Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)c1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)c1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
To a solution of ethyl 2-[2-(4-fluorophenyl)-5-(3-thienyl)-oxazol-4-yl]-2-methylpropionate (54 mg) in methylene chloride (3 ml) was added boron tribromide (0.45 ml, 1.0M methylene chloride solution) under ice-cooling, and the mixture was allowed to warm to room temperature. To the mixture, another portion of boron tribromide (1.05 ml, 1.0M methylene chloride solution) was added to the mixture, and the resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added water and ethyl acetate, the organic layer was collected, washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: chloroform:methanol=15:1) to obtain 2-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]-2-methylpropionic acid (32 mg). The product was dissolved in methanol, sodium methoxide (0.19 ml, 0.5M methanol solution) was added to the solution and after the mixture was stirred for 10 minutes, the solvent was removed under reduced pressure. The resulting residue was triturated with acetone to obtain sodium 2-[2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl]-2-methyl-propionate (30 mg) as pale brownish powder.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3]1.[BH4-].[Na+]>C(O)C>[NH3:10].[OH:7][CH:6]1[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3][CH:2]1[CH3:1]
Reactant: CC1OC2(CCN(C)CC2)CC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1OC2(CCN(C)CC2)CC1O
Product: N
Temperature: 25 °C
Reaction time: 2 h
Yield: 197.8 %

Procedure:
To a solution of 2,8-dimethyl-1-oxa-8-azaspiro[4.5]-decan-3-one (200 mg) in 7 ml ethanol, was added 25 mg sodium borohydride at room temperature, and the mixture was stirred at room temperature for two hours. The reaction mixture was cooled in an ice-water bath, acidified by addition of 6N--HCL (to about pH 4), and stirred for about 20 minutes with the ice-water bath removed. Ethanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography by using, as eluent, a mixed solvent of chloroform/methanol/conc. ammonia (5:1:0.1 by volume), giving 200 mg of 3-hydroxy-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane as oil. It was dissolved in ether, and ehtanolic hydrogen chloride was added to this solution, thus giving its hydrochloride as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O>CCOCC>[CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[Cl:17]
Reactant: CN(C)c1ccc2nc[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CN(C)c1ccc2ncnc(Cl)c2c1
Temperature: 25 °C

Procedure:
A mixture of 12.4 g. of 6-dimethylamino-quinazolin-4(3H)-one and 50 ml. of phosphorus oxychloride is refluxed under nitrogen for 10 minutes, cooled to room temperature, 150 ml. of ether added, the crystals recovered by filtering, washed with ether and dried. The solids are added to 500 ml. of ice-water, concentrated ammonia is added to neutralize the solution which is extracted with 1.0 liter of chloroform. The chloroform extract is dried and filtered through 300 ml. of silica gel using chloroform as an eluant. Evaporation of the eluant yields 6-dimethylamino-4-chloroquinazoline, m.p. 126°-127.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:34])[CH:25]=1.CCN(CC)CC>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[C:26]([F:34])[CH:25]=2)[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(CBr)ccc1C(F)(F)F
Reactant: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-yl]-methyl-amine (2.20 g, 7.31 mmol) in THF (70 ml) was added 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene (2.25 g, 8.75 mmol) and Et3N (1.21 ml, 8.75 mmol). The reaction mixture was stirred overnight at 40° C., concentrated under vacuo, diluted with EtOAc, washed with H2O. The organic phase was dried over Na2SO4 and the product purified by flash chromatography (SiO2, EtOAc/Heptane 1:3) to afford 2.0 g (57%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(Cl)=O)(C)C.C(N(CC)CC)C.[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>CS(C)=O>[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44]3=[N:45][CH:46]=[N:47][C:48]([O:49][CH:50]4[CH2:55][CH2:54][N:53]([C:13]([C:11]5[O:12][C:8]([CH2:7][N:1]6[CH2:2][CH2:3][O:4][CH2:5][CH2:6]6)=[CH:9][CH:10]=5)=[O:15])[CH2:52][CH2:51]4)=[C:43]3[CH:42]=[N:41]2)=[CH:36][CH:35]=1)(=[O:32])=[O:33]
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)cc1
Agent: CC(C)OC(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCN(C(=O)c5ccc(CN6CCOCC6)o5)CC4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Morpholin-4-ylmethyl-furan-2-carboxylic acid (0.12 mmol, 25 mg), and isopropylchloroformate (0.12 mmol, 17 μL) and triethylamine (0.12 mmol, 17 μL) were dissolved in DMSO (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (0.12 mmol, 50 mg) and excess triethylamine were added. The mixture was heated in a microwave for 5 minutes at 120° C. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided compound A116 as a white solid. LCMS (ESI), m/z 567.3 (MH+, 100%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:35])=[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.Cl.CCOC(C)=O>CO>[F:35][C:11]1[C:12]([C:16]2[CH:17]=[N:18][C:19]([CH:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[N:20][CH:21]=2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3F)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cccc(-c2cnc(C3CCNCC3)nc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
tert-Butyl 4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidin e-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4M hydrogen chloride/EtOAc (0.17 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and 10% MeOH/CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were added to the residue. Then, the reaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl3 was added to the obtained residue, followed by stirring for 30 minutes. The filtrate was concentrated under reduced pressure to obtain {2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[OH-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6]
Reactant: CCNCCO
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CCO)CCCCl
Yield: 38.8 %

Procedure:
2-Ethylamino ethanol (6.2 g, 70 mmol), acetone (18 ml, 3 vol), 5M NaOH solution (16.8 ml, 1.2 eq.) and 1-bromo-3-chloropropane (16.5 g, 105 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (4.5 g, 39%) as a colourless oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([O:53][C:54]([N:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C>[C:49]([O:53][C:54]([N:56]1[CH:60]=[CH:59][CH:58]=[C:57]1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:62]=1)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
DIEA (0.009 mL, 0.053 mmol) was added to 8-hydroxy-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. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.014 g of product in 62% yield: LCMS (ESI) m/z 447 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[N:4]1([CH2:3][CH2:2][N:26]([C:24]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([Cl:15])[CH:25]=2)[S:27]([CH3:30])(=[O:28])=[O:29])[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Reactant: BrCCn1cccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(CCn2cccc2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 μL of 1-(2-bromoethyl)-1H-pyrrole and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate. 230 mg of methyl 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoate was hydrolyzed via Procedure M to yield 221 mg of crude 4-(N-(2-(1H-pyrrol-1-yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH:15][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cccc(Cl)c1
Product: COC(OC)C(=O)NCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a vial were added methyl dimethoxyacetate (1.9 g, 14 mmol) and 3-chlorobenzylamine (2.0 g, 14 mmol), this mixture was stirred at room temperature over two days. The product was triturated with hexane (3×) and re-crystallized from hexane, affording the desired product as oil that solidified over time. 1H NMR (400 MHz, CDCl3): δ=3.43 (s, 6H), 4.47 (d, J=6.1 Hz, 2H), 4.77 (s, 1H), 6.91 (br. s., 1H), 7.15-7.21 (m, 1H), 7.25-7.30 (m, 3H). MS (ES+): m/z=243.93/245.81 [MH+]. HPLC: tR=2.80 min (ZQ2, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([F:21])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]#[N:18])=[N:10]2)=[C:6]([F:22])[CH:5]=1)[CH3:2].C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:31]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:31])[NH2:18])=[N:10]2)=[C:19]([F:21])[CH:20]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.73 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carbonitrile 1-1-1 (25.5 mmol, 1.00 eq) were suspended in 100 mL methanol. 7.65 mL sodium methanolate in methanol (2.23 g, 41.3 mmol, 1.62 eq.) were added at rt. The reaction mixture was stirred for 4 h at rt. 2.36 mL acetic acid (2.45 g, 41.3 mmol, 1.62 eq.) and 2.05 g ammonium chloride (38.2 mmol, 1.50 eq.) were added and the reaction mixture was stirred at 50° C. for two days. The mixture was concentrated in vacuo and the residue was filtered off and washed with methanol. The filtrate was suspended in water and aqueous hydrochloric acid (4N). DCM was added, the aqueous layer was washed with DCM twice. To the aqueous layer aqueous sodiumhydroxid solution (2N) was added to reach pH 12. The aqueous layer was extracted with DCM/isopropanol (4:1) three times. The united organic layers were dried over a silicone filter, concentrated in vacuo to provide 2.67 g (7.99 mmol, 31.3%) of analytically pure target compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH:21](OC)=[O:22]>C1COCC1.O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([CH:15]=1)[CH:21]=[O:22]
Reactant: COC=O
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of N,N-diisopropylamine (8.87 mL, 62.9 mmol, 1.1 eq) in dry THF (80 mL) at −78° C. was added n-BuLi (2.5M in hexane, 27.5 mL, 68.5 mmol, 1.2 eq). The resulting mixture was stirred for 30 min then 1-bromo-4-fluoro-benzene (10 g, 57.1 mmol, 1 eq) in dry THF (20 mL) was added. The resultant mixture was stirred at −78° C. for 2 h then methyl formate (3.8 g, 62.9 mmol, 1.1 eq) was added and the reaction was stirred a further 30 min at −78° C. The reaction was allowed to warm to room temperature and stirred a further 1 h. The reaction was then diluted with water (100 mL), and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a yellow oil (6.25 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.[CH3:10]N(C=O)C.C([O-])([O-])=O.[K+].[K+].IC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([O:8][CH3:10])[CH:7]=1
Reactant: Oc1cc(Cl)ccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a mixture of 5-chloro-2-fluorophenol (4.68 g) and DMF (dry) (50 mL) were added K2CO3 (8.83 g) and iodomethane (3.99 mL) at room temperature. The mixture was stirred at room temperature for 4.5 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (4.60 g).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[N:5]([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([O:12]C)=[O:11])=[N+:6]=[N-:7]>CCOCC>[CH3:1][N+:2]([CH3:8])([CH3:4])[CH3:3].[N:5]([C:8]([F:16])([F:17])[C:9]([F:15])([F:14])[C:10]([O-:12])=[O:11])=[N+:6]=[N-:7]
Reactant: CN(C)C
Reactant: COC(=O)C(F)(F)C(F)(F)N=[N+]=[N-]
Solvent: CCOCC
Product: C[N+](C)(C)C
Product: [N-]=[N+]=NC(F)(F)C(F)(F)C(=O)[O-]
Reaction time: 4 h

Procedure:
Trimethylamine (10.6 g, 0.18 mole) was distilled into a solution of 37.0 g (0.184 mole) of methyl 3-azidotetrafluoropropionate, prepared as in Example 9, in 100 ml of ether. Precipitation of product was accompanied by a small exotherm. The reaction was determined by gas chromatography to be nearly complete after 4 hr. The mixture was stirred overnight, then evaporated under vacuum until dry. The residue was 31.8 g (68%) of tetramethylammonium-3-azidotetrafluoropropionate, mp 144°-145° (dec.). IR (nujol): 2170 (N3), 1680 (broad, CO21-), and 1250-1100 cm-1 (CF), NMR (DMSO-d6): H 3,25 ppm (s, CH3); 19F -90.8 (t, JFF 6.2 Hz, 2F, CF2N3) and -115.8 ppm (t, JFF 6.2 Hz, 2F, CF2C=O).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:26])=[C:7]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Br)cc21
Yield: 92.4 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (328 mg, 773 μmol) was stirred in TFA (2 mL, 26.9 mmol) at room temperature for 25 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as an off-white solid (263 mg). MS (m/e)=368.1 (M+H)+. Calculated for C15H14BrNO5 367.01.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=O)[CH:11]=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][N:9]=[C:10]([Br:22])[CH:11]=[CH:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(C=CSc1ccccc1)NOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrC(C=CSc1ccccc1)=NOCc1ccccc1
Yield: 45.5 %

Procedure:
Pyridine (2.7 ml) was added to THF (80 ml) solution of 3-(phenylthio)acryloyl chloride (3.0 g) and hydrochloric acid salt of Q-benzylhydroxylamine (2.6 g) under ice-cooling and stirred at the same temperature for one hour and at room temperature for three hours. The reaction mixture was concentrated under reduced pressure. Chloroform (150 ml) was added to the residue, washed successively with 1N hydrochloric acid, pure water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 2:1) to obtain N-benzyloxy-3-(phenylthio)acrylamide (3.5 g) as colorless oil. N-benzyloxy-3-(phenylthio)acrylamide (11.0 g) was dissolved to acetonitrile (70 ml), carbon tetrabromide (2.3 g) and triphenylphosphine (1.8 g) were added thereto under ice-cooling, then heat refluxing for four hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate 20:1) to obtain N-benzyloxy-3-(phenylthio)acrylimidoyl bromide (1.1 g) as light yellow oil.
Reaction SMILES: [C:1]1([CH3:50])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:42])=[O:41])[CH2:14][CH2:15][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:53][N:54]([CH2:58][CH2:59]Cl)[CH2:55][CH2:56]Cl>CN(C=O)C>[CH3:53][N:54]1[CH2:58][CH2:59][N:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:18][CH2:17][N:16]([S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:31])=[O:32])[CH2:15][CH2:14][N:13]([S:40]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)(=[O:41])=[O:42])[CH2:12][CH2:11][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:50])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:56][CH2:55]1
Reactant: CN(CCCl)CCCl
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a stirred solution of 1,4,7,10-tetra(p-toluenesulfonyl)-1,4,7,10-tetraazadecane prepared as in Example 15B (66.5 g, 0.0872 mole) in anhydrous DMF (1 l) was added sodium hydride (5.22 g-80% in mineral oil, 0.174 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (13.6 g, 0.0872 mole) in anhydrous DMF (200 ml) was added dropwise over a 1.5 h period, maintaining the temperature at 100° C. After stirring an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 750 ml. H2O was slowly added at room temperature to crystallize the product. The resulting brown solid was filtered, washed thoroughly with H2O and dried in vacuo over P2O5 to give 62.9 g (85% yield) of the crude product as a brown solid. The product was purified by crystallization from DMF-H2O to give a yellow solid: mp 170°-1° C.; 1H NMR (CDCl3) δ 2.15 (s, 3 H), 2.43 (s, 6 H), 2.44 (s, 6 H), 2.51 (t, J=5.5 Hz, 4 H), 3.15 (t, J=5.5 Hz, 4 H), 3.29 (m, 8 H), 3.36 (s, 4 H), 7.32 (m, 8 H), 7.69 (m, 8 H).