Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[C:24]([NH2:29])[CH:25]=[N:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:1]([CH2:2][CH2:3][CH3:4])=[N:29][C:24]=3[CH:25]=[N:26][C:27]=2[CH:28]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 105 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Trimethyl orthobutyrate (29.75 mL, 0.1859 mol) was added in three portions to a solution of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine (54.6 g, 0.170 mol) in toluene (795 mL). Pyridine hydrochloride (1.96 g) was then added, and the reaction was heated at 105° C. and stirred for four hours. Additional trimethyl orthobutyrate (7 mL, 40 mmol) was then added, and the reaction was stirred for three hours. The reaction was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The oily residue was treated with chloroform, which was removed under reduced pressure to remove residual toluene, and then again diluted with chloroform (1.2 L). The resulting solution was washed sequentially with 5% aqueous sodium bicarbonate, water, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to yield 60.3 g of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an oily brown solid, containing a small amount of toluene (0.93 equivalents).
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:22])[C@H:9]([CH2:18][S:19][CH2:20][CH3:21])[NH:10]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:23]>C(OCC)(=O)C>[ClH:23].[N:1]1([NH:7][C:8](=[O:22])[C@H:9]([CH2:18][S:19][CH2:20][CH3:21])[NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)NN1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCSC[C@H](N)C(=O)NN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
In 50 ml of tetrahydrofuran was dissolved 5.46 g (21.9 mmole) of S-ethyl-N-t-butoxycarbonyl-L-cysteine and 3.05 ml (21.9 mmole) of triethylamine was added thereto. Upon cooling to -15° C., 2.87 ml (21.9 mmole) of isobutyl chloroformate was added dropwise and the mixture was stirred for 20 minutes at that temperature. Upon cooling to -30° C., a solution of 2.79 g (32.9 mmole) of piperidine in 5 ml of tetrahydrofuran was added in one portion and the mixture was stirred for 2.5 hours under ice cooling. After addition of 70 ml of ethyl acetate, the mixture was washed successively with 30 ml of aqueous 5% sodium bicarbonate, 2×30 ml of aqueous 10% citric acid, 2×30 ml of aqueous 5% sodium bicarbonate and 2×30 ml of saturated saline and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated in vacuo to give 6.66 g of S-ethyl-N-t-butyloxycarbonyl-L-cysteine piperidylamide as an oil, 96% yield. ##STR14## A solution of 6.55 g (20.7 mmole) of S-ethyl-N-t-butyloxycarbonyl-L-cysteine piperidylamide in 100 ml of ethyl acetate was added dropwise over 20 minutes to 80 ml of ice-cooled 16% solution of hydrogen chloride in ethyl acetate. After stirring for 3 hours at room temperature, the reaction mixture was concentrated in vacuo, resulting in the formation of crystals. The crystals were collected, washed with ethyl acetate and then with ethyl ether and dried to give 3.66 g of S-ethyl-L-cysteine piperidylamide hydrochloride, 74% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][CH2:27][CH2:26][C@H:25]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.I[CH3:37]>>[CH3:37][N:23]([S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([CH3:1])[CH:11]=2)=[CH:19][CH:18]=1)(=[O:22])=[O:21])[C@H:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CI
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CCC[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Yield: 93 %

Procedure:
According to the procedure of Example 15, Step 2, the reaction of 250.0 mg (0.5 mmol) of tert-butyl cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate with iodomethane provided 238.0 mg of tert-butyl cis-2-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate in 93% yield. MS: 511.2 (M+H)+
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.ClCCl>[CH2:5]([O:12][C:13]([NH:15][C:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([Cl:3])=[O:24])=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1

Procedure:
Thionyl chloride (0.21 ml) and dimethylformamide (2 drops) were added to a solution of 4-(1-benzyloxycarbonylamino-1-methylethyl)-benzoic acid (780 mg) in dichloromethane (10 ml), and the mixture was refluxed under heating for 1 hour. After the reaction, the solvent was evaporated under reduced pressure to give 4-(1-benzyloxycarbonylamino-1-methylethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml), and the solution was dropwise added to a solution of 4-aminopyridine (195 mg) and diisopropylethylamine (0.5 ml) in acetonitrile (10 ml) under ice-cooling. The mixture was stirred at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-hexane to give 750 mg of N-(4-pyridyl)-4-(1-benzyloxycarbonylamino-1-methylethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1.N1C=CC=CC=1>CC(N(C)C)=O>[N:9]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: C1CNC1
Reactant: Clc1ccc(Br)cn1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: Brc1ccc(N2CCC2)nc1
Temperature: 170 °C

Procedure:
A mixture of 5-bromo-2-chloropyridine (Sigma-Aldrich, Buchs, Switzerland, 196 mg, 1.018 mmol), azetidine (Sigma-Aldrich, Buchs, Switzerland, 0.213 ml, 3.06 mmol) and pyridine (0.124 ml, 1.528 mmol) in DMA (2.5 ml) was heated under microwave irradiation at 150° C. for 10 min and 170° C. for 10 min. The reaction was not completed. Again azetidine (0.106 ml) was added and the RM was heated under microwave irradiation at 170° C. for 1 h. Then the RM was quenched with saturated aqueous NaHCO3 (50 ml) and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as an off-white solid. (HPLC: tR 1.97 min (Method A); M+H=213, 215 (Br-pattern) MS-ES. 1H-NMR (d6-DMSO, 400 MHz) 8.12 (s, 1H), 7.70-7.60 (m, 1H), 6.37-6.29 (m, 1H), 3.96-3.86 (m, 4H), 2.34-2.24 (m, 2H))
Reaction SMILES: CN1CC[O:5][CH2:4]C1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[N:16]2)=[CH:11][CH:10]=1.C(Cl)(Cl)=O>C(Cl)Cl>[N:8]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:17]([C:24]([F:27])([F:26])[F:25])=[N:16]2)=[CH:13][CH:14]=1)=[C:4]=[O:5]
Reactant: CN1CCOCC1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C=Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To morpholinomethyl polystyrene (Novabiochem, substitution=3.55 mmol/g, 1.02 g, 3.62 mmol) in methylene chloride (18.5 mL) under argon was added 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.555 g, 1.88 mmol). The mixture was cooled to 0° C. and phosgene (1.93M in toluene, Fluka, 1.95 mL, 3.76 mmol) was added. After thirty minutes the reaction mixture was filtered, washed with methylene chloride (2×30 mL) and concentrated to give 1-(4′-isocyanatophenyl)-3,5-bis(trifluoromethyl)pyrazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH2:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:19].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:18]([O:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:32])[CH:26]([NH:31][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:5]=[C:4]([S:16][CH3:17])[N:3]=1)[CH2:27][CH:28]([CH3:29])[CH3:30])[CH3:19]
Reactant: CCOCCCNC(=O)C(N)CC(C)C
Reactant: CSc1nc(Cl)cc(COC2CCCCC2)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCCNC(=O)C(CC(C)C)Nc1cc(COC2CCCCC2)nc(SC)n1

Procedure:
A mixture of 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidine, the hydrochloride salt of 2-amino-4-methylpentanoic acid (3-ethoxypropyl)amide (60 mg), and diisopropylethylamine (61 mg) in dimethylsulfoxide (0.5 mL) was heated at 95° C. for 16 h. The mixture was partitioned in water and ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (30% ethyl acetate in hexanes) to give 2-(6-cyclohexyloxymethyl-2-methylsulfanyl-pyrimidin-4-ylamino)-4-methyl-pentanoic acid (3-ethoxy-propyl)-amide (12 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20][C:19]=1[N:25]1[CH2:26][CH2:27][N:28]([C:11]([C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:16])=[CH:15][CH:14]=2)=[O:13])[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C)c(N2CCNCC2)cn1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)cn1
Yield: 37 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (165 mg) described in Preparation Example 16 and 1-(4,6-dimethylpyridin-3-yl)piperazine (131 mg) described in Preparation Example 95 and by the reaction and treatment in the same manner as in Example 87, the title compound (105 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:31])[CH:14]([P:23]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C)(C)C>ClCCl>[CH2:29]([O:28][P:23]([CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([OH:31])=[O:12])([O:25][CH2:26][CH3:27])=[O:24])[CH3:30]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (4 mL) was added drop wise to a stirring solution of 2-(diethoxy-phosphoryl)-4-phenyl-butyric acid tert-butyl ester (1.00 g, 2.81 mmol) in anhydrous dichloromethane (16 ml). The mixture was stirred for 2 hours at room temperature followed by the removal of the solvent. The crude residue was purified by flash chromatography (100% dichloromethane-2.5% methanol in dichloromethane) to afford the desired compound as a yellowish oil. 1H NMR (CDCl3, 400 MHz) δ 11.21 (br s, 1H), 7.29–7.14 (m, 5H), 4.24–4.12 (m, 4H), 3.09–3.00 (m, 1H), 2.82–2.75 (m, 1H), 2.64–2.57 (m, 1H), 2.35–2.27 (m, 1H), 2.15–2.11 (m, 1H), 1.31–1.25 (m, 6H); 13C (CDCl3, 100 MHz) δ 170.4, 140.4, 128.4, 128.3, 126.1, 63.4, 63.2, 45.1, 43.8, 34.0, 28.5, 16.0; 31p (CDCl3, 400 MHz) δ 24.3; HRMS calcd. for C14H21O5P 300.1127. found 300.1129.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[NH:19][C:18]2=[O:30])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:32][CH3:33].C([O-])(O)=O.[Na+]>>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([C:26]([F:29])([F:28])[F:27])=[C:20]3[N:19]([CH2:32][CH3:33])[C:18]2=[O:30])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=c1[nH]c2c(C(F)(F)F)ccnc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of NaH (40.9 mg), 3-[4-(benzyloxy)phenyl]-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) in DMF(dry) (3 mL) was added iodoethane (0.082 mL), and the mixture was stirred at room temperature for 3 h. To the mixture was added sat. NaHCO3 aq. and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (197 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].[Cl:11]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:11][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1cc[n+]([O-])c(C)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(CCl)c1C

Procedure:
A solution of 13.3 g of 2,3,4-trimethylpyridine N-oxide in 130 ml of abs. chloroform is boiled at reflux under argon and treated through the condenser with 33.2 ml of trichloroacetyl chloride. After 18 hours the reaction mixture is poured on to ice, whereupon 10% sodium bicarbonate solution is added, the mixture is extracted with methylene chloride and the methylene chloride solution is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel (solvent: methylene chloride/ether [5:1]). The 2-chloromethyl-3,4-dimethylpyridine obtained is processed directly.
Reaction SMILES: CI.[Cl:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([N:10]([CH3:29])[C:11]2[C:12]3[CH:13]=[N:14][N:15]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[C:16]=3[CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ncc3c(N(C)c4ccnc(Cl)n4)cccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
Methyl iodide (1.021 mL, 16.40 mmol) was added dropwise to a stirred suspension of N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (4 g, 10.93 mmol, Example 3 starting material) and potassium carbonate (2.267 g, 16.40 mmol) in DMF (40 mL) at 0° C. under nitrogen. The resulting suspension was stirred at 0° C. for 15 minutes and was allowed to warm to room temperature. The reaction mixture was stirred at room temperature overnight, filtered off and washed with ethyl acetate. The filtrate was concentrated to dryness, diluted with dichloromethane (40 ml), washed with water (40 ml), brine (40 ml), dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 45% ethyl acetate in petroleum ether to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-N-methyl-1H-indazol-4-amine (3.4 g, 82%) as a pale orange solid. NMR Spectrum: (DMSOd6) 3.50 (s, 3H), 3.71 (s, 3H), 5.63 (s, 2H), 6.19 (d, 1H), 6.89 (d, 2H), 7.16 (d, 1H), 7.29 (d, 2H), 7.49 (dd, 1H), 7.81 (d, 1H), 7.96 (d, 1H), 8.00 (s, 1H); Mass spectrum: MH+ 380.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([O:15][CH3:16])[CH2:12][NH:11][CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cncc(OC)c2)cc1
Solvent: CC(=O)O
Product: CCc1ccc(C2CNCC(OC)C2)cc1

Procedure:
A solution of 1.0 g (4.7 mmol) of 3-(4-ethylphenyl)-5-methoxypyridine in 120 ml of acetic acid was reacted according to General Method 5A. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol gradient). Yield: 880 mg (86% of theory)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](I)[CH:9]=1)(=[O:3])[CH3:2].[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:28]2[O:27][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Reactant: OB(O)c1ccco1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2ccco2)c1

Procedure:
By carrying out the operation analogously to example 3, starting from 3-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation I, and 2-furanboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: [OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:23])[F:22])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH:4]=[C:3]1[CH3:11].Cl.[CH3:26][O:27][NH2:28].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:1][C:2]1([C:12]#[C:13]/[C:14](/[C:21]([F:24])([F:22])[F:23])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]([CH3:8])([CH3:9])[CH2:6][C:5](=[N:28][O:27][CH3:26])[CH:4]=[C:3]1[CH3:11]
Reactant: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=O)CC1(C)C)C(F)(F)F
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C=C(\C#CC1(O)C(C)=CC(=NOC)CC1(C)C)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Ethyl (2E)-5-(1-hydroxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)-3-(trifluoromethyl)pent-2-en-4-ynoate (60 mg, 0.17 mmol), O-methylhydroxylamine hydrochloride (17 mg, 0.21 mmol) and sodium acetate (30 mg, 0.37 mmol) were dissolved in a 1:1 mixture of ethanol and water (4 ml) and then stirred at a temperature of 60° C. for 4 h. After cooling to room temperature, ethanol was removed under reduced pressure and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), ethyl (2E)-5-[1-hydroxy-4-(methoxyimino)-2,6,6-trimethylcyclohex-2-en-1-yl]-3-(trifluoromethyl)pent-2-en-4-ynoate (40 mg, 58% of theory) was obtained in the form of a colorless solid. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.65/6.63 (s, 1H), 6.00/5.94 (s, 1H), 4.27 (q, 2H), 3.89/3.86 (s, 3H), 2.62/2.56 (br. s, 1H, OH), 2.46 (d, 1H), 2.39 (m, 1H), 2.08/2.05 (s, 3H), 1.31 (t, 3H), 1.18 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]=[N+]=[N-])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([NH2:10])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4]
Reactant: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution of 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (838 mg, 2.2 mmol), THF (10 ml) and P(Ph)3 (1.15 g, 4.4 mmol) and water (0.08 ml, 4.4 mmol) was refluxed for 6 hours and then concentrated in vacuo. The residue was dissolved in Et2O and treated with HCl (0.1N, 20 ml). The aqueous layer was extracted with Et2O, washed with Na2CO3 (10% aq.), dried over anhydrous MgSO4 and concentrated to afford the amine as colorless oil which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:23][CH:24]3[CH2:26][O:25]3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.[CH3:35][NH:36][CH3:37]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:23][CH:24]([OH:25])[CH2:26][N:36]([CH3:37])[CH3:35])([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: CNC
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC2CO2)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(O)CN(C)C)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(oxiran-2-ylmethyl)-1,3-oxazinan-2-one and dimethylamine following a procedure analogous to that described in Example 265 Step 2. Two isomers were isolated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH3:34])=[O:32])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.350 g, 1.44 mmol) in DCM (5 ml) EDCI (0.331 g, 1.73 mmol) and HOBt (0.234 g, 1.73 mmol) were added at 0° C. After 10 minutes, (S)-methyl 2-amino-4-methylpentanoate hydrochloride (0.780, 4.32 mmol) and Et3N (1.2 ml, 8.64 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, sat. NaHCO3 solution, water, 1N HCl, water and saturated brine and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 65% EtOAC in hexane) to afford the title compound as a solid. Wt: 0.210 g; Yield: 39.4%; 1H NMR (300 MHz, CDCl3): δ 5.56 (d, 1H), 4.75 (d, 1H, J=9 Hz), 4.70-4.60 (m, 1H), 3.88-3.79 (m, 1H), 3.73 (s, 3H), 2.48-2.25 (m, 2H), 2.14-1.99 (m, 1H), 1.70-1.48 (m, 3H), 1.43 (s, 9H), 1.32 (s, 3H), 0.95-0.91 (m, 9H); Mass: [M+Na]+ 393 (100%); IR (KBr, cm−1): 3344, 2960, 2873, 1743, 1689, 1664, 1531, 1458, 1366, 1271, 1174, 1050, 1028, 873, 827, 744; M.R: 100.5° C.-103.9° C.