Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18]([OH:27])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:30](Br)(=[O:32])[CH3:31]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18]([O:27][C:30](=[O:32])[CH3:31])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCCN1CCC(O)(c2ccccc2)CC1)OCc1ccccc1
Reactant: CC(=O)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1(c2ccccc2)CCN(CCCNC(=O)OCc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.9 %

Procedure:
To a solution of N-benzyloxycarbonyl-3-(4-hydroxy-4-phenylpiperidin-1-yl)propylamine (0.5 g, 1.36 mmol) in THF (20 mL) at 0° C., sodium hydride (60% suspension in paraffin, 65 mg, 1.63 mmol, 1.2 eq.) was added and the mixture was stirred for 1.5 h. To this acetyl bromide (0.12 mL, 1.63 mmol) was injected and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 3 h. Solvent was evaporated, the residue was mixed with dichloromethane (100 mL), and washed with water (2×20 mL). Solvent was evaporated from the dried dichloromethane solution gave the product as a viscous oil (0.485 g, 87%). The 1H-NMR showed this product to be pure and was used in the next step without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:29][CH3:30])=[CH:20][C:21]([CH2:27]O)=[C:22]([C:23]([F:26])([F:25])[F:24])[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:51]>C1COCC1>[Br:51][CH2:27][C:21]1[CH:20]=[C:19]([O:29][CH3:30])[C:13]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[N:11][C:12]=2[C:22]=1[C:23]([F:24])([F:26])[F:25]
Reactant: BrC(Br)(Br)Br
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(CO)cc(OC)c21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(C(F)(F)F)c(CBr)cc(OC)c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 655 mg (1.52 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-4-trifluoromethyl-1H-benzoimidazol-5-yl]-methanol in 10 ml THF, 604 mg (2.28 mmol) triphenylphosphine and 764 mg (2.28 mmol) carbon tetrabromide are added at 0° C. The mixture is stirred at 0° C. for 10 min and 30 min at room temperature. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=2:1−>1:1) to afford 660 mg of the title compound as a colorless crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27]O)[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][S:38]([CH3:37])(=[O:40])=[O:39])[CH3:2]
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 85.4 %

Procedure:
The non-polydispersed alcohol XXIII (0.835 g, 1.97 mmol) was dissolved in 3.5 ml dry dichloromethane and placed under a nitrogen atmosphere. Triethylamine (0.301 ml, 0.219 g, 2.16 mmol) was added and the mixture was chilled in an ice bath. After two minutes, the methanesulfonyl chloride (0.16 ml, 0.248 g, 2.16 mmol) was added. The mixture was stirred for 15 minutes at 0° C., then at room temperature for two hours. The reaction mixture was filtered through silica gel to remove the triethylammonium chloride, and the filtrate was washed successively with water, saturated NaHCO3, water and brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 9/1 ethyl acetate/methanol) to give non-polydispersed XXIV as a clear oil (0.819 g, 83%). FAB MS: m/e 503 (M+H).
Reaction SMILES: [F-:1].[K+:2].[Al:3]>O>[F-:1].[F-:1].[F-:1].[F-:1].[F-:1].[F-:1].[Al+3:3].[K+:2].[K+:2].[K+:2]
Reactant: [Al]
Agent: [F-]
Agent: [K+]
Solvent: O
Product: [Al+3]

Procedure:
Repeated treatments were made by a solution of HF and KF at a molar ratio of 1:1 being added to suspensions of aluminium powder (Carlfors Bruk A100) in pure water at temperatures from 10° C. to 80° C. The total concentration of fluoride in the treatment solutions varied between 0.1 and 5 M and the total amount of added fluoride was 0.1-5% of the molar amount of the aluminium. The fluoride solution was added to the suspension of aluminium powder under vigorous agitation, and the powder was filtered off and dried as soon as all fluoride solution had been added. A surface layer of tripotassium hexafluoroaluminate formed on the particles. FIG. 4 shows the TG graph for the thus treated powder where the total amount of added fluoride was 2%.
Reaction SMILES: C([NH:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[Br:23])=[CH:7][C:6]=1[F:24])(=O)C>CO.Cl>[NH2:4][C:5]1[CH:17]=[C:16]2[C:8]([C:9]3[C:14]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:15]2)[CH2:13][CH2:12][C:11](=[O:22])[C:10]=3[Br:23])=[CH:7][C:6]=1[F:24]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(NC(C)=O)cc1C2
Agent: Cl
Solvent: CO
Product: CCCCC12CCC(=O)C(Br)=C1c1cc(F)c(N)cc1C2
Temperature: 80 °C
Yield: 48.3 %

Procedure:
A solution of 7-(acetylamino)-4-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (33 mg, 0.1 mmol) in methanol (0.5 mL) was diluted with aqueous 6N HCl (0.5 mL). The resulting mixture was stirred in a capped flask and heated in an oil bath at 80° C. for 40 minutes. After cooling, the mixture was partitioned between water and EtOAc. The organic solution was washed with aqueous 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated under vacuum to an oil. The oil ws purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 2:1 hexanes-EtOAc. The major UV visible band was eluted with 5% MeOH in CH2Cl2, the eluant was evaporated under vacuum, and the residue was lyophilized from benzene to provide 7-amino-4-bromo-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (17 mg, 47%) as an amorphous solid.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[O:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:23]=[C:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:23][C:24]([N:14]1[C:15](=[O:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C1NC2(CCCCC2)NC12CCCCC2
Reactant: CCCCCCN=C=O
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CCCCCCNC(=O)N1C(=O)C2(CCCCC2)NC12CCCCC2
Reaction time: 24 h

Procedure:
5.5 Parts of 7,14-diazadispiro[5.1.5.2]pentadecan-15-one, 3.2 parts of n-hexylisocyanate and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 36 hours. The solvent was evaporated in vacuo and the residue stirred with 100 parts of water for 24 hours. This phase was extracted three times with 100 parts of chloroform and the extracts dried over magnesium sulphate. Evaporation of the solvent in vacuo gave an oil which was distilled at 157°C (0.3 mm pressure). This liquid, 14-n-hexylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecan-15-one, gave the following elemental analysis by weight:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12](Br)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C([Sn](F)(CCCC)CCCC)CCC.[Si]([O:55][CH:56]([O:58][CH3:59])[CH3:57])(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:16]([O:15][C:14]1[C:13](=[O:23])[C:12]([CH2:57][C:56]([O:58][CH3:59])=[O:55])=[CH:11][N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[C:9]=1[C:7](=[O:8])[NH:6][CH2:5][C:4]1[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(C)O[Si](C)(C)C(C)(C)C
Reactant: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: [Fe+2]
Agent: [Pd]
Agent: CCCC[Sn](F)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 62.1 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (300 mg) obtained in Example 161, Step 2 in toluene were added under an argon stream tributyltin fluoride (518 mg), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (58 mg), 1,1′-bis(diphenylphosphino)ferrocene (64 mg) and 1-(tert-butyldimethylsilyloxy)-1-methoxyethane (525 mg), and the mixture was stirred at 100° C. for 15 hr. After cooling to room temperature, aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography (ethyl acetate) to give methyl [5-benzyloxy-6-(3-chlorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridin-3-yl]acetate (184 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[OH-].[K+].Cl.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30]Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:30][CH2:29][N:28]([CH3:32])[CH3:27])[C:12]3[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccc(OC)cc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1ccc([C@@H]2Sc3ccc(OC)cc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 0.828 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.307 g of potassium hydroxide and 15 ml of dimethylsulfoxide is stirred at room temperature for 2 hours, and then 0.396 g of 2-(dimethylamino)ethyl chloride hydrochloride is added thereto. The mixture is stirred at room temperature for 16 hours. After the reaction is completed, the mixture is poured into ice-water, and the aqueous solution is extracted with ethyl acetate. The ethyl acetate solution is extracted with a 10% hydrochloric acid solution. The extract is adjusted to about pH 10 with potassium carbonate. The alkaline solution is extracted witn ethyl acetate, and the extract is washed with water, dried and then evaporated to remove solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane. 0.82 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-7-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained. Yield: 82%
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH2:24]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)[CH3:41])=[O:39])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH2:24]([N:31]1[CH2:32][CH2:33][N:34]([CH2:37][C:38]([N:40]([C:42]2[CH:43]=[CH:44][C:45]([NH:46]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:47][CH:48]=2)[CH3:41])=[O:39])[CH2:35][CH2:36]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 43 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(4-benzylpiperazinomethylcarbonyl)-N-methylamino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:16]=[C:17]([NH2:33])[N:18](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([NH2:33])=[NH:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[CH3:15]
Reactant: Cc1cc(N=C(N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1N1C[C@@H]2C[C@H]1CN2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=N)N)ccc1N1C[C@@H]2C[C@H]1CN2C

Procedure:
A solution of [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine (0.100 g) in CH2Cl2 (20 mL) with TFA (5 mL) was stirred at ambient temperature for 4 h. The reaction progress was monitored by TLC (silica gel). The resulting mixture was concentrated and the lyophilized to afford [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl]guanidine, as a TFA salt; LCMS: purity: 89%; MS (m/e): 260 (MH+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:18](Cl)([Cl:20])=[O:19]>C1C=CC=CC=1>[Cl:20][C:18]([O:1][N:2]=[C:3]([C:9]#[N:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=NOC(=O)Cl
Reaction time: 2 h

Procedure:
In dry benzene (50 ml), ethyl 2-hydroxyimino-2-cyanoacetate (7.2 g) and triethylamine (7.0 ml) are dissolved, and the resulting solution is dropwise added to a solution of phosgene (0.05 mol) in benzene (52.5 ml) at 5°C. The mixture is stirred at the same temperature for 2 hours and allowed to stand at room temmperature over night to give a solution of ethyl 2-chlorocarbonyloxyimino-2-cyanoacetate.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[I-].C(N(CC)CC)C.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:22]1([C:28]#[C:29][NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][CH:2]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Reactant: C#Cc1ccccc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)(F)Oc1ccc(NC#Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2-bromo-4-trifluoromethoxyaniline (0.500 g), cupper iodide (I) (18.6 mg), bis(triphenylphosphine)palladium (II) dichloride (68.5 mg), triethylamine (0.817 mL) and tetrahydrofuran (7.8 mL) was added phenylacetylene (0.279 mL) at room temperature under stirring, and the mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether (30 mL) and then filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (206 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:19][C:20]1[C:21](F)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.C(N(CC)CC)C>C(O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:21]2[C:20]([Cl:19])=[CH:25][C:24]([C:26]([F:29])([F:27])[F:28])=[CH:23][N:22]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCN2)no1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)C2CCCN2c2ncc(C(F)(F)F)cc2Cl)no1
Temperature: 175 °C

Procedure:
A microwave reaction vessel is charged with (S)-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride, 3-chloro-2-fluoro-5-trifluoromethylpyridine, triethylamine and ethanol. The mixture is heated in a microwave reactor at 175° C. for 1 h, maintaining the watts at 60 to keep the reactor from shutting down. The reaction is cooled to room temperature and concentrated in vacuo to afford an oil which is purified by reverse phase preparative HPLC. Product fractions are combined and concentrated in vacuo to afford title compound (64.4 mg). ESI m/z 417 [M+H]+.
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:51])[CH2:16][N:17]([CH2:34][C:35](=[O:50])[NH:36][CH2:37][CH2:38][O:39][C@@H:40]2[O:48][C@@H:47]([CH3:49])[C@@H:45]([OH:46])[C@@H:43]([OH:44])[C@@H:41]2[OH:42])[C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]>O.O[Pd]O>[C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:51])[CH2:16][N:17]([CH2:34][C:35](=[O:50])[NH:36][CH2:37][CH2:38][O:39][C@@H:40]2[O:48][C@@H:47]([CH3:49])[C@@H:45]([OH:46])[C@@H:43]([OH:44])[C@@H:41]2[OH:42])[C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Agent: O[Pd]O
Solvent: O
Product: C[C@@H]1O[C@@H](OCCNC(=O)CN(CC(=O)NCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)O)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
To a stirred solution of benzyl 6-{bis[2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-2-oxoethyl]amino}-6-oxohexanoate (900 mg, 1.233 mmol) in H2O (5 mL) at rt was added dihydroxypalladium (866 mg, 1.233 mmol). The mixture was degassed and then stirred under a balloon of H2. After stirring at rt under H2 for 16 hr, the reaction mixture was filtered through a Celite pad and washed with CH3OH (3×10 mL). The filtrate was concentrated to give the title compound. LC-MS Method A: m/e=640.17 [M+1]; Rt=0.98 min.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24]([O:27][CH:28](Cl)[CH3:29])(=[O:26])[CH3:25]>>[C:24]([O:27][CH:28]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:29])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)Cl
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 5, piroxicam (2.00 g, 6.0 mmol) and alpha-chloroethyl acetate (2.22 g, 18.1 mmol) were converted to chromatographed title product, 1.17 g of yellow solid (2.8 mmol, 46.4%) which gave white crystals (1.08 g) upon crystallization from isopropyl alcohol: mp 161°-162° C.; IR (KBr) 1755, 1677 cm-1 ; 1H NMR (CDCl3) delta 1.72 (d, J=6 Hz, 3H), 1.95 (s, 3H), 3.13 (s, 3H), 6.39 (q, J=6 Hz, 1H), 7.07-7.18 (m, 1H), 7.65-7.96 (m, 5H), 8.30-8.42 (m, 2H), 9.52 (br s, 1H); precise mass calcd for C17H15N3O5S m/e (P+ --C2H4O) 373.0738, found 373.0678.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:10]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 95.9 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.57 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](Cl)(=[O:21])=[O:20].[NH3:23]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[O:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=2)=[O:7])=[CH:4][C:3]=1[S:19](=[O:21])(=[O:20])[NH2:23]
Reactant: O=C(c1ccc(Cl)c(S(=O)(=O)Cl)c1)c1cc2ccccc2o1
Reactant: N
Product: NS(=O)(=O)c1cc(C(=O)c2cc3ccccc3o2)ccc1Cl
Reaction time: 8 h

Procedure:
3.3 g 2-(4-Chloro-3-chlorosulfonylbenzoyl)-benzo[b]furan are introduced into 19 ml 25% aqueous ammonia solution, and after standing overnight, the liquid is distilled off. After addition of water, the pH is adjusted to 6 by means of dilute HCl, agitation is continued for a further 30 minutes, and the product is crystallized from a small amount of glacial acetic acid. Colorless crystals, m.p. 181° C.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I-:16].[Na+]>CC(C)=O>[I:16]/[CH:2]=[CH:3]/[C:4](=[O:15])[C:5]([CH3:14])([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [I-]
Reactant: CC(C)(Cc1ccccc1)C(=O)/C=C/Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)C(=O)/C=C/I

Procedure:
A solution of 5.7 g. of 1-chloro-4,4-dimethyl-5-phenyl-trans-1-penten-3-one in 30 ml. of dry acetone was treated with 4.3 g. of sodium iodide and refluxed under nitrogen for 20 hours. The mixture was cooled, filtered and evaporated. The residue was dissolved in ether, washed with water and dried with magnesium sulfate. Evaporation of the solvent gave 7.6 g. of the title product as an oil, λmaxfilm 3.5, 5.91, 6.4, 6.68, 6.80, 7.7, 9.3, 9.56, 10.0, 10.58, 13.4 and 14.2 μ.