Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:7]1[S:8][C:9]([NH2:12])=[N:10][N:11]=1)([F:6])[CH:3]([Cl:5])[Cl:4].[C:13](Cl)(Cl)=[O:14]>ClC1C=CC=CC=1>[F:1][C:2]([C:7]1[S:8][C:9]([N:12]=[C:13]=[O:14])=[N:10][N:11]=1)([F:6])[CH:3]([Cl:4])[Cl:5]
Reactant: Nc1nnc(C(F)(F)C(Cl)Cl)s1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=Nc1nnc(C(F)(F)C(Cl)Cl)s1
Yield: 73.1 %

Procedure:
21.7 g (0.1 mol) of 2-(1',1'-difluoro-2',2'-dichloroethyl)-5-amino-1,3,4-thiadiazole were suspended at room temperature in 500 ml of chlorobenzene, and a solution of 30 g of phosgene in 200 ml of chlorobenzene was rapidly added with agitation. With further agitation and feeding-in of gaseous phosgene, the temperature was raised by 15°C per hour until 110°C were attained (a clear solution was obtained from 60°C onward). The solution was then allowed to cool, nitrogen was passed through the solution to remove the residual phosgene, and the solution was concentrated. A brittle mass remained which became pulverulent on trituration with petroleum ether (boiling point 80°-110°C). By suction-filtration and drying, 19 g (73 %) of 2-(1',1'-difluoro-2',2'-dichloro-ethyl)-5-isocyanato-1,3,4-thiadiazole were obtained. Decomposition temperature: 200°C.
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13].ClC1C=CC=C(C(OO)=[O:24])C=1>>[CH3:15][C:2]1([CH2:3][O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH:11][C:12](=[O:14])[CH3:13])[CH2:1][O:24]1
Reactant: C=C(C)COc1ccccc1NC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)Nc1ccccc1OCC1(C)CO1
Yield: 64.9 %

Procedure:
The compound (0.56 g, 65%) was prepared from N-{2-[(2-methyl-2-propenyl)oxy]phenyl}acetamide (800 mg, 3.90 mmol) and m-chloroperbenzoic acid (80%, 1.10 g, 5.22 mmol) analogously to that described in Example 8 (ii).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Cl)Cl>>[CH:7]1[C:4]([CH:5]=[O:6])=[CH:3][C:2]2[O:1][CH2:11][O:10][C:9]=2[CH:8]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: ClCCl
Product: O=Cc1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
One process for preparing piperonal from 3,4-dihydroxybenzaldehyde comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride and alkali in a non-protic polar solvent such as dimethyl sulfoxide, and gives a 61% yield of piperonal (British Pat. No. 1,097,270). Another process comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride in aqueous alkali under the influence of an interphasic moving catalyst such as quaternary ammonium compound, and gives a 70-73% yield of piperonal. However, the catalyst used in this process is expensive and, by nature, easily soluble in both aqueous and organic phases. Accordingly, the recovery of the catalyst is too low to make this process practicable (Japanese Patent Application Disclosure Nos. 23,265/'76 and 113,967/'77). In any event, neither of these process can provide satisfactory yields based on the amount of the starting material. In addition, James H. Clark et al. have described still another process in which 3,4-dihydroxybenzaldehyde is reacted with dibromomethane in N,N-dimethylformamide under the influence of an excess of potassium fluoride or cesium fluoride to give a 90% yield of piperonal [Tetrahedron Letters, No. 38, pp. 3361-3364 (1976)]. This process is of advantage in that no strong base is used, the reaction time is relatively short, and a high yield can be obtained. However, an expensive fluoride must be used in large excess as a halogen trapping agent and cannot be recycled because its fluorine component is stoichiometrically replaced by the halogen atoms in the dihalomethane used. Accordingly, this process is not satisfactory for industrial applications. Moreover, when based on the amount of pyrocatechol used, the yield attainable with this process does not reach 70%.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]3=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]3[CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 42.0 g) in THF (dry) (350 mL) was added 2-chloroethanesulfonyl chloride (44.5 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-((tert-butyl(dimethyl)silyl)oxy)phenyl)pyridin-2-amine (78.8 g) in THF (dry) (350 mL) was added at 0° C. and the mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0° C. carefully. Additional water was added to form precipitates which were washed with water and EtOAc and collected to give the title compound (65.5 g) as an off-white solid.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=C2C([S:26][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:37](Cl)=[O:38])[C:32]=3[C:33]2=[O:36])=CC=1>O>[CH3:20][C:14]1[CH:19]=[C:18]2[C:17]([S:26][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([C:37]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:38])[C:32]=3[C:33]2=[O:36])=[CH:16][CH:15]=1
Reactant: Cc1ccccc1
Reactant: CCCCCCCCCCCCO
Reactant: Cc1ccc2sc3cccc(C(=O)Cl)c3c(=O)c2c1
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1cccc2sc3ccc(C)cc3c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.43 g (2.31 mmoles) of 1-dodecyl alcohol are added to a toluene solution containing 0.22 g (0.76 mmoles) of 7-methyl-9-oxo-9H-thioxanthene-1-carbonyl chloride. After stirring 1 hour at room temperature, the mixture is poured in water, the organic phase is separated and washed with water. After evaporation of the solvent the oil is purified by flash chromatography (SiO2—eluent: Petroleum Ether:AcOEt 8:2) obtaining 50 mg of a yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[O:16][C:15]=1[C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>C(=O)=O.ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]([C:15]1[O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[C:14]=1[CH2:13][C:12](=[O:11])[C:31]([CH3:32])([CH3:33])[CH3:34])=[O:30]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(O)C(C)(C)C)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)C(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Cool 1.5 mL dichloromethane in dry ice bath under nitrogen. Add 38 mg oxalyl chloride followed by 47 mg DMSO. Stir for 30 minutes. Add a solution of 49.9 mg 1-[3-(2-hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzofuran-2-yl]-2,2-dimethylpropan-1-one from the Step A above in 2.5 mL dichloromethane. After another 25 minutes, 167 μL triethylamine were added. After stirring for additional 25 minutes, the reaction mixture was removed from the cooling bath and allowed to warm to room temperature. After 2 hours, solvents were removed under reduced pressure and the residue was purified directly on RP-HPLC using 70-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. 1H NMR (CDCl3, 500 MHz) 7.43 (d, J=8.9 Hz, 1H), 7.10 (dd, J=2.5 & 8.9 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 4.39 (s, 2H), 3.87 (s, 3H), 1.42 (s, 9H), 1.34 (s, 9H). LC-MS: 4.17 min. (m/Z=247.2, 353.3, 331.4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].CS([C:16]1[N:21]=[C:20]2[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:23]=[CH:24][C:19]2=[C:18]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])[N:17]=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:16]1[N:21]=[C:20]2[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:23]=[CH:24][C:19]2=[C:18]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])[N:17]=1
Reactant: C[C@@H](O)CNc1nc(S(C)(=O)=O)nc2c1cnn2COCC[Si](C)(C)C
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2c1cnn2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 43.7 %

Procedure:
2,4-Difluorophenol (510 mg, 3.922 mmol) was dissolved in 5 mL dry DMF, and sodium hydride (152 mg of 60% suspension in mineral oil, 3.791 mmol) was added. The reaction mixture was stirred for 25 minutes, and then (R)-1-[6-Methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (525 mg, 1.307 mmol) was added. The reaction mixture was heated to 100° C. for four hours with stirring, then was stirred for 16 hours at room temperature. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (8% MeOH in methylene chloride) to give 258 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=452.
Reaction SMILES: [NH4+].[N:2]#[C:3][S-:4].[Cl:5][C:6]1[CH:11]=[C:10]([C:12](Cl)=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1.[F:16][C:17]1([F:27])[O:21][C:20]2[CH:22]=[CH:23][C:24]([NH2:26])=[CH:25][C:19]=2[O:18]1>CC(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([NH:2][C:3]([NH:26][C:24]2[CH:23]=[CH:22][C:20]3[O:21][C:17]([F:27])([F:16])[O:18][C:19]=3[CH:25]=2)=[S:4])=[O:13])[CH:9]=[C:8]([CH3:15])[N:7]=1
Reactant: Cc1cc(C(=O)Cl)cc(Cl)n1
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)NC(=S)Nc2ccc3c(c2)OC(F)(F)O3)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thiocyanic acid, ammonium salt (1:1) (9.35 g; 0.1230 mol) was stirred in 2-propanone (300 ml) at room temperature. 2-Chloro-6-methyl-4-pyridinecarbonylchloride (22.2 g; 0.1170 mol) was then added and the reaction mixture was stirred for 2 hours at room temperature. 2,2-Difluoro-1,3-benzodioxol-5-amine (19.2 g; 0.1110 mol) in some 2-propane was added and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then poured onto ice and the residue was filtered off and dried. Yield: 38.1 g of intermediate D1.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:18].N1C=CC=CC=1.Cl>ClCCl>[CH3:8][O:9][C:10](=[O:19])[C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3]
Reactant: COC(=O)c1c(N)cccc1F
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(F)cccc1NC(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.8 %

Procedure:
Add isopropyl chloroformate (20.7 mL, 20.7 mmol, 1.0 M in toluene) dropwise to a solution of 2-Amino-6-fluor-benzoic acid methyl ester (3.5 g, 20.7 mmol) and pyridine (4.2 mL, 51.75 mmol) in dichloromethane (41 mL) at 0° C. under an atmosphere of nitrogen and stir at room temperature for 14 h. Add 1M HCl and separate the layers. Extract the aqueous layer with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (3.00 g, 63%). MS (ES+): 256 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14][CH3:15])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:14]([CH3:15])=[O:24])[CH:4]=1
Reactant: COc1ccnc(-c2sccc2SC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccnc(-c2sccc2S(C)=O)c1

Procedure:
The product of step (c) above was dissolved in ethyl acetate (100 ml) and cooled to -10°. m-Chloroperbenzoic acid (2.98 g) was added and after 1.5 hour the mixture was worked-up then chromatographed (ethyl acetate) to give the sub-title compound as a solid, mp 103°-105°.
Reaction SMILES: C[O-].[Na+].[C:4]([O:11]C)(=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:13][C:14]1[C:15]([C:20](OC)=[O:21])=[N:16][CH:17]=[CH:18][N:19]=1>CO>[CH3:9][O:8][C:6]([C:5]1[C:4]([OH:11])=[N:13][C:14]2=[N:19][CH:18]=[CH:17][N:16]=[C:15]2[C:20]=1[OH:21])=[O:7]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(=O)c1nccnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(O)nc2nccnc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium methoxide (6.5 mL) (30% by weight in methanol) was dissolved in methanol (75 mL) at room temperature. Dimethyl malonate (3.7 mL) was added dropwise at ambient temperature over a period of 20 minutes and the reaction stirred at ambient temperature for 1 hour. Methyl 3-aminopyrazine-2-carboxylate (5.0 g) was added in portions at ambient temperature over a period of 40 minutes. The reaction mixture was heated to reflux for 3 days, and then allowed to cool. The solvent was concentrated. The residue was dissolved in water and acidified with concentrated hydrochloric acid (36% by weight in water). The precipitate was isolated, washed with water, methanol and ethyl acetate, and dried under high vacuum to give 6,8-dihydroxypyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester as a beige solid (4.16 g). 1H NMR (d6-DMSO): 3.80 (s, 3H), 8.59 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Cl:9][CH:10]([Cl:29])[C:11]([NH:13][C@H:14]([CH2:27][F:28])[C@H:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([Sn](C)(C)C)=[CH:18][CH:17]=1)=[O:12].[F-].[Cs+].[C:32]1([CH3:38])C=CC=CC=1>O.[Cu]I>[C:1]([O:5][C:6](=[O:8])[NH:7][CH2:10][C:11]1[O:12][C:32]([C:19]2[CH:20]=[CH:21][C:16]([C@@H:15]([OH:26])[C@H:14]([NH:13][C:11](=[O:12])[CH:10]([Cl:29])[Cl:9])[CH2:27][F:28])=[CH:17][CH:18]=2)=[CH:38][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OC(N)=O
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ncc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)o1
Temperature: 100 °C

Procedure:
To a stirred solution of 5-Bromo-oxazol-2-ylmethyl)-carbamic acid tert-butyl ester (0.035 g, 0.13 mmol) and 2,2-Dichloro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]acetamide (0.05 g, 0.11 mmol) in dry toluene (2.0 mL) is added CsF (0.034 g, 0.22 mmol) followed by CuI (0.002 g, 0.011 mmol) at room temperature. The resulting reaction mixture is degassed with nitrogen for 30 minutes then Pd2(PPh3)Cl2 (0.008 g, 0.011 mmol) is added and heated in microwave at 100° C. for 30 min. Reaction mixture is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 10% methanol in CH2Cl2 follow by second purification using preparative HPLC to give the title compound (0.006 g, pure). LC-Ms (m/z): [M−H]=476.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)(CCCc1cccnc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 15.0 g (42.8 mmol) of diethyl [4-aminobutyl][3-(3-pyridyl)propyl]-malonate in 115 ml methylene chloride is cooled to 0° and 0.1 g 4-dimethylaminopyridine is added followed by 8.4 ml (60 mmol) triethylamine and 10.12 g (46.5 mmol) p-chlorophenylsulfonyl chloride. The solution is stirred at room temperature for 48 h and then washed with saturated aqueous sodium bicarbonate solution. The organic phase is dried (MgSO4), filtered and evaporated to give diethyl [4-(p-chlorophenylsulfonamido)butyl][3-(3-pyridyl)propyl]-malonate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=O)[NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]([NH:47][NH2:48])=O)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:36])=[O:35])=[CH:30][C:29]=1[C:49]([F:52])([F:51])[F:50]>CC#N>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:39]([C:45]3[N:7]([C:8]4[CH:12]=[CH:11][O:10][N:9]=4)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:48][N:47]=3)=[N:40][CH:41]=[C:42]([Cl:44])[CH:43]=2)(=[O:35])=[O:36])=[CH:30][C:29]=1[C:49]([F:50])([F:52])[F:51]
Reactant: CCOC(=O)C(=O)Nc1ccon1
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1-c1ccon1
Temperature: 0 °C
Yield: 20.1 %

Procedure:
To a vial equipped with a teflon coated septum and a nitrogen inlet were added ethyl(isoxazol-3-ylcarbamoyl)formate (370 mg, 2.0 mmol), MeCN (2 mL) and 2,6-lutidine (0.6 mL, 5.2 mmol). The vial was cooled to 0° C. POCl3 (0.4 mL, 4.3 mmol) was added, and the solution maintained at 0° C. for 30 min. The solution was then warmed to 40° C. for 3 h. After cooling to room temperature, solid 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)-benzenesulfonamide (500 mg, 1.2 mmol) was added, and the reaction heated to 80° C. for 1 h. The volatiles were removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 12 g of silica gel (50→100% gradient of EtOAc in hexanes). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (139 mg, 20% yield). HPLC retention time=2.96 minutes. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J=2.0, 1H), 8.19 (d, J=2.0, 1H), 8.12 (d, J=2.4, 1H), 7.98 (d, J=2.0, 1H), 7.90 (dd, J=2.4, 8.4, 1H), 7.58 (d, J=8.4, 1H), 6.62 (d, J=2.0, 1H), 4.41 (q, J=7.2, 2H), 1.40 (t, J=7.2, 3H). MS (ES) [M+H]+ expected 577.0. found 577.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>CN(C)C=O.O>[CH3:14][O:15][CH2:16][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COCCl
Reactant: Oc1cccc2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cccc2ncccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-hydroxyquinoline (10.3 g) in dimethylformamide (140 ml) was ice-cooled. To the solution was added sodium hydride (3.0 g, 62.6% in oil) and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added methoxymethyl chloride (6.5 ml) and then the mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added ice. The reaction mixture was stirred and then diluted with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1N aqueous solution of sodium hydroxide, water and a saturated aqueous solution of sodium chloride subsequently, dried over anhydrous magnesium sulfate, and then concentrated to give the title compound (10.4 g) having the following physical data. The obtained compound was used without purification in the subsequent reaction.
Reaction SMILES: Cl.Cl.Cl.[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29]N5CCN(C)CC5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5]1.C1(NC(C2C3C=C(C4C([Cl:58])=CN=C(Cl)N=4)SC=3C=CC=2)=O)CC1.[CH3:60][C:61]1([CH3:72])[CH2:66]C(=CCN)[CH2:64][C:63]([CH3:71])([CH3:70])[NH:62]1>>[ClH:25].[ClH:58].[CH:4]1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH:28]=[C:29]5[CH2:64][C:63]([CH3:71])([CH3:70])[NH:62][C:61]([CH3:72])([CH3:66])[CH2:60]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC1(C)CC(=CCN)CC(C)(C)N1
Agent: Cl
Product: CC1(C)CC(=CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC(C)(C)N1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-(2,2,6,6-tetramethyl-piperidin-4-ylidene)-ethylamine and isolated as a yellow solid. ES+(m/z) 510 (35Cl) and 512 (37Cl) [M(free base)+H].
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[C@H:26]([O:27][C:28](=O)[CH3:29])[NH:25][C:24]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:32]CCO.O>C1C=CC=CC=1.C1(C)C=CC=CC=1.O.O.C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]1[C@H:26]([O:27][CH2:28][CH2:29][Br:32])[NH:25][C:24]1=[O:31])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: OCCBr
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@H]1OCCBr)OCc1ccccc1
Yield: 12 %

Procedure:
A mixture of (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)amino-4-acetoxy-azetidin-2-one (4.57 g, 10.8 mmole), 2-bromoethanol (1479 mg, 11.83 mmole), and zinc acetate dihydrate (1.78 g, 8.128 mmole) in a mixture of benzene (150 ml) and toluene (150 ml) was refluxed for 7 hrs using Dean-Stark water separator. After cooling, the reaction mixture was partitioned between ethyl acetate (1000 ml), acetone (100 ml) and water (500 ml). The organic layer was washed with water, brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (55:45) as eluent and (3S,4S)-3-(N-benzyloxycarbonyl-L-phenylalanyl)amino-4-bromoethoxy-azetidin-2-one was obtained (650 mg, 12% yield).