Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27]C)=[O:26])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-3-methoxybiphenyl-4-carboxylate (0.43 g, 1.01 mmol) was suspended in THF (10 mL), MeOH (5 mL) and water (5 mL), and NaOH (0.40 g, 10 mmol) was added. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 0.41 g (99%) of the title compound as a light brown solid. LC/MS m/z 413.3 (MH+), retention time 3.44 min. 1H NMR (400 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.17 (t, 1H), 7.24-7.29 (m, 2H), 7.58-7.78 (m, 5H), 8.63 (t, 1H), 10.45 (br, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:21]>CCO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1-c1ccc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Sodium hydroxide (5M; 4.7 mL; 23.4 mmol; 3 eq.) was added to a solution of methyl 2′-methoxy-2-methylbiphenyl-4-carboxylate (2 g; 7.8 mmol; 1 eq.) in EtOH (60 mL) and the reaction mixture was stirred at 60° C. for one hour then concentrated in vacuo. The residue was taken up in water (400 mL) and washed with ethyl acetate (2×200 mL) then acidified to pH 2 with conc. HCl. The solution was concentrated to ca. 80 mL, the precipitate filtered off and dried to afford the title compound as a brown solid.
Reaction SMILES: [CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[CH:21]=4)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2].[C:30]1([CH2:36][CH2:37]C=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([C@:3]1([OH:29])[C:26]2[CH:25]=[C:24]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:23])[CH:18]=[C:19]([F:22])[C:20]=3[C:21]=4[CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:9](=[O:27])[C:8]=2[CH2:7][O:6][C:5](=[O:28])[CH2:4]1)[CH3:2]
Reactant: O=CCCc1ccccc1
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3c(F)cc(F)cc3nc2-1
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)cc(F)c1c2CCc1ccccc1

Procedure:
The product of Example 100 is treated with 3-phenylpropanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19]([CH:20]=O)=[C:18]([O:29][CH2:30][C:31]2[NH:35][N:34]=[N:33][N:32]=2)[CH:17]=1>>[CH3:14][O:15][C:16]1[C:23]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[CH:22][C:19](/[CH:20]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])=[C:18]([O:29][CH2:30][C:31]2[NH:32][N:33]=[N:34][N:35]=2)[CH:17]=1
Reactant: COc1cc(OCc2nnn[nH]2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OCc2nnn[nH]2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Yield: 60 %

Procedure:
The title compound was prepared by condensing 4-acetyl-benzenesulfonamide (Ex-26A) and 4-methoxy-2-(1H-tetrazol-5-ylmethoxy)-5-thiophen-2-yl-benzaldehyde (Ex-89A) in a similar manner as described in Ex-22. Yellow solid, mp 163–164° C. (dec), 60% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.31–8.34 (m, 3H), 7.92–8.15 (m, 4H), 7.70 (d, 1H, J=4.0 Hz), 7.54 (m, 3H), 7.15–7.17 (m, 1H), 6.92 (s, 1H), 4.64 (brs, 2H), 4.03 (s, 5H). MS (ESI) m/z=498 ([M+H]+, 100%). Anal. Calcd. for C22H19N5O5S2.1½H2O: C, 50.37; H, 4.23; N, 13.35; S, 12.23. Found: C, 50.48; H, 4.24; N, 12.95; S, 12.35.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([N+:10]([O-])=O)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:13](O)(=O)C>C(OC)(OC)OC.[Zn]>[CH3:1][S:2][C:3]1[C:4]2[N:10]=[CH:13][NH:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: CSc1cccc(N)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: COC(OC)OC
Product: CSc1cccc2[nH]cnc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6 g of 3-methylsulfanyl-2-nitrophenylamine were dissolved in 150 ml of glacial acetic acid and 60 ml of trimethyl orthoformate. Zinc powder (7 g) was added and the mixture was stirred for 2 h at 60° C. The solids were removed by filtration, the solvent was evaporated in vacuo and the residue was taken up in water and EA (200 ml each) and made basic with potassium carbonate. The precipitate was filtered off and the filtrate was extracted with EA, the combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by flash chromatography (200 g silica gel; DCM/MOH, gradient from 100:0 to 90:10). 2 g of the title compound were obtained as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[C:4]#[N:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH2:4][NH2:5]
Reactant: COCc1cc(Cl)cc(Cl)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCc1cc(Cl)cc(Cl)c1CN
Temperature: 60 °C

Procedure:
A soln. of BH3 (3.5 mL, 1M in THF) was added to a solution of 2,4-dichloro-6-(methoxymethyl)benzonitrile (0.88 mmol) in 3 mL THF. The reaction mixture was heated to 60° C. for 2 h. At 0° C., 3.5 mL MeOH was dropwise added and the mixture was stirred until gaz evolution was finished. An aq. soln. of 10% NaOH was added still under cooling. The solvent was removed under vacuo, the residue was diluted with water and extracted 3 times with EtOAc. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 3 h
Yield: 920 %

Procedure:
To the solution of 1-tert-butoxycarbonyl-4-hydroxypiperidine (20.13 g, 10 mmol) and triethylamine (16.7 mL, 120 mmol) in THF (200 mL) was added dropwise methanesulfonyl chloride (9.3 mL, 120 mmol) under ice cooling, and the mixture was stirred at the same temperature for 3 hours. To the mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (200 mL, 100 mL×2). The organic layer was washed with 1N-hydrochloric acid (50 mL×2), a saturated aqueous solution of sodium hydrogencarbonate (50 mL×2), saturated sodium chloride solution (50 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. To the concentrate were added diisopropyl ether (100 ml) and hexane (100 mL), and the resulting precipitates were collected by filtration. The precipitates were washed with diisopropyl ether/hexane (1/1) mixed solvent (100 mL), and dried under reduced pressure to give the titled compound (25.65 g, 92 mmol, Yield 92%) as white crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>C(#N)C>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:25][CH2:24][CH3:26])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(C)I
Reactant: CC(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(C)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 263 (M+, 4), 235 (15), 234 (bp), 163 (3), 133 (4).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=[NH:83])(C1C=CC=CC=1)C1C=CC=CC=1.NO>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:83])[C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: NO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(C(C)(C)O[SiH2]C(C)(C)C)ccnc1N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
An oven dried flask under N2 was charged with 4-(tert-butyl-dimethyl-silanyloxymethyl)-2-chloro-3-methyl-pyridine (10-1, 1.00 g, 3.68 mmol), NaOtBu (0.495 g, 5.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.067 g, 0.070 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.137 g, 0.22 mmol) and anhydrous toluene (10 mL). Benzophenone imine (0.740 mL, 4.41 mmol) was added and the reaction was heated to 80° C. After 3 hours the reaction was allowed to cool to room temperature and was diluted with 50 mL of diethyl ether. The resulting mixture was filtered through celite, washing with ether. The filtrate was concentrated, redissolved in 10 mL MeOH and hydroxylamine (50% aqueous, 0.676 mL, 11.0 mmol) was added. After stirring overnight, an additional 0.680 mL of hydroxylamine solution was added. After 8 hours the solution was concentrated in vacuo. The residue was purified by flash column chromatography (sample was loaded in DCM and eluted with a DCM to 9:1 DCM/MeOH gradient) to afford the title product. 1H NMR indicates that product is contaminated with BINAP dioxide. 1H NMR (CDCl3) δ 7.80 (d, 1H), 6.85 (d, 1H), 4.65 (s, 2H), 4.35 (bs, 2H), 2.00 (s, 3H), 0.95 (s, 9H), 0.15 (s, 6H).
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1COCC1>[I:11][C:3]1[CH:4]=[CH:5][C:6]([S:7]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:9])=[O:8])=[CH:1][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(I)cc2)CC1
Temperature: 25 °C

Procedure:
Pipsyl chloride (1.21 g, 4.0 mmol) was dissolved in THF (12 mL) and 4-methylpiperazine (1.1 mL, 12.2 mmol) was added dropwise. The resulting suspension was allowed to stir at RT over night. Filtration and washing with THF afforded crop 1 of compound 58. The mother liquors were concentrated, taken up in CH2Cl2, washed with H2O and brine, then dried over Na2SO4 to afford a second crop of compound 58.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](O)[CH:6]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([Br:26])[CH:14]=1)[C:7](=O)[CH2:8][CH2:9][CH2:10][CH3:11])C.O.[NH2:30][NH2:31]>C(O)(=O)C>[Br:26][C:15]1[CH:14]=[C:13]([C:6]2[CH:5]=[C:4]([OH:3])[N:30]=[N:31][C:7]=2[CH2:8][CH2:9][CH2:10][CH3:11])[CH:18]=[CH:17][C:16]=1[O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NN
Reactant: CCCCC(=O)C(c1ccc(OC2CCCCC2)c(Br)c1)C(O)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(O)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(3-bromo-4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (4.39 mmol, 2.0 g) and hydrazine hydrate (2.0 mL) in acetic acid (10 mL) was kept stirring at 120° C. for 3 h. The reaction mixture was concentrated under reduced pressure and to the residue was added water, extracted with ethyl acetate dried and concentrated under reduced pressure, dried to provide 5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-ol (1.7 g).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([OH:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21](OC)(=[O:24])[CH2:22][SH:23].[NH2-].[Li+]>C1(C)C=CC=CC=1>[C:21]([O:18][CH:13]1[CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:19])([CH3:20])[CH2:12]1)(=[O:24])[CH2:22][SH:23]
Reactant: COC(=O)CS
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CS)CC1(C)C

Procedure:
The general procedure of Example 1 is followed using 2.09 grams (7.0 mmol) of 1-octyloxy-4-hydroxy-2,2,6,6-tetramethylpiperidine, 0.74 gram (7.0 mmol) of methyl thioglycolate and 0.17 gram of lithium amide in 50 ml of toluene to afford the title compound after purification by silica gel chromatography.
Reaction SMILES: [N:1]1([C:7]([C:9]2([CH2:21][NH2:22])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:32][C:33]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:34]=1[C:35]([NH:22][CH2:21][C:9]1([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][CH3:20])(=[O:17])=[O:16])[CH2:11][CH2:10]1)=[O:36]
Reactant: CCCS(=O)(=O)N1CCC(CN)(C(=O)N2CCOCC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of {[4-(morpholin-4-ylcarbonyl)-1-(propylsulfonyl)piperidin-4-yl]methyl}amine (I-5) (33 mg, 0.10 mmole), DIEA (35 μL, 0.20 mmole), and 2,4-dichlorobenzoyl chloride (23 mg, 0.11 mmole) in DCM (2 mL) was shaken 1 h at room temperature. After this time, LCMS indicated that the reaction was completion. DCM was removed by nitrogen gas flow and the residue was purified by LCMS to afford the title compound (I-6) as a white solid. Analytical LCMS: single peak (214 nm), 2.867 min. 1H NMR (600 MHz, CD3CN): δ 7.52 (dd, J=0.9, 1.5 Hz, 2H), 7.39 (m, 2H), 6.98 (t, J=5.9 Hz, 1H), 3.63 (m, 10H), 3.49 (m, 2H), 3.05 (m, 2H), 2.89 (t, J=7.8 Hz, 2H), 2.30 (m, 2H), 1.74 (m, 2H), 1.62 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); HRMS: calc'd for C21H29Cl2N3O5S [M+H], 506.1278; found 506.1248.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([OH:26])=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].Cl.CN(C)CCCN=C=NCC.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:26])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1nc2c(Cl)ccc(OCC(=O)NS(C)(=O)=O)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetic acid (0.050 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g), methanesulfonamide (0.020 g), and 4-(N,N-dimethylamino)pyridine (0.005 g) in dichloromethane (5.0 mL) was stirred at room temperature 1 hour. The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 95% of organic modifier) gave title compound as a yellow solid, 0.010 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])=[N:8][C:7](=O)[C:6]=2[CH:20]=1.Cl.[NH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[NH2:23].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=3[OH:18])[N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:23]=2)[CH:20]=1
Reactant: O=c1nc(-c2cc(Cl)ccc2O)oc2ccc(Cl)cc12
Reactant: NNCc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1ccc(Cl)cc1-c1nc(-c2cc(Cl)ccc2O)n(Cc2ccccn2)n1

Procedure:
3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benz[e][1,3]oxazin-4-one are boiled under reflux for 5 h with 1.7 9 of 2-hydrazinomethylpyridine hydrochloride and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. After drying, 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridin-2-ylmethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 227-229 C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH:19]([C:20]([O:22][CH3:23])=[O:21])[C:18](=[O:24])[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:24][CH:30]([CH3:35])[CH3:31])[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:16]=4)[O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCOc1ccc2c(c1)C(=O)C(C(=O)OC)C(c1ccc3c(c1)OCO3)O2
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCCCOc1ccc2c(c1)C(OC(C)C)=C(C(=O)OC)C(c1ccc3c(c1)OCO3)O2
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The compound (VII-3) was converted to methyl 2-(benzo[1,3]dioxol-5-yl)-6-butoxy-4-oxo-chroman-3-carboxylate (IV-3) by a similar method as Step 5 of Reference Example 2. Compound (V-3) (250 mg, 0.628 mmol), triphenylphosphine (247 mg, 0.943 mmol) and isopropanol (57 mg, 0.943 mmol) were dissolved in 7 ml of THF and cooled to −10° C. A solution of diethylazodicarboxylate (164 mg, 0.943 mmol) in THF (2 ml) was added dropwise and stirred for 2 h at the same temperature. After the solvent was removed under reduced pressure, the residue was purified by 10 g of silica gel chromatography (ethyl acetate/hexane=1:4) to give the compound (Ia-11) (220 mg, 80%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=O)=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl.[NH2:17][C:18]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[C:18]([NH:17][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:23]
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(Br)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=415.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].C([O-])(=O)C.[K+].[I:15]Cl>C(O)(=O)C>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([I:15])=[CH:7][N:6]=1
Reactant: ClI
Reactant: CCc1ccnc(N)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1cc(N)ncc1I
Temperature: 80 °C
Yield: 73.8 %

Procedure:
4-ethyl-2-aminopyridine (10.0 g, 81.9 mmol) and potassium acetate (8.00 g, 81.9 mmol) were dissolved in 100 mL of acetic acid and heated to 80° C. with continuous stirring. In a separate flask, iodomonochloride (13.2 g, 81.9 mmol) was dissolved in 30 mL of acetic acid and added to the above reaction mixture drop wise. Once the addition was completed, the reaction mixture was heated for an additional 4 h. Progress of the reaction was monitored by gas chromatography and HPLC. When the reaction was completed, the reaction mixture was cooled to room temperature and quenched with an aqueous solution of saturated sodium bisulfite (10 mL). Acetic acid was removed under vacuum and the residue was dissolved in ethyl acetate and neutralized with saturated NaHCO3. The organic layer was separated from the aqueous layer and the solvent was removed under vacuum. The crude was purified by silica gel column chromatography eluting with 25% ethyl acetate/hexanes. 15 g of desired product was obtained (74% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:14]1([O:20][CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:21][O:20][C:14]1[CH:19]=[CH:18][C:17]([C:9]([C:8]2[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccccc1
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(NC(C)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A round-bottomed flask was charged with 4-acetamidobenzoyl chloride (0.95 g, 4.57 mmol), anisole (0.60 mL, 5.48 mmoL) and CH2Cl2 (15 mL). Cooled in an ice bath, AlCl3 (0.93 g, 6.85 mmol) was added in portions. The mixture was stirred at 0° C. for 4 h. The resulting dark brown solution was poured into 1 N HCl (25 mL) with ice and the mixture was extracted with EtOAc (2×60 mL). The combined EtOAc extract was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give brown solid. The crude product was purified by chromatography on a silica gel column eluted with hexanes:EtOAc (1:1) to give 0.55 g (45%) of compound 56 as light brown solid. mp 160-162° C. 1H NMR (400 MHz, CDCl3): δ 2.22 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.34 (br s, 1H), 7.55-7.65 (m, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H). LCMS (ESI): m/z 270 (M+H)+, 268 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH2:8][OH:9])=[CH:6][CH:7]=1>CO>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[O:4]1
Reactant: OCc1ccc(CO)o1
Solvent: CO
Product: OCC1CCC(CO)O1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Into a 300 ml stainless steel autoclave was charged 40.03 g. 2,5-bis-(hydroxymethyl)furan, 100 ml methanol and 3 g. of cationic ruthenium zeolite. After pressurizing with H2 to 1900 psig and initiating stirring, the exothermic reduction occurred increasing the temperature from 30° C. (reaction temperature) to 61° C. The reduction temperature started to decrease as the reduction slowed down. The reduction was complete in 30 minutes and workup gave 99 percent 2,5-bis-hydroxymethyl tetrahydrofuran as the sole product (verified by analysis).