Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:2]1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]>CN(C=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][N:1]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[N:2]=2)[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1cncc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
15.45 g of 3-(1H pyrazol-3-yl)-pyridine prepared as indicated in CA 68 P 95812 g (1968) is introduced dropwise over 1 hour while maintaining the temperature below 30° C. or equal to 30° C. into a mixture of 20 ml of DMF and 6.13 g of sodium hydride. A solution of 29.90 g of 2-(4-bromobutyl)-1H-isoindole-1,3(2H)-dione and 110 ml of DMF is added dropwise. The reaction medium is agitated for 30 minutes at ambient temperature, followed by concentrating, pouring into 300 ml of water cooled down to 10° C., extracting with ethyl acetate, washing with water, drying, filtering and concentrating. The residue is taken up in methylene chloride, followed by drying, filtering and concentrating. 35.87 of a product is obtained which is crystallized from ethyl ether, dried, washed with water and dried. 22.93 g of sought product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[CH:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1.CO>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]=1)(=[O:41])[CH3:39]
Reactant: COC(=O)Cn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)c1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)Cn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (E)-3-{[1-(methoxycarbonylmethyl)pyrrol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (12.1 g) in toluene (100 ml) were added thioacetic acid (3.5 ml) and N,N-dimethylformamide dineopentyl acetal (13.7 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent. The amorphous solid obtained was dissolved in methanol (100 ml), and the resulting mixture was stirred at 50° C. for 2 days. The reaction mixture was concentrated in vacuo to afford the title compound (12.8 g, yield: 95%) as a pale yellow amorphous solid.
Reaction SMILES: [OH:1]O.[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O>C(OCC)C>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:1]
Reactant: OB(O)c1cccc(F)c1F
Reactant: OO
Solvent: CCOCC
Product: Oc1cccc(F)c1F

Procedure:
Hydrogen peroxide (10%, 340 cm3, 1 mol) was added dropwise to a stirred solution of compound from Example 36 (47 g, 0.3 mol) in diethyl ether (350 cm3) heated under reflux. The stirred mixture was heated under reflux for a further 2.5 h then cooled. The ethereal layer was separated and the aqueous layer extracted with diethyl ether (2×200 cm3). The combined ethereal layers were washed with sodium hydroxide (10%, 4×100 cm3) and the separated aqueous layers acidified with 36% hydrochloric acid. The product was extracted into diethyl ether (3×100 cm3), and the combined ethereal extracts washed with water and dried (MgSO4). The solvent was removed in vacuo to give an off white solid.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([NH2:17])=[O:16])=[S:13])[CH:7]=[CH:8][C:9]=1[Cl:10].O>CCO>[Cl:3][C:4]1[CH:5]=[C:6]([N:11]=[C:12]2[S:13][NH:17][C:15](=[O:16])[N:14]2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: NC(=O)N(Cc1cccc(C(F)(F)F)c1)C(=S)Nc1ccc(Cl)c(Cl)c1
Agent: BrBr
Solvent: O
Solvent: CCO
Product: O=c1[nH]sc(=Nc2ccc(Cl)c(Cl)c2)n1Cc1cccc(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 103.5 %

Procedure:
Bromine (16 mg in 0.5 mL of EtOH) was added dropwise to a solution of 1-[(3,4-dichlorophenyl)carbamothioyl]-1-[[3-(trifluoromethyl)phenyl]methyl]urea (42 mg, 0.1 mmol) in 0.5 mL EtOH at 0° C. HPLC-MS analysis revealed almost complete conversion to product after 30 min of stirring. The reaction was worked up after 1.5 h. Water (3 mL) was added and the resulting aqueous phase was extracted with Et2O (3×15 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 43.5 mg of crude material (approximately 90% purity). The material was purified by preparative HPLC (basic conditions) XTerra Prep MS C18 5 mm 19×50 mm column, flow 25 ml/min, 50 mM pH10 NH4HCO3/ACN, 5-97% ACN in 6 min, fractions collected based on UV-signal (254 nm) to give the product in 21.7 mg (52%). HPLC purity: 98.5%, MS: m/z: 420 (M+H), 1H NMR (500 MHz, Chloroform-d) 8 ppm 7.81 (s, 1 H) 7.70 (d, J=7.81 Hz, 1 H) 7.60 (d, J=7.81 Hz, 1 H) 7.49 (t, J=7.69 Hz, 1 H) 7.40 (d, J=8.55 Hz, 1 H) 7.06 (d, J=2.44 Hz, 1 H) 6.79 (dd, J=8.55, 2.44 Hz, 1 H) 5.04 (s, 2 H).
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=[C:15]4[N:14]=[C:13]([CH3:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12.N12CCCCC1C=NCCC2.[C:40]([O:46][CH2:47]I)(=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42].C(OCC)(=O)C>CC(C)=O.CCOCC.O>[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([O:26][CH2:47][O:46][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=[C:15]4[N:14]=[C:13]([CH3:23])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: CC(C)(C)C(=O)OCI
Reactant: COCc1nc2nc(C)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Agent: C1=NCCCN2CCCCC12
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: COCc1nc2nc(C)cc(SCC3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)C(N)[C@H]4SC3)n2n1
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
In 80 ml of acetone was suspended 16.9 g of 7-amino-3-[(2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-3-cephem-4-carboxylic acid and ice-cooled, and then 5.98 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) was added dropwise to the solution and the mixture was stirred for 30 minutes. After 9.68 g of pivaloyloxymethyl iodide was added dropwise to the mixture, the mixture was stirred at room temperature for 20 minutes. After the reaction mixture was poured into a mixed solution of 280 ml of ethyl acetate and 200 ml of water and stirred, an organic layer was separated therefrom, washed with water, further washed with a saturated saline solution and dried over anhydrous magnesium sulfate. By removing a solvent, an oily product was obtained. This oily product was purified through silica gel column chromatography. To the oily product obtained was added ether to powderize, and it was collected by filtration and dried to obtain 10.17 g of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]([CH2:18][CH2:19][CH2:20][OH:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[C:2]([O:1][CH2:2][CH2:3][CH2:4][Si:5]([CH2:18][CH2:19][CH2:20][O:21][C:20](=[O:21])[CH:19]=[CH2:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:1])[CH:3]=[CH2:4]
Reactant: OCCC[Si](CCCO)(c1ccccc1)c1ccccc1
Solvent: O
Product: C=CC(=O)OCCC[Si](CCCOC(=O)C=C)(c1ccccc1)c1ccccc1

Procedure:
After completion of the reaction, the reaction mixture was diluted with water and extracted with ether. The extract was dried over magnesium sulfate. The solvent was distilled off to obtain 24.2 g (yield: 94.8%) of bis(3-hydroxypropyl)diphenylsilane (B) (m.p. 80°-81° C.).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[CH:12]=2)=[O:8])=[CH:4][CH:3]=1.[CH:20]([C@@H:23]1[CH2:27][O:26][C:25](=[O:28])[NH:24]1)([CH3:22])[CH3:21].CN(C)CCN.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[N:19]1[CH:18]=[CH:17][N:14]2[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:7]([C:5]3[S:6][C:2]([N:24]4[C@H:23]([CH:20]([CH3:22])[CH3:21])[CH2:27][O:26][C:25]4=[O:28])=[CH:3][CH:4]=3)=[O:8])=[CH:12][C:13]=12
Reactant: CC(C)[C@@H]1COC(=O)N1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)[C@@H]1COC(=O)N1c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
A solution of 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (84 mg, 0.25 mmol), (R)-4-isopropyloxazolidin-2-one (32 mg, 0.25 mmol), N,N-dimethylethane-1,2-diamine (2 mg, 0.025 mmol), copper(I) iodide (5 mg, 0.025 mmol) and potassium carbonate (121 mg, 0.88 mmol) in dioxane (1 ml) was stirred at 110° C. overnight. Concentration and reverse phase chromatography provided the title compound. 1H NMR (400 MHz, methanol-d4) δ ppm 9.13 (t, J=5.3 Hz, 1H), 8.74 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.62 (d, J=4.1 Hz, 1H), 7.47 (d, J=7.0 Hz, 1H), 6.77 (d, J=4.2 Hz, 1H), 4.72 (s, 2H), 4.61-4.42 (m, 3H), 2.46 (ddd, J=10.2, 6.9, 3.5 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H); (APCI(+)) m/e 385 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([Cl:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:26][C:24]1[CH:25]=[C:2]([Cl:1])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:22]([Cl:29])[CH:23]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)c3ccc(F)cc3)c2)c(Cl)c1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 4-(2,6-dichloro-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (454 mg, 0.99 mmol) in a mixture of ethanol (10 mL) and EtOAc (20 mL) was added catalyst 10% Pd/C (100 mg). The mixture was hydrogenated under 45 psi at RT for 2 h. The mixture was filtered through Celite and concentrated to give the title compound of Step C (405 mg) as a solid. The title product of Step C was used in the next step without further purification. MS (APCl−) Calc.: 427.0. Found: 426.1 (M−1).
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[C:4]([CH3:10])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1.Cl.[CH3:13][N:14]1CCCC1=O>O>[F:11][C:3]1[C:4]([CH3:10])=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: CN1CCCC1=O
Reactant: Cc1c(F)c(F)cc(Br)c1F
Agent: Cl
Solvent: O
Product: Cc1c(F)c(F)cc(C#N)c1F
Reaction time: 4.5 h

Procedure:
A mixture of 3-bromo-2,5,6-trifluorotoluene (11.0 g) and cupric cyanide (5.3 g) in N-methylpyrrolidone (15 ml) was stirred at 150° to 160° C. in a sealed tube for 4.5 hours. After cooling, to the reacting mixture was added a solution of ferric chloride (20 g) and concentrated hydrochloric acid (5 ml) in water (30 ml) and stirred at 50° to 60° C. for 20 minutes. The reacting mixture was extracted with ether, the organic layer was washed with aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (7.83 g) as pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].O1CCCC1.O1CCCC1.B.Cl>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1OC
Reaction time: 1.5 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate (0.1 g, 0.5 mmol) and tetrahydrofuran (2 mL). Cool in an ice bath. Add a solution of borane tetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol). After 1.5 hours, again add a solution of borane tetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol). After 2 hours, add a 1 M aqueous solution of hydrochloric acid (2 mL) and stir. After 15 minutes, dilute the reaction mixture with ethyl acetate. Separates the layers, extract the aqueous layer three times with ethyl acetate and combine the organic layers. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give methyl 2-methoxy-5-hydroxymethylbenzoate: Rf=0.32 (silica gel, ethyl acetate).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:17][C@@H:16]([CH2:18][OH:19])[CH:15]=[CH:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:12][C@@H:13]1[CH2:17][C@H:16]([CH2:18][O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]=[CH:14]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C=C[C@@H](COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.76 mL, 9.8 mmol) was added to a solution of cis-(4-hydroxymethyl-cyclopent-2-enyl)-carbamic acid tert-butyl ester (2 g, 9.4 mmol) and triethyl amine (1.96 mL,14.1 mmol) in CH2Cl2 (30 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. After filtration CH2Cl2 was added, and the organic phase was washed with 1M HCl, dried and concentrated under reduced pressure to yield of cis- methanesulfonic acid 4-tert-butoxycarbonylamino-cyclopent-2enylmethyl ester (2.64 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:10]([N:16]=[C:17]=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Cl:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17]([NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:18])[CH:7]=1
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]cc(Cl)c(=O)[nH]1
Product: CCCCCCNC(=O)n1cc(Cl)c(=O)[nH]c1=O
Yield: 31 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from 5-chlorouracil (0.10 g, 0.68 mmol); 1.2 equivalents of hexyl isocyanate were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc from 70:30 to 50:50) to afford the title compound (0.06 g, 31%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (t, J=6.8 Hz, 3H), 1.21-1.35 (m, 6H), 1.46-1.54 (m, 2H), 3.24-3.29 (m, 2H), 8.41 (s, 1H), 9.07 (t, J=5.3 Hz, 1H), 12.24 (s, 1H). 13C NMR (101 MHz, DMSO-d6) δ 13.85, 21.97, 25.81, 28.57, 30.82, 40.55, 109.55, 135.56, 149.21, 150.61, 158.78. MS (ESI) m/z: 272 [M-H]−.
Reaction SMILES: OC1C(C)=C(OCC2ON=C(CC3C=CC=C(I)C=3)N=2)C=CC=1C(=O)C.[Cl:27][C:28]1[C:29]([OH:38])=[C:30]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[OH:34].Cl[CH2:40][C:41]1[O:45][N:44]=[C:43]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([I:53])=[CH:49][CH:48]=2)[N:42]=1>>[Cl:27][C:28]1[C:29]([OH:38])=[C:30]([C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][C:33]=1[O:34][CH2:40][C:41]1[O:45][N:44]=[C:43]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([I:53])=[CH:49][CH:48]=2)[N:42]=1
Reactant: ClCc1nc(Cc2ccc(I)cc2)no1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 1-{2-hydroxy-4-[3-(3-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone, employing 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone and 5-Chlormethyl-3-(4-iodo-benzyl)-[1,2,4]oxadiazole. LC-MS (m/e): 485 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH:12]3[CH2:15][O:14][CH2:13]3)=[CH:7][CH:8]=2)[N:3]=1.[O:16]1CCOCC1>O>[O:14]1[CH2:13][CH:12]([C:6]2[CH:5]=[C:4]3[C:9]([CH:10]=[CH:11][C:2]([CH:1]=[O:16])=[N:3]3)=[CH:8][CH:7]=2)[CH2:15]1
Reactant: Cc1ccc2ccc(C3COC3)cc2n1
Reactant: C1COCCO1
Solvent: O
Product: O=Cc1ccc2ccc(C3COC3)cc2n1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
2-Methyl-7-(oxetan-3-yl)quinoline (0.020 g, 0.100 mmol) was dissolved in dioxane (5 mL) and water (0.05 mL). The reaction was treated with SeO2 (0.013 g, 0.120 mmol) and the mixture was heated to reflux for 2 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure to give 7-(oxetan-3-yl)quinoline-2-carbaldehyde (0.020 g, 0.0938 mmol, 93.4% yield) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:27][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: OCCCCCCCCCO
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,9-nonanediol under conditions shown in Table 19, ethyl N-{2-(9-hydroxynonyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 8.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21]>CC#N.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[NH:8][C:5]3=[N:6][CH:7]=2)[CH:15]=[C:14]([O:13][CH3:12])[C:19]=1[O:20][CH3:21]
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3c(c2)CC(=O)N3)cc(OC)c1OC
Temperature: 150 °C
Yield: 30.1 %

Procedure:
A mixture of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (200 mg, 0.939 mmol), 3,4,5-trimethoxyphenylboronic acid (239 mg, 1.127 mmol) and dichlorobis(triphenylphosphine)palladium (II) (33 mg, 0.047 mmol) in CH3CN (5 ml) and 1 M Na2CO3 (5 ml) was heated in a microwave reactor for 10 min at 150° C. The reaction mixture was filtered, evaporated, partitioned between water and DCM and purified by silica gel chromatography with 0-10% MeOH:DCM to obtain 85 mg (30%) of compound #. 1H NMR (CDCl3/DMSO-d6, 300 MHz): δ 10.19 (bs, 1H), 8.18 (d, J=1.1 Hz, 1H), 7.54 (s, 1H), 6.57 (s, 2H), 3.80 (s, 6H), 3.75 (s, 3H), 3.47 (s, 2H).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[C:19]([CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)(=[S:21])[NH2:20].[OH-].[NH4+]>O1CCOCC1.O>[NH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[S:21][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:20]=2)[CH2:23][CH2:24]1
Reactant: CCOC=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(C2CCNCC2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ethyl 3-ethoxyacrylate (1.50 g, 10.38 mml) was dissolved in dioxane/water and chilled to −10° C. N-Bromosuccinimide (2.03 g, 11.42 mmol) was added and the mixture was stirred 1 hour at room temperature. tert-Butyl 4-carbamothioylpiperidine-1-carboxylate (2.54 g, 10.38 mmol) was added and the mixture was heated at 100° C. for 1 hour. The reaction mixture was poured into 25 mL saturated ammonium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[CH3:20][C:21]([CH3:23])=O>>[CH3:20][C:21]1([CH3:23])[O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: CC(C)=O
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)CC(=O)O1

Procedure:
As described in CA 2:14217, 52 g. of malonic acid, 60 ml. of acetic anhydride, 1.5 ml. of sulfuric acid and 40 ml. of acetone were stirred at 0° for 8 hours. The solid was filtered and washed with water, giving 37 g. of product.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[CH3:29][C:30]1([CH3:38])[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32](O)[CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([O:19][CH:32]1[CH2:33][CH:34]([CH3:36])[CH2:35][C:30]([CH3:38])([CH3:29])[CH2:31]1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC1CC(OC(=O)[C@@H]2CCC(=O)N2C(=O)OCc2ccccc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
34.2 g (0.13 mol) of N-benzyloxycarbonyl-L-pyroglutamic acid (prepared according to Berichte 97, 2434 [1964] or Annalen 649, 183 [1961] ) are added to 150 ml of dimethylformamide, followed by 2 g of dimethylaminopyridine and then 18.48 g (0.13 mol) of 3,3,5-trimethylcyclohexanol (mixture of 90% trans isomer and 10% cis isomer) diluted in 50 ml of dimethylformamide. 26.8 g (0.13 mol) of dicyclohexylcarbodiimide are then run in over a period of about 15 minutes, the reaction medium being kept at +5° C. The mixture is then stirred at room temperature for 24 hours, after which the solvent is evaporated off, the residue is taken up with dilute hydrochloric acid and extraction is carried out with chloroform.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]=[C:19]=[O:20])=[CH:14][CH:13]=1
Reactant: Nc1ccc(Oc2ccc3ccccc3c2)cc1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2ccc3ccccc3c2)cc1
Yield: 92.3 %

Procedure:
A solution of 4-(2-naphthyloxy)aniline (4 g) in toluene (100 ml) was dropwise added to a solution of phosgene (3.5 g) in toluene (50 ml), and the resulting mixture was refluxed for 1 hour. After removal of the solvent from the reaction mixture by distillation under reduced pressure, the residue was distilled in vacuo to give 4-(2-naphthyloxy)phenyl isocyanate (4.1 g) as a fraction boiling at 137° to 149° C./0.8 mmHg. M.P., 75°-77° C.