Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[C:27](F)[CH:28]=2)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:21]1=[O:41]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[C:27]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:28]=2)[C:23](=[O:32])[N:22]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:21]1=[O:41]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccccc2F)c(=O)n1OCc1ccccc1
Yield: 89 %

Procedure:
Using General Method 4, the reaction of pyrrolidine (0.063 mL, 0.75 mmol), triethylamine (0.106 mL, 0.75 mmol), and 1-(2-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example F-1, 0.1 g, 0.25 mmol) provided 0.1 g of the title compound as a solid.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:11]([CH2:12][C:13]3[S:19][CH:18]=[CH:17][C:14]=32)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CC(Cl)OC(Cl)=O>ClC(Cl)C>[S:19]1[C:13]2[CH2:12][CH:11]3[CH:15]([C:14]=2[CH:17]=[CH:18]1)[CH2:16][NH:8][CH2:9][CH2:10]3
Reactant: c1ccc(CN2CCC3Cc4sccc4C3C2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: c1cc2c(s1)CC1CCNCC21
Temperature: 22 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
The product from step g) (963 mg, 3.58 mmol) in dichloroethane (18 ml) was treated with K2CO3 (1.97 g, 14.3 mmol) and Ace-Cl (1.54 ml, 14.3 mmol) at 80° C. for 16 hours. Next, the reaction mixture was filtered, concentrated and the residue was dissolved in anhydrous MeOH (25 ml) and stirred for 1 h at 22° C. The MeOH was concentrated and triturated with ether to give 467 mg (61%) of the subtitle compound. MS calculated for C10H13NS+H 180, observed 180.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=O.ClC(OCC)=O.C([N:20](CC)CC)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C=CC=CC=1.[OH-].[Na+]>O1CCCC1.O1CCCC1.CO>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]#[N:20]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(I)c(O)c1
Reaction time: 0.25 h

Procedure:
22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid was dissolved in 300 ml of tetrahydrofuran. 19.7 ml (206 mmol) of ethyl chloroformate and 28.7 ml (206 mmol) of triethylamine was added to the solution at 0° C. After stirring for 15 minutes, the obtained triethylamine hydrochloride was taken by the filtration. The filtrate was added to 300 ml of tetrahydrofuran solution, in which ammonia had been bubbled, at 0° C. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was dissolved in 450 ml of dioxane. 17.4 ml (117 mmol) of Trifluoromethanesulfonic anhydride and 21.8 ml (269 mmol) of pyridine were added to the solution at 0° C. After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure. The residue was treated with chloroform as the extractant by an ordinary method to obtain an oily residue. This residue was dissolved in 180 ml of tetrahydrofuran/methanol (1:1). 90 ml (90.0 mmol) of 1 N aqueous sodium hydroxide solution was added to the solution at room temperature. After stirring under these conditions for 4 hours, the solvent was evaporated under reduced pressure, and the residue was washed with dichloromethane. The residue was acidified with 1 N aqueous hydrogen chloride solution, and treated with ethyl acetate as the extractant by an ordinary method to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:18](CC)CC)C.C(OC(Cl)=O)C(C)C.N.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.CO.C1COCC1.CCOC(C)=O>[C:10]([C@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])#[N:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C#N
Temperature: -25 °C
Reaction time: 0.75 h
Yield: 44.1 %

Procedure:
To a solution of 2 grams (9.3 mmols) of N-Boc-D-Proline in 19 mL of dichloromethane was added 4.2 grams (42 mmols) of triethylamine. The reaction mixture was cooled to −25° C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring at this low temperature for 45 minutes, 0.83 grams (49 mmols) of ammonia was added to the mixture as a 7M solution in methanol. The reaction vessel was warmed slowly to ambient temperature and the solution was stirred for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed with four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was immediately subjected to general procedure E using 2 grams (18.9 mmols) of triethylamine and 2.3 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After previously described purification procedures (column chromatography, 25% EtOAc in hexanes), 0.8 grams (4.1 mmols, 44%) of the title product was recovered. 1H and 13C NMR data were identical to that reported for 28.
Reaction SMILES: C([O:8][CH2:9][C:10]1[NH:11][C:12]([C:19]2[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])=[C:13]([C:15](F)(F)F)[N:14]=1)C1C=CC=CC=1.[OH-].[NH4+:32]>>[C:15]([C:13]1[N:14]=[C:10]([CH2:9][OH:8])[NH:11][C:12]=1[C:19]1[C:20]([CH3:30])=[CH:21][C:22]([CH3:29])=[C:23]([CH:28]=1)[C:24]([O:26][CH3:27])=[O:25])#[N:32]
Reactant: [NH4+]
Reactant: COC(=O)c1cc(-c2[nH]c(COCc3ccccc3)nc2C(F)(F)F)c(C)cc1C
Agent: [OH-]
Product: COC(=O)c1cc(-c2[nH]c(CO)nc2C#N)c(C)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 5-(2-((benzyloxy)methyl)-4-(trifluoromethyl)-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 219.4, 100 mg, 0.30 mmol) in ammonium hydroxide (5%) (30 mL). The reaction mixture was stirred for 2 h at 60° C. The reaction mixture was extracted with 2×50 mL of dichloromethane, the organic layers combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 80 mg (92%) of the title compound as a light yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C:9]1([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:15]=[CH:14][C:13]=2[C:12](=[O:32])[CH2:11][CH2:10]1>C1C=CC=CC=1.[Zn]>[OH:32][C:12]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:11][CH2:10][C:9]([CH3:8])([CH3:33])[C:18]2[CH:17]=[C:16]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Temperature: 25 °C

Procedure:
To a refluxing solution of 1.00 g (15.30 mmol) of 20 mesh, granular zinc (activated prior to use by washing with 2% HCl, water, 95% ethanol, acetone, anhydrous Et2O and then dried in vacuum for several hours) in 20 ml of dry benzene was slowly added a mixture of 0.23 ml (1.62 mmol) of ethyl bromoacetate, 0.28 g (0.81 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 10 ml of dry benzene. The resulting mixture was refluxed for 2 hours, cooled to room temperature and the precipitate filtered through Celite. The filtrate was washed with cold 15% H2SO4, sat. aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and concentrated in vacuo to a yellow oil. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[CH:26]([C:31]2[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[C:33]([Cl:39])[CH:32]=2)[C:27]([F:30])([F:29])[F:28])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:5]>Cl.O1CCOCC1>[Br:1][C:2]1[CH:23]=[C:22](/[CH:24]=[CH:25]/[CH:26]([C:31]2[CH:32]=[C:33]([Cl:39])[C:34]([Cl:38])=[C:35]([Cl:37])[CH:36]=2)[C:27]([F:30])([F:28])[F:29])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reaction time: 18 h
Yield: 94.7 %

Procedure:
(E)-tert-Butyl 4-(2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamido)piperidine-1-carboxylate (0.75 g, 1.11 mmol) was added to dioxane HCl (10 mL) at 0° C. and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure and triturated with diethylether to afford the compound as a light brown solid (0.6 g, 88%).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.Cl.[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10].[OH-].[Na+]>O1CCOCC1>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:5])(=[O:11])[NH2:10]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(C)C2)cc1
Reaction time: 1 h

Procedure:
10.86 ml of dimethyl sulfate were added to a solution of 30 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride in a mixture of 36 ml of 20% w/v aqueous solution of sodium hydroxide and 470 ml of dioxane, and the resulting mixture was stirred at a temperature of between 22° C. and 23° C. for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was extracted with 2 liters of ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solution was then concentrated by evaporation under reduced pressure, until crystals emerged, and then 400 ml of diisopropyl ether were added to the mixture and the crystals which precipitated were collected by filtration, to give 23 g of the title compound as crystals, melting at 113°-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:18]([C:19]2[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=2[C:25]#[N:26])=[CH:17][C:5]([C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1.[H-].[Na+].I[CH3:36]>CN(C=O)C>[Cl:1][C:2]1[C:18]([C:19]2[CH:20]=[N:21][C:22]([C:27]([F:29])([F:28])[F:30])=[CH:23][C:24]=2[C:25]#[N:26])=[CH:17][C:5]([C:6]([N:8]([C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])[CH3:36])=[O:7])=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: CI
Reactant: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)Nc1c(C)cccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
To 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-benzamide (55.0 mg, 0.12 mmol) in dry DMF (0.5 mL) was added NaH (9.6 mg, 0.32 mmol) and iodomethane (0.15 mL, 0.24 mmol). The mixture was stirred at rt overnight, quenched with 0.5 mL of MeOH and 2 drops of trifluoroacetic acid, and purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2,6-dimethyl-phenyl)-2-methoxy-N-methyl-benzamide 39-1 (8.3 mg). MS [M+H]+471.1; tR=6.25 min (method 3)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10]>[Ni].CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Ni]
Solvent: CN(C)C=O
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1

Procedure:
Second, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide was prepared by reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (prepared using the procedure of Example 4) with Raney Nickel. In particular, to a 500 mL pressure vessel was added N′-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (2.00 g, 4.27 mmol), DMF (30.0 mL) and Raney Nickel (1.79 g). The reaction mixture was hydrogenated (50 psi) for 23 h (reaction monitored by HPLC). The reaction mixture was filtered, washed with DMF (20 mL) and the filtrate concentrated to a 5 mL volume (distilled below 70° C. under vacuum). Water (33.0 mL) was added, the precipitate filtered, washed with water (20 mL) and dried in a vacuum oven (65° C.) to yield the amine as a cream colored solid (1.67 g, 91.3%). Purity 98.67% by HPLC.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(Br)C1C=CC=CC=1>>[Cl:1][C:2]1[N:11]([CH2:15][C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH3:18])[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: BrCc1ccccc1
Product: Cc1ccccc1Cn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Reaction time: 24 h

Procedure:
From 8-Chorotheophylline (10 g, 47 mmol) and 2-methylbenzyl bromide (13.6 ml, 103 mmol). The benzyl bromide was added in two portions. First half at reaction start as described in general procedure (E), and the other half after 24 hours as the reaction had not completed.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[N+:17]([O-:19])=[O:18].Br[CH2:21][CH2:22][CH3:23]>C(#N)C>[F:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:21][CH2:22][CH3:23])[CH:12]=[C:11]2[N+:17]([O-:19])=[O:18]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1c[nH]c2ccc(F)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCn1cc([N+](=O)[O-])c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
Potassium carbonate (1.5 g, 11.1 mmol) was added to a solution of 5-fluoro-3-nitro-indole (1.0 g, 5.6 mmol) and 1-bromo-propane (820 mg, 6.7 mmol) in ACN (20 mL) at rt. The reaction was heated to 80° C. and stirred overnight. The solution was filtered and concentrated, and the residue was purified by silica gel chromatography to give 520 mg (42%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 0.86 (3H, t, J=7.2 Hz), 1.81-1.87 (2H, m), 4.30 (2H, t, J=7.2 Hz), 7.28 (1H, td, J=2.4, 9.2 Hz), 7.77-7.86 (2H, m), 8.84 (1H, s).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccccc3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2cccc(N3CCNCC3)n2)cc1

Procedure:
A solution of 0.7 g (2.06 mmol) of tert.butyl 4-(6-phenyl-pyridin-2-yl)-piperazine-1-carboxylate and 3 ml of trifluoroacetic acid in 30 ml of dichloromethane is stirred for three hours at ambient temperature. The solvent is then distilled off, the residue is combined with water and made basic with sodium hydroxide solution. It is then extracted with dichloromethane and the organic phase is separated off and dried over sodium sulphate.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([OH:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14]
Reactant: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Reaction time: 14 h
Yield: 74.7 %

Procedure:
6-Fluoro-3-hydroxy-2-nitrobenzoic acid (22 mg, 0.11 mmol) was dissolved in acetic acid (2 mL). Sodium acetate (10 mg, 0.12 mmol) and Br2 (10 μL, 0.19 mmol) was added and the reaction mixture was left at room temperature for 14 h. The temperature was raised to 50° and the reaction was continued for another 4 h. Evaporation gave a residue which was dissolved in water, and after adjustment of the pH the aqueous phase was extracted with EtOAc. Washing of the organic phase with water and evaporation gave a crude product which was purified by flash chromatography on SiO2. Eluation with toluene-EtOAc-HOAc afforded the product (23 mg). 1NMR (CD3OD): δ8.0 (d, J=8.7, 1H); MS (EI, 70 eV): m/z (rel. int.) 279/281 (M+, 40/38)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11](/[CH:13]=[CH:14]/[CH2:15][OH:16])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([O:25][C@@H:26]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]>>[CH2:23]([O:25][C@@H:26]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:16][CH2:15]/[CH:14]=[CH:13]/[C:11]2[CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[C:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)=[CH:37][CH:38]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]
Reactant: OC/C=C/c1cc(-c2ccccc2)cc(-c2ccccc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cc(-c3ccccc3)cc(-c3ccccc3)c2)cc1)OCC
Yield: 80.1 %

Procedure:
The title compound (426 mg, 80%) was prepared from (E)-3-[1,1′;3′,1″]terphenyl-5′-yl-prop-2-en-1-ol (300 mg, 1.05 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (262 mg, 1.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:8]=1)[NH2:7].[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=O.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:8]=[C:6]2[C:5]([CH:13]=[C:11]([C:10]([OH:15])=[O:14])[NH:7]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ccc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 110 °C

Procedure:
5-Chloro-2-iodoaniline (5.8 g, 23 mmol) and pyruvic acid (8 mL, 115 mmol) were dissolved in DMF (100 mL). DABCO (12.8 g, 115 mmol) was added and N2 (g) was bubbled through solution for 20 minutes, then palladium acetate (1.03 g, 4.6 mmol) was added. The reaction was heated to 110° C. for 1 hour then submitted to aqueous workup and purified by silica gel chromatography (0-100% EtOAc in hexanes) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([OH:24])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].N1C=CC=CC=1.C1C=CC=CC=1.[Cl:37][C:38]([Cl:43])([CH3:42])[C:39](Cl)=[O:40]>C(Cl)Cl>[CH3:1][N:2]([O:24][C:39](=[O:40])[C:38]([Cl:43])([Cl:37])[CH3:42])[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:11]=2[Cl:20])[CH:6]=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: CN(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(OC(=O)C(C)(Cl)Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]hydroxyamine (500 mg, 1.38 mmol) in methylene chloride (2 ml) is added pyridine (0.16 ml, 2.00 mmol) and benzene (3 ml), followed by α,α-dichloropropionyl chloride (328 mg, 1.5 eq.). The mixture is stirred at RT for 2 hours. The resulting reaction mixture is then taken up in methylene chloride, washed, dried and evaporated to dryness. The crude product is purified by prep. TLC to yield N-methyl-N-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenyl]-α,α-dichloropropionyloxyamine. nmr (CDCl3) τ7.77(S,3H,COC Cl2CH3), 6.67(S, 3H, NCH3).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:24]([OH:39])[C:25]([N:27]2[CH2:38][CH2:37][CH2:36][C@H:28]2[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=1)=[O:4].[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[O:55]1[CH2:56][CH2:57][N:52]([CH2:51][CH2:50][NH:49][CH2:2][C:3]([NH:5][C:6]2[CH:48]=[CH:47][C:9]([O:10][CH2:11][C:12]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:24]([OH:39])[C:25]([N:27]3[CH2:38][CH2:37][CH2:36][C@H:28]3[C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:26])=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:53][CH2:54]1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CBr)cc1
Reactant: NCCN1CCOCC1
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)COc1ccc(NC(=O)CNCCN2CCOCC2)cc1

Procedure:
Following a procedure similar to that described in Example 38, but using 100 mg (0.137 mmol) of 1-{(2S,3S)-3-[N2 -(4-bromoacetamidophenoxy)acetyl-L-asparaginyl]amino-2-hydroxy-4-phenylbutyryl}-N-t-butyl-L-prolinamide and 1 ml of 4-(2-aminoethyl)morpholine, 17 mg of the title compound were obtained as a colorless powder, melting at 123°-132° C.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:8](=[O:9])(=[O:10])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Reactant: O=S(=O)(Nc1ccccc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Oc1ccc(S(=O)(=O)Nc2ccccc2)cc1)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a mixture of 24.93 g (0.10 mol) of N-phenyl-4-hydroxybenzenesulfonamide, 10.12 g (0.10 mol) of triethylamine and 150 ml of methylene chloride was added, dropwise, a solution of 24.75 g (0.10 mol) of 4-(2-bromoethyl)benzoyl chloride in 150 ml of methylene chloride over a period of 12 minutes. The reaction mixture was stirred at room temperature for 3 hours, after which 500 ml of methylene chloride were added. The solution was washed once with 2% HCl and twice with water, dried over magnesium sulfate and concentrated to a white solid. Recrystallization from ethanol gave 39.7 g (86.1% of theory) of 4-(N-phenylsulfamoyl)phenyl 4-(2-bromoethyl)benzoate, mp=156°-7° C.