Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([O:9]CC)=[O:8]>O.CO>[CH3:3][O:4][N:5]=[C:6]([C:12]1[N:13]=[N:14][S:15][CH:16]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(=NOC)c1csnn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C(=O)O)c1csnn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.2 %

Procedure:
A solution of sodium hydroxide (0.47 g.) in water (10 ml.) was added to a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (2.1 g.) in methanol (20 ml.) and the resulting mixture was stirred for 6 hours at ambient temperature. Methanol was removed from the reaction mixture and to the residue was added water. The resulting mixture was washed with ether, adjusted to pH 1 with 10% hydrochloric acid and extracted twice with ether (50 ml.). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off to give oil of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1.3 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=3[CH:18]=2)=[C:10]([F:25])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:17]=3[CH:18]=2)=[C:10]([F:25])[N:9]=1)[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc2oc(-c3ccc(NC(=O)OC(C)(C)C)nc3F)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)nc3F)cc2c1
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a stirred solution of [6-fluoro-5-(5-methoxy-benzofuran-2-yl)-pyridin-2-yl]-carbamic acid tert-butyl ester (78 mg, 0.218 mmol) in DMF (5 mL) at 0° C., NaH (11 mg, 0.26 mmol, 57% dispersion in oil) was added and the resulting mixture was stirred for 10 minutes. Methyl iodide (15 μL, 0.24 mmol) was then added and the stirring was continued for 30 minutes at room temperature. Additional portions of NaH (11 mg, 0.26 mmol, 57% dispersion in oil) and methyl iodide (15 μL, 0.24 mmol) were added and the solution was stirred for 1 hour. The reaction mixture was quenched with water (5 mL) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification of the crude product by flash column chromatography using 10% ethyl acetate in hexane afforded title compound (66 mg) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ: 8.25-8.33 (m, 1 H) 7.87 (m 1H) 7.41 (d, J=9.37 Hz, 1 H) 7.14 (s, 1 H) 7.06 (d, J=2.34 Hz, 1 H) 6.92 (d, J=8.98 Hz, 1 H) 3.86 (s, 3 H) 3.43 (s, 3 H) 1.56 (s, 9 H)
Reaction SMILES: C([O:8][C:9]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])C1C=CC=CC=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:26]([O:25][C:23]([C:22]1[C:21](=[O:20])[C:12]2[C:10](=[C:9]([OH:8])[C:15]([O:16][CH3:17])=[CH:14][CH:13]=2)[NH:11][CH:28]=1)=[O:24])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1OCc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2c(O)c(OC)ccc2c1=O
Temperature: 25 °C
Yield: 42.7 %

Procedure:
Two grams of 2-benzyloxy-3-methoxyaniline and 2.3 g of diethyl ethoxymethylenemalonate were heated at a temperature of 100°-120° C. for 1 hour. Fifty milliliter of diphenyl ether was added to the mixture, and the resulting mixture was further heated at 250°-270° C. for 1.5 hours. After the mixture was cooled down to room temperature, it was purified by silica gel column chromatography (Wako Gel C-200, 100 g). Elution with a mixed solvent of chloroform (95 parts) and methanol (5 parts) gave 980 mg of 3-ethoxycarbonyl-8-hydroxy-7-methoxy-4(1H)-quinolone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:28]([CH3:27])[CH2:29][C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[CH:22][CH:23]=3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(CCl)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CNCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(Cc1ccncc1)Cc1ccc(CCC(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Reaction time: 24 h

Procedure:
A reaction mixture of 70 mg (0.18 mmol) of N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)propionamide, 18 mg (0.15 mmol) of methylpyridin-4-ylmethylamine, and 41 mg (0.3 mmol) of potassium carbonate in 5 mL of acetone is agitated for 24 hours at reflux temperature. The reaction mixture is evaporated down. The residue is triturated with water and diisopropyl ether, suction filtered and dried in the air. Yield: 52 mg (87% of theory); melting point: 102° C.; C29H28ClN3O (M=470.01); calc.: molecular ion peak (M+H)+: 470/72 (Cl); found: molecular ion peak (M+H)+: 470/72 (Cl).
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17][CH2:18][CH3:19])[CH3:16])[CH2:8][C:7]1=[O:20])(=O)[CH2:2][CH2:3][CH3:4].[CH2:21]([O:23][NH2:24])[CH3:22]>C(O)C>[CH2:21]([O:23][NH:24][C:1](=[C:6]1[C:11](=[O:12])[CH:10]([CH3:13])[CH:9]([CH2:14][CH:15]([S:17][CH2:18][CH3:19])[CH3:16])[CH2:8][C:7]1=[O:20])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCCC(=O)C1C(=O)CC(CC(C)SCC)C(C)C1=O
Reactant: CCON
Solvent: CCO
Product: CCCC(NOCC)=C1C(=O)CC(CC(C)SCC)C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
Into 10 ml of ethanol, 2.97 g of 2-butyryl-5-(2-ethylthiopropyl)-4-methylcyclohexane-1,3-dione was dissolved and 0.81 g of ethoxyamine was dropped thereto at 0° C. and the resulting solution was stirred at room temperature for 3 hours. After pouring the reaction solution into ice-cold water, the mixture was extracted with chloroform. The chloroform solution was washed with water and extracted with 1N-sodium hydroxide solution. The sodium hydroxide solution was acidified with 1N-hydrochloric acid and the acidified mixture was extracted with chloroform. The chloroform solution was washed with water and dried over anhydrous magnesium sulfate. The removal of chloroform by distillation under reduced pressure gave 3.0 g of the desired product as yellow oily material. Yield 88%, nD19.5 1.5375.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:26]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:26])[C:3](=[O:2])[N:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(CCc2ccccc2)c1C
Temperature: 25 °C
Yield: 71.1 %

Procedure:
MeOH (220 mL) was added to a flask containing 4-(1-phenethylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (7.0 g, 23.1 mmol). NaOMe solution (5.3 mL, 23.1 mmol, 4.375 M in MeOH) and N-bromosuccinimide (4.93 g, 27.7 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl (200 mL) and CH2Cl2 (200 mL). The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-40% EtOAc/hexanes) to give 5.75 g of the title compound as a pale yellow solid. MS: (+) m/z 372.14, 374.16 (M+Na, 79/81Br).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[CH:61]=[CH:60][CH:59]=[C:58]1[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:63]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccn4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 31.7 %

Procedure:
DIEA (0.009 mL, 0.053 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.010 g, 0.048 mmol) and HATU (0.02 g, 0.053 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-pyrrole-1-carboxylic acid tert-butyl ester (0.013 g, 0.048 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.007 g of product in 29% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: [CH3:1][Mg]Br.[Cl-].[Li+].[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH3:6][C:7]1[N:8]([C:13]2[N:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([C:30]4[N:35]=[CH:34][C:33]([C:36]5[N:41]=[N:40][C:39]([C:42]([OH:44])([CH3:1])[CH3:43])=[CH:38][CH:37]=5)=[CH:32][CH:31]=4)([CH3:29])[CH:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=3)=[CH:15][N:14]=2)[C:9]([CH3:12])=[CH:10][CH:11]=1
Reactant: CC(=O)c1ccc(-c2ccc(C(C)(c3ccc(-c4cnc(-n5c(C)ccc5C)nc4)cc3)C(C)C)nc2)nn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1ncc(-c2ccc(C(C)(c3ccc(-c4ccc(C(C)(C)O)nn4)cn3)C(C)C)cc2)cn1
Reaction time: 1 h

Procedure:
Methyl magnesium bromide (32.4 mL of a 1.4 M solution in THF:toluene (25:75)) was added to a stirred solution of lithium chloride (1.93 g, 45.4 mmol) and 4z (11.7 g, 22.7 mmol) in THF (70 mL) at 0° C. After approximately 1 h at 0° C., the reaction was quenched by the dropwise addition of 1.0 M hydrochloric acid, and the resulting mixture stirred for 15 min. The resulting mixture was poured slowly into saturated aqueous sodium bicarbonate and extracted with EtOAc. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 35%-75% EtOAc/hexanes as eluent) to furnish the title compound 4e. m/z (ES) 533 (MH)+. 1HNMR (500 MHz, CDCl3): δ 9.23 (d, 1H, J=2.1 Hz), 8.95 (s, 2H), 8.39 (dd, 1H, J=2.3, 8.5 Hz), 7.89 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=8.9 Hz), 7.57 (m, 4H), 7.46 (d, 1H, J=8.5 Hz), 5.92 (s, 2H), 4.20 (s, 1H), 3.22 (m, 1H), 2.38 (s, 6H), 1.81 (s, 3H), 1.70 (s, 6H), 0.93 (d, 3H, J=6.4 Hz), 0.88 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].[Br:12]Br>CC(O)=O>[Br:12][C:7]1[C:2]([CH3:1])=[C:3]([C:10]#[N:11])[C:4](=[O:9])[NH:5][C:6]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(C#N)c(C)c1Br
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred suspension of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5 g, 33.78 mmol) in AcOH (25 mL) was dropwise added bromine (2.5 mL) at rt. Resulting solution was stirred for 1 h. Solvent was removed under reduced pressure. Obtained solid was recrystallised in hot EtOH and H2O to give the title compound as a white solid (5.5 g, 72%).
Reaction SMILES: [NH2:1]C1C=CC(C)=CC=1.C(N(CC)CC)C.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([S:22]([NH2:1])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 132.6 %

Procedure:
To an ice cold stirred solution of p-toluidine (5.00 g, 47 mmol) and triethylamine (6.5 ml, 51 mmol) in dry THF (100 ml) under argon was slowly added benzenesulphonyl chloride (5.9 ml, 47 mmol). A white precipitate formed. The ice bath was removed and the reaction stirred at ambient temperature for four hours. THF was evaporated under reduced pressure and the resulting oil partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (100 ml). The organic layer was separated and washed with 2M hydrochloric acid (3×75 ml), water (75 mi), 5% sodium hydrogen carbonate (3×75 ml) and finally water (75 ml). 4-he solution was then dried over MgSO4, filtered and evapourated to give the crude sulphonamide, which was crystallised from ethyl acetate/hexane to give N-4-methylbenzll phenylsulphonamide (9.8 g, 85%) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: COC(=O)c1cccc(N)c1F
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g, 32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added. 2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was stripped onto silica and column chromatographed on silica with 5% to 100% EtOAc:Hexane to give 9.75 g (87%) of the title compound of Step C. 1H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t, J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]+.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH2:32][CH:33]([CH3:39])[C:34]([O:36]CC)=[O:35])[CH:27]=[C:28]([F:31])[C:29]=1O>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:7]([CH2:6][O:5][C:29]3[C:28]([F:31])=[CH:27][C:26]([CH2:32][CH:33]([CH3:39])[C:34]([OH:36])=[O:35])=[CH:25][C:24]=3[F:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Product: CC(Cc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1)C(=O)O

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate (prepared according to PCT Application WO2010/048207A2) followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD): δ 7.76 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.81 (d, J=9.6 Hz, 2H), 5.18 (s, 2H), 2.88-2.93 (m, 1H), 2.51-2.59 (m, 2H), 1.11 (d, J=6.3 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for: C21H15ClF5NO3S: 492.0 (M+H). found 492.0.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(Cl)Cl>[OH:8][CH2:7][CH2:6][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:10](=[O:11])[O:12][CH2:13][CH3:14]
Reactant: CCOC(=O)Cl
Reactant: CCCCNCCO
Solvent: ClCCl
Product: CCCCN(CCO)C(=O)OCC
Reaction time: 2 h

Procedure:
117.2 g of 2-(n-butylamino)-ethanol are placed in 300 ml of methylene chloride. Then 54.3 g of ethyl chloroformate are allowed to drop in during 1 hour at 30°-35° C. with ice-cooling. After stirring for an additional 2 hours, the methylene chloride is evaporated and the residue is distilled to yield pure ethyl (2-hydroxyethyl)-n-butylcarbamate; b.p. 112° C./0.1 Torr.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[N:29][CH:28]=[CH:27][N:26]=2)[CH:20]=1)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[N:29][CH:28]=[CH:27][N:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and 3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (298 mg, 1.0 mmol) in xylene (20 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light red solid (258 mg, 67%).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1.C>C(O)C>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2([OH:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:3][CH2:2][C:1]#[N:4])[C:13]2=[O:21])[CH:9]=[CH:10][CH:11]=1
Reactant: C=CC#N
Reactant: O=C1Nc2ccccc2C1(O)c1cccc(Cl)c1
Solvent: CCO
Product: N#CCCN1C(=O)C(O)(c2cccc(Cl)c2)c2ccccc21

Procedure:
Acrylonitrile (1.06 g.) was added to a solution of 3-(m-chlorophenyl)-3-hydroxyindolin-2-one (2.6 g.) in ethanol (50 ml.) containing Triton B (40% aqueous solution, 3 drops) and the resulting mixture stirred and heated under reflux for 6 hours. Charcoal was added and the mixture filtered and evaporated to about 15 ml. The product crystallised as colourless prisms 1.57 g., m.p. 149°-50°. (Analysis: Found C, 65.5; H, 4.4; N, 8.8%. C17H13ClN2O2 requires C, 65.3; H, 4.2; N, 8.9%).
Reaction SMILES: [N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[N:1]([C@H:4]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][CH:6]([O:7][CH3:8])[C@@H:5]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:2]=[N-:3]
Reactant: COC1O[C@H](CO)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COC1O[C@H](COC(=O)c2ccccc2)[C@@H](O)[C@H](N=[N+]=[N-])[C@H]1OCc1ccccc1
Yield: 78 %

Procedure:
Methyl 3-azido-2-O-benzyl-3-deoxy-D-glucopyranoside (93 mg) was dissolved in 0.84 mL of pyridine. Benzoyl chloride (45 μL) was added to the solution at −20° C. with stirring, and the mixture was stirred at −20° C. for one hr. Water (14 μL) was added thereto, and the mixture was stirred at −20° C. for 30 min. The contents were concentrated to dryness. Chloroform (10 mL) was added thereto, and the mixture was washed three times with 5 mL of a saturated aqueous sodium bicarbonate solution, three times with 5 mL of a 5% aqueous potassium bisulfate solution and three times with 5 mL of water, was dried over a Glauber's salt and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (25 g, hexane:ethyl acetate=3:1) to give the title compound (97 mg, yield 78%).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].[Na+].[Cl-]>C1COCC1.CCCCCC>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2.08 g (16.10 mmol, 1 equivalent) of (4S)-4-isopropyl-oxazolidin-2-one in 15 ml of THF is cooled to -78° C. and mixed drop by drop with 11.6 ml (18.52 mmol, 1.15 equivalents) of a 1.6 M solution of n-BuLi solution in hexane. Then, a solution of 2.95 g (20.13 mmol, 1.25 equivalents) of hept-6-enoyl chloride in 10 ml of THF is added at -78° C. It is allowed to heat to room temperature, and the reaction solution is poured onto saturated NaCl solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4, and the solvent is distilled off in a rotary evaporator. The residue is purified by column chromatography with PE:DE=3:1. 3.55 g (14.82 mmol, 92%) of oxazolidinone 21 is obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([O:21]C)=O)[C:9]1=[O:23])(=[O:5])=[O:4].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CCO>[CH3:24][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][N:8]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([C:19]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[O:21])[C:9]1=[O:23])(=[O:5])=[O:4]
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O
Solvent: CCO
Product: CN(C)S(=O)(=O)CCn1c(=O)c(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc21

Procedure:
Methyl 1-{2-[(dimethylamino)sulfonyl]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.3 g, 0.84 mmol) was suspended in 8 mL of absolute EtOH and treated with 4-fluorobenzyl amine (0.29 mL, 2.53 mmol). The mixture was brought to reflux for 2.5 hours, cooled, and the solids collected and washed with a little cold EtOH to give the product as a white solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cccc2ccccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of naphthalene-1-carboxylic acid (300 mg, 1.74 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (357 mg, 1.74 mmol), HATU (992 mg, 2.61 mmol) in anhydrous DMF (8 mL) is added DIPEA (431 μL, 2.61 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (41) as white solid (383 mg, 61%).