Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:11]2[O:12]CC(C)(C)N=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O:27]C1C(CC2C=CC=CC=2)=C(C2OCC(C)(C)N=2)C=CC=1OC>>[CH3:1][O:2][C:3]1[C:4]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[C:11]([OH:12])=[O:27]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(Cc2ccccc2)c1OC
Product: COc1ccc(C(=O)O)c(CCc2ccccc2)c1OC

Procedure:
Similarly prepared from the corresponding product of step (a) or (b) were:-
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[C:24]1([CH2:30][CH:31]=O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: O=CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in dimethylformamide (3 mL) was added phenylacetaldehyde (101 mg, 0.840 mmol) and oxone (258 mg, 0.420 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (110 mg, 42% yield) as light brown amorphous mass.
Reaction SMILES: [Cl:1][C:2]1[C:9](CC)=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.ClC1C=C(F)C=C[C:15]=1[O:21]C>>[Cl:1][C:2]1[C:9]([O:21][CH3:15])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COc1ccc(F)cc1Cl
Reactant: CCc1cc(C=O)c(F)cc1Cl
Product: COc1cc(C=O)c(F)cc1Cl

Procedure:
Following the procedure for Intermediate 390.2, 2-chloro-4-fluoro-1-methoxybenzene (1.0 g, 6.3 mmol) afforded 840 mg of Intermediate 392.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.90-7.00 (m, 1H) 7.41 (dd, J=9.35, 6.32 Hz, 1H) 10.27 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17]>>[Cl:8][C:6]1[C:5]([O:14][CH2:15][CH:16]([OH:17])[CH2:18][OH:19])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: OCC(O)CO
Reactant: Fc1nc(F)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC(O)COc1nc(F)c(Cl)cc1Cl

Procedure:
To a solution of 12.9 grams (0.07 mole) of 3,5-dichloro-2,6-difluoropyridine in 50 milliliters of glycerol was added over an 8 minute period 2.9 grams of sodium hydroxide in 25 milliliters of glycerol. The mixture was maintained at ~85° C. for ~17 minutes, cooled and poured into 200 milliliters of cold water. The solid which precipitated was air dried and taken up in benzene, dried and most of the benzene was removed by evaporation under reduced pressure. The residue was mixed with hexane and cooled and the crystalline 3-(3,5-dichloro-6-fluoro-2-pyridyloxy)-1,2-propanediol product which precipitated was recovered by filtration. The product was covered in a yield of 10 grams (56 percent of theoretical). The product melted at 78°-80° C. and was found upon analysis to have carbon, hydrogen, chlorine and nitrogen contents of 37.5, 2.9, 27.6 and 5.6 percent, respectively, as compared with the theoretical contents of 37.5, 3.2, 27.7 and 5.5 percent, calculated for the above-named compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISP): 506.1 (M+H)+ and MS (ISN): 503.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>CCO>[Br:1][C:2]1[C:3]([OH:15])=[C:4]([NH2:12])[C:5](=[C:9]([F:11])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Solvent: CCO
Product: Nc1c(O)c(Br)cc(F)c1C(=O)O
Yield: 2.1 %

Procedure:
4-Bromo-6-fluoro-3-hydroxy-2-nitrobenzoic acid (22 mg 0.78 mmol) was dissolved in EtOH (10 mL) and PtS2 (2 mg) was added. Hydrogenation at room temperature and at atmospheric pressure for 14 h followed by filtration and evaporation gave a crude product. Purification by flash chromatography (SiO2, toluene-EtOAc-HOAc) afforded the product (4 mg). 1H NMR (CD3OD): δ 6.44 (d, J=11.3 Hz, 1 H); MS (EI, 70 eV): m/z (rel. int.) 249/251 (M+, 93/90).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:31]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Reactant: O=C(Cl)c1cccc2ccccc12
Product: CCOC(=NC(=O)c1cccc2ccccc12)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2-thienylcarbonyl chloride, there is obtained ethyl N-(2-thienylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e:M+ 376 (10), 347 (13), 194 (100), 111 (48); starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 1-naphthoyl chloride, there is obtained ethyl N-(1-naphthylcarbonyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a foam, mass spectrum m/e: M+ 420 (8), 391 (6), 194 (100), 155 (32), 27 (28);
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:27].C1CCCCC=1.B(Br)(Br)Br>C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)(=[O:18])=[O:17])[C@H:5]2[CH3:27]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1=CCCCC1
Product: C[C@H]1c2cc(F)ccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1
Reaction time: 20 h
Yield: 90.5 %

Procedure:
(S)-8-Fluoro-5-(4-methoxy-benzenesulfonyl)-6-methyl-5,6-dihydrophenanthridine (1.26 g, 3.29 mmol) was suspended in cyclohexene (6.0 mL, 59 mmol). Boron tribromide (20 mL, 1.0 M solution in dichloromethane) was added dropwise at room temperature. The solution was stirred for 20 hours. A solution of saturated, aqueous sodium bicarbonate (300 mL) was added dropwise and then the mixture was extracted with dichloromethane (6×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (1:19 to 1:4 ethyl acetate:hexane) and then recrystallization (dichloromethane-hexane) to afford the title compound as white crystals (1.1 g, 90%), m.p. 193° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:24]2([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]2)[O:23][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][CH2:18][C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C:12](=[O:22])[CH2:11]2.[Br:31]Br>O1CCCC1>[Br:31][C@@H:13]1[CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][C@@H:4]3[O:23][C@@:24]4([O:30][CH2:29][C@H:27]([CH3:28])[CH2:26][CH2:25]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11][C:12]1=[O:22]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: BrBr
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@H](Br)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of (5α,25R)-spirostan-3-one (1.00 g, 2.41 mmol) and tetrahydrofuran (10 mL) was cooled to -78° C. under nitrogen atmosphere. Bromine was added (0.39 g, 2.41 mmol) and the reaction mixture was gradually warmed to room temperature. After three hours, the reaction was quenched by the addition of saturated sodium bisulfite solution. The mixture was diluted with ethyl acetate, washed with saturated sodium bisulfite solution (1×), saturated sodium bicarbonate (1×), brine (1×), dried (sodium sulfate), filtered, and concentrated in vacuo, Upon addition of ether, a precipitate formed which was filtered and washed with hexanes to give 1.20 g, (85%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]1[C@@H:13]([OH:14])[CH2:12][NH:11][CH2:10]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:10][CH2:9][C@@H:13]([OH:14])[CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O[C@@H]1CCNC1
Solvent: Cc1ccccc1
Product: O[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 2,5-dibromopyridine (10.0 g, 42.2 mmol) and (R)-hydroxypyrrolidine (11.0 g, 126 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→heptane/EtOAc 1:2) yielded the title compound (8.63 g, 84%). LC-MS: tR=0.48 min; ES+: 243.15.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[S:4][C:3]=1C(O)=O.CN1CCNCC1.CN1CCCC1=O.CCOC(C)=O>O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][CH:3]=[C:2]([NH2:1])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: Nc1cc(-c2ccc(Br)cc2)sc1C(=O)O
Agent: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1csc(-c2ccc(Br)cc2)c1
Temperature: 160 °C
Reaction time: 5 h
Yield: 44 %

Procedure:
3-amino-5-(4-bromophenyl)thiophene-2-carboxylic acid (11.21 mmol), N-methyl piperazine (11.21 mmol) and N-methylpyrrolidinone (13.5 mL) were mixed together The reaction mixture was stirred at 160° C. for 5 hours and cooled down to room temperature. EtOAc and water were added, organics were separated, dried over Na2SO4, concentrated under reduced pressure and filtrated over silica (DCM/MeOH). Diisopropyl ether was added to the crude material and the residue obtained was filtered to give Intermediate IX.1 as a beige solid in 44% yield, which was characterized by the following spectroscopic data: MS (ESI, EI+) m/z=255 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.O>O1CCCC1.CO.[OH-].[Na+]>[Br:1][C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(Cc1c[nH]c(Br)c1)C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
tert-Butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0 g) was dissolved in a mixed solvent of tetrahydrofuran (15 mL) and methanol (5 mL), and 8 mol/L aqueous sodium hydroxide solution (1.5 mL) was added dropwise at not more than 10° C. After stirring at the same temperature for 4 hr, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→4:1) to give the title compound as a pale-yellow oil (yield 410 mg, 61%).
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>ClCCl>[S:14]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Temperature: 25 °C

Procedure:
Cyclobutanemethanol(5 g, 58 mmol) was dissolved in dichloromethane (150 ml) and cooled in an ice water bath. Triethylamine (10.5 ml,-75.5 mmol) was added followed by the dropwise addition of a solution of tosyl chloride (13.3 g, 69.8 mmol) in dichloromethane (50 ml). The cooling bath was removed and the mixture allowed to warm to room temperature over 16 hours. The mixture was washed with water (2×100 ml) dried (MgSO4) and concentrated in vacuo to give cyclobutanemethanol tosylate as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](SC)=[N:14][CH:15]=3)[N:10]([CH2:20][CH3:21])[C:9]2=[O:22])=[CH:6][C:5]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[C:4]([F:37])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:49][NH2:50]>>[Cl:1][C:2]1[C:7]([N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13]([NH:50][CH3:49])=[N:14][CH:15]=3)[N:10]([CH2:20][CH3:21])[C:9]2=[O:22])=[CH:6][C:5]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:25])=[C:4]([F:37])[CH:3]=1
Reactant: CN
Reactant: CCN1C(=O)N(c2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(F)cc2Cl)Cc2cnc(SC)nc21
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCN1C(=O)N(c2cc(NC(=O)Nc3cccc(C(F)(F)F)c3)c(F)cc2Cl)Cc2cnc(NC)nc21
Yield: 88 %

Procedure:
Using a procedure analogous to Example A2, the sulfide was oxidized with mCPBA to the sulfone and then treated with methylamine to provide 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)-2-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)urea (0.279 mmol, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.96 (brs, 1H), 7.87 (s, 1H), 7.64 (d, J=11 Hz, 1H), 7.50 (m, 2H), 7.33 (m, 1H), 7.02 (m, 1H), 4.60 (d, J=14 Hz, 1H), 4.40 (d, J=14 Hz, 1H), 3.95 (m, 2H), 2.78 (d, J=5 Hz, 3H), 1.15 (t, 3H); MS (ESI) m/z: 538.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([OH:41])=O)([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1.C(N=C=NCCCN(C)C)C.Cl.[CH:55]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56]1.N12CCCN=C1CCCCC2>CN(C)C1C=CN=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1.ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:20]3[CH2:37][CH:36]4[N:22]([C:23](=[O:42])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:61][S:58]([CH:55]6[CH2:57][CH2:56]6)(=[O:60])=[O:59])=[O:41])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCOC(=O)N4C3)cc(-c3ccccc3)nc2c1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred suspension of the acid 22 (0.041 g, 0.072 mmol) in 3:1 dichloromethane-dimethylformamide (1.2 mL) was added N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide×HCl (0.027 g, 0.143 mmol) upon which a solution was obtained. The reaction mixture was stirred 10 min, after which 4-(dimethylamino)pyridine (0.009 g, 0.072 mmol) was added, and the reaction mixture was stirred another 40 min at room temperature. Then, a solution of the cyclopropylsulfonamide, prepared as described in WO03/053349, (0.035 g, 0.287 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (0.043 ml, 0.287 mmol) was added and the tube was sealed and then put in the microwave at 100° C. for 40 minutes. The reaction mixture was then partitioned between ethyl acetate (20 mL), aq. 1 M hydrochloric acid and brine. The organic layer was pooled with the organic layer of another batch starting from 0.062 g, 0.108 mmol of the acid treated similar as above. The resulting solution was dried (Na2SO4), filtered and concentrated onto silica. The residue was purified by flash chromatography (gradient AcOEt:toluene 50:50 to 100:0+0.5% AcOH followed by AcOEt/MeOH, 9:1). Appropriate fractions were concentrated and further purified on Preparative HPLC (Column: ACE 5 C8, 100×21.2 mm, ACE-122-1020) using flow=15 mL/min, gradient 55% methanol/5% acetonitrile in aq. 10 mM ammonium acetate to 90% methanol in 10 min. Appropriate fractions were concentrated, re-dissolved in methanol, concentrated and lyophilized overnight to obtain an off-white solid. Finally this material was subjected to column chromatography (AcOEt/toluene, 1:1), to give 39 mg (32%) of the desired product 23 as a white powder: m/z=675 (M+H)+. 13C-NMR (125 MHz, CDCl3): 6.4, 6.5, 22.8, 24.0, 25.3, 28.0, 31.3, 33.4, 37.4, 43.0, 53.8, 56.2, 58.2, 63.7, 76.1, 98.9, 108.3, 115.4, 118.8, 123.3, 126.0, 127.4, 128.0, 128.9, 129.3, 129.6, 130.3, 131.2, 139.8, 151.4, 154.5, 158.5, 160.5, 161.6, 169.9, 175.6.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH3:12].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>ClCCl>[C:20]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH3:12])(=[O:22])[CH3:21]
Reactant: Cc1ccc(Cl)cc1CCCO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OCCCc1cc(Cl)ccc1C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-(3-hydroxypropyl)-4-chloro-toluene (6.2 g, 33.5 mmol) and triethylamine (9.34 mL, 67 mmol) in dichloromethane (25 mL) was added acetic anhydride (5.1 mL, 50.3 mmol) at room temperature. The mixture was stirred for 2 h and concentrated in vacuo. The residue was diluted with aq. KHSO4 and extracted with AcOEt. The extracts were dried and concentrated. The residue was dissolved in dichloromethane (50 mL). NO2 +BF4- (5.77 g, 36.85 mmol) was added at 0° C. The mixture was stirred for 30 min at 0° C. and poured into water. The mixture was extracted with AcOEt and the extracts was dried and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/AcOEt to give 5.0 g of the title compound: 1H NMR (CDCl3) δ7.63 (bs, 1H), 7.36 (bs, 1H), 4.13 (t, 2H, J=7.2 Hz), 2.78 (t, 2H, J=7.2 Hz), 2.41 (s, 3H), 2.09 (s, 3H), 1.89~2.01 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[C@H:29]([CH2:47][OH:48])[CH2:28]3)[CH:25]=2)[CH:20]=[N:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)[C@H](CO)C3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(N3CCN(C(=O)[C@H]4CCCN4)[C@H](CO)C3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-((S)-4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-indazol-6-yl)-2-(hydroxymethyl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.072 g, 0.12 mol) in dichloromethane (2 mL) and the mixture was stirred at room temperature for 30 min. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (15 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-30% methanol in dichloromethane) to give the title compound as a white solid (0.012, 0.024 mol, 20%). 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1 H), 7.56 (d, J=8.4 Hz, 1 H), 7.37 (d, J=2.0 Hz, 1 H), 7.18-7.09 (m, 2 H), 6.80 (d, J=7.6 Hz, 1 H), 6.60 (s, 1 H), 6.09 (q, J=6.8 Hz, 1 H), 4.82-4.78 (m, 2 H), 4.64-4.60 (m, 1 H), 4.12-4.07 (m, 2 H), 3.76-3.58 (m, 4 H), 3.43-3.38 (m, 2 H), 2.90-2.76 (m, 2 H), 2.48-2.36 (m, 1 H), 2.13-2.20 (m, 3 H), 1.98 (d, J=6.8 Hz, 3 H); MS: (ES) m/z calculated for C25H30Cl2N5O2 [M+H]+ 502.2, found 502.4.
Reaction SMILES: C([O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][C:10]2[O:11][C:12]3[C:19]([Cl:20])=[CH:18][C:17]([CH2:21][CH2:22][CH3:23])=[C:16]([O:24][C:25](=[O:27])[CH3:26])[C:13]=3[C:14]=2[CH3:15])=[CH:7][CH:6]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC(C)=O)cc3)c(C)c2c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1OC(C)=O
Yield: 79.7 %

Procedure:
A solution of 2-(p-acetoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (150 mg, 0.36 mmole) in methanol 5 mL) and a saturated solution of potassium carbonate (3 mL) was stirred at room temperature for 5 minutes. The reaction was poured in water, extracted with methylene chloride, washed with brine, dried (Na2SO4), and concentrated in vacuo to yield 107 mg (79%) of 2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.
Reaction SMILES: C([OH:5])CCC.C(O)(=O)C.O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.[NH2:24][C@@H:25]([C:33](N1CCC[C@H]1C(N[C@H](C(CCl)=O)CCCNC(=N)N)=O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>Cl>[NH2:24][C@H:25]([C:33]([OH:34])=[O:5])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCCCO
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](N)Cc1ccccc1)C(=O)CCl
Agent: Cl
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Thin layer chromatography on silica gel plates (Merck) with butanol:acetic acid:water (4:1:1) indicated a single spot, Rf 0.37, by uv and by ninhydrin and Sakaguchi stains. Amino acid analysis of the D-Phe-Pro-ArgCH2Cl. 2HCl following hydrolysis in 2 ml of 6.0 N HCl for 24 hr. at 110° C. gave Phe=0.98 and Pro=1.00.