:23]=[CH:24]\[C:25]([OH:26])=[O:36].[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:27])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1
Reactant: CO
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)O
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-[4-(6-fluoro-1H-3-indazolyl)-1-piperidinyl]ethylamine (6.1 g, 23.3 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature under nitrogen. The reaction mixture was warmed to 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of the desired product as a white solid. The maleate salt was prepared in methanol (75 ml) using maleic acid (2.1 eq.). The precipitated salt was collected via filtration and recrystallized from acetonitrile to give a white solid, m.p. 193-195° C.
Reaction SMILES: [H-].[Na+].[CH:3](OCC)=[O:4].[CH:8]1([CH:13]2[C:18]([O:19][CH3:20])=[CH:17][CH2:16][CH2:15][C:14]2=[O:21])[CH2:12][CH2:11][CH2:10][CH2:9]1.P([O-])([O-])(O)=O.[Na+].[Na+]>C1C=CC=CC=1>[CH:8]1([C:13]2[C:14](=[O:21])[C:15](=[CH:3][OH:4])[CH2:16][CH2:17][C:18]=2[O:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC1=CCCC(=O)C1C1CCCC1
Reactant: CCOC=O
Agent: O=P([O-])([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC1=C(C2CCCC2)C(=O)C(=CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.9 %

Procedure:
To a suspension of sodium hydride (2.04 g, 60% suspension, 51 mmol) in benzene (100 mL), a mixture of ethyl formate (6.7 g) and 2-cyclopentyl-3-methoxycyclohex-3-en-1-one (2.82 g, 17 mmol) in benzene was added dropwise at 5° C. The reaction mixture was stirred at ice temperature for 1 hour and 18 hours at room temperature. The reaction mixture was cooled in ice bath, and 200 mL of 10% sodium hydrogen phosphate solution was added dropwise. The organic layer was separated, and aqueous layer was extracted with ethyl acetate (2×50 mL). Combined organic extract was washed with brine and dried over anhydrous sodium sulfate. 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 viscous liquid (2 g, 60%).