Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[N+:23]([C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[O:10][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:8][C:7]=2[CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
352 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 16a were introduced and treated with a mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid. The mixture was stirred for 2 hours at 60° C. After cooling, the mixture was poured into ice-water and extracted using methylene chloride. The methylene chloride phase was washed with sodium hydrogencarbonate solution and dried and then evaporated on a rotary evaporator. The yield was 392 g (91% of theory), and the melting point was 125° C. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.5 and -81.0 ppm. 1H-NMR: 4.86 ppm.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl.Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:9][CH2:8][CH2:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCCCC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCCCC1CCCC1)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 83.1 %

Procedure:
To a solution of 3-cyclopentyl-1-propanol (2.0 g, 15.6 mmol) in triethylamine (3.25 ml, 23.4 mmol) and dichloromethane (50 ml) was added 4-bromobenzenesulfonyl chloride (4.4 g, 17.6 mmol). The solution was stirred for 16 h, diluted with 2 N aqueous hydrochloric acid (100 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (100 ml) and brine (100 ml), dried (MgSO4) and concentrated in vacuo to give the title compound as a white crystalline solid (4.50 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](Cl)[CH:12]=[CH2:13]>[OH-].[Na+].C(O)(C)C>[CH2:13]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH:12]=[CH2:11]
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C=CCOc1c(C)cc(Br)cc1C
Temperature: 60 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A mixture of 4-bromo-2,6-dimethyl-phenol (20.1 g, 100 mmol) and allylchloride (32.7 g, 428 mmol) in 3 N aq. NaOH (100 mL) and isopropanol (250 mL) is stirred at 60° C. for 15 h before it is diluted with 1 N aq. NaOH (100 mL). The mixture is extracted with diethyl ether (300 mL, 150 mL) and the combined org. extracts are washed with 1 N aq. NaOH (2×100 mL), 1 M aq. NaH2PO4 (50 mL), dried over Na2SO4, filtered and concentrated to give 2-allyloxy-5-bromo-1,3-dimethyl-benzene (23.6 g) as a yellow oil, LC-MS: tR=1.08 min, [M+1]+=241.20.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][C@H:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:14]=[CH2:15])[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:24]1[CH:25]=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.NC1C2C(C3C=NC4C(C=3)=CC=CC=4)=C3N(C=2N=CN=1)C[C@@H](NC(=O)OC(C)(C)C)CC3>>[Si:17]([O:16][C@@H:13]1[CH2:14][CH2:15][C:2]2[N:11]([C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:10])[C:4]=3[C:3]=2[C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12]1)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19]
Reactant: C=C[C@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Yield: 64.3 %

Procedure:
In accordance with Example 10, except that the (R)-6-bromo-7-(2-((tert-butyldimethylsilyl)oxy)but-3-en-1-yl)-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.0 g) obtained in Reference Example 11 was used in place of the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Example 10, (R)-8-((tert-butyldimethylsilyl)oxy)-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-4-amine (546 mg) (yield: 64%) was obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[NH2:2][CH2:3][C@H:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@@H:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5]1
Reactant: [H][H]
Reactant: COc1cccc2c1CC(c1ccccc1)C=C2CN
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cccc2c1C[C@@H](c1ccccc1)C[C@H]2CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To 0.22 g (0.73 mmol) of 1-aminomethyl-5-methoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, from Step 2, of Example 2, in 5 mL of absolute ethanol, was added 0.05 g of 10% palladium supported on carbon. The reaction mixture was sealed under a blanket of hydrogen and stirred overnight at ambient temperature. The reaction mixture was flushed with nitrogen before it was filtered through Celite filter aid and washed with 15 mL of absolute ethanol and 15 mL of methylene chloride. The filtrate was concentrated to give 0.16 g (79% yield) of [1R,3S] 1-aminomethyl-5-methoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene hydrochloride, m. p. 235°-237° C.; 1H NMR (d6-DMSO) δ2.15-2.25 (m, 2H), 2.5-2.65 (m, 1H), 2.8-2.95 (m, 2H), 3.0-3.1 (m, 1H), 3.1-3.4 (m, 1H), 3.45-3.5 (m, 1H), 3.72 (s, 3H), 6.43 (d, 1H), 6.62 (d, 1H), 6.94 (t, 1H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:18]N1CCNCC1=O>>[CH3:18][N:7]1[CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH2:3][C:2]1=[O:1]
Reactant: CN1CCNCC1=O
Reactant: O=C1CN(Cc2ccc(C(=O)O)cc2)CCN1
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1=O

Procedure:
Utilising the procedure described for 4-[(3-oxo-1-piperazinyl)methyl]benzoic acid, but employing 1-methylpiperazin-2-one in place of piperazin-2-one afforded the title compound as cream crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:34]=[CH:33][C:5]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:21]=3)[C:7]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH3:59][S:60]([NH2:63])(=[O:62])=[O:61].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:15][C:12]1[CH:13]=[CH:14][C:7]2[CH:6]([C:16]3[C:17](=[S:32])[NH:18][C:19](=[O:31])[N:20]([CH2:22][C:23]4[O:24][CH:25]=[C:26]([C:28]([NH:63][S:60]([CH3:59])(=[O:62])=[O:61])=[O:29])[N:27]=4)[CH:21]=3)[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:34][C:33]=3[CH:10]=[CH:9][C:8]=2[CH:11]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)O)co2)c(=O)[nH]c1=S
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(Cc2nc(C(=O)NS(C)(=O)=O)co2)c(=O)[nH]c1=S

Procedure:
The product of example 37(0.2 g), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (0.38 g), 4-dimethylaminopyridine (0.07 g), methanesulphonamide (0.095 g) and N,N-diisopropylethylamine (0.43 ml) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 16 h. The mixture was partitioned between aqueous tartaric acid and ethyl acetate. The organic solution was dried (MgSO4) and evaporated. Purification was by reverse phase silica gel chromatography (C18-sep-pak) eluting with 50% methanol in 0.1% aqueous ammonium acetate. Yield 0.032 g.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:12][CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([OH:24])=[CH:16][N:15]=1>CCOC(C)=O.C([O-])(O)=O.[Na+]>[OH:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([CH2:13][NH:12][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ncc(O)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NCc1ncc(O)c2ccccc12)c1ccccc1
Reaction time: 0.25 h

Procedure:
Benzoyl chloride (0.018 ml) is added dropwise to a stirred mixture of the product from step 3 (20 mg) in a mixture of 2 ml EtOAc and 2 ml of saturated aqueous NaHCO3 solution. After 15 minutes stirring, the organic layer is separated, washed with water, dried and concentrated to a solid. The solid is washed with hexane and dried to yield 20 mg of the title compound as a white solid, m.p. 130-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:10]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:18][C:14]=1[C:15](O)=[O:16])(=[O:12])=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:10]([C:13]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:18][C:14]=1[CH2:15][OH:16])(=[O:12])=[O:11]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2C(=O)O)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)cc2CO)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-5-((tetrahydro-2H-pyran-4-yl)methoxy)benzoic acid (40 mg, 0.084 mmol) in tetrahydrofuran (THF) (1 mL) at 0° C. was added lithium aluminium hydride (1.0M in diethyl ether) (0.084 mL, 0.084 mmol) and the reaction mixture was stirred at 0° C. for 30 minutes then warmed to 25° C. for 1 hour. The reaction mixture was quenched carefully with water. The organic solvent was removed in vacuo and the remaining aqueous layer was extracted with ethyl acetate (20 mL×3). The organics were combined and concentrated in vacuo to give a yellow oil. The crude was then purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were concentrated under a stream of nitrogen in a Radleys blowdown apparatus to give the required product, 25.2 mg. LCMS [LCMS2] Rt 1.40 min, m/z (ES+) 462 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][S:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:17]([OH:19])=[O:18])(=[O:13])=[O:12]>>[N+:6]([C:21]1[CH:20]=[C:16]([CH:15]=[C:14]([S:11]([Cl:10])(=[O:13])=[O:12])[C:22]=1[Cl:23])[C:17]([OH:19])=[O:18])([O-:9])=[O:7]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)c(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a mixture of concentrated sulfuric acid (87 ml.) and concentrated nitric acid (16 ml., density = 1.42) is added 3-chlorosulfonyl-4-chlorobenzoic acid (11.5 g.; 0.045 mole). The reaction mixture is heated at 85°-90° C. with stirring for 20 hours then poured into ice water. The 3-nitro-4-chloro-5-chlorosulfonylbenzoic acid which separates is filtered, washed with water and dried, m.p. = 189°-90° C. (corr.); yield, 6.6 g. (50%).
Reaction SMILES: [F:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH:32]C(=O)OCC5C=CC=CC=5)(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:44])(=[O:43])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1>CO>[F:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH2:32])(=[O:31])=[O:30])=[CH:27][C:21]=4[S:20](=[O:43])(=[O:44])[N:19]=3)=[C:14]([OH:45])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:46][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2)OCc1ccccc1
Solvent: CO
Product: NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.7 %

Procedure:
The crude benzyl [N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-sulfamoyl]carbamate was dissolved in methanol (5 mL) and the mixture was degassed and backfilled with nitrogen (3×). Palladium on carbon (10% dry, 180 mg) was added and the mixture was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product, which was further purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 150×21.2 mm, 5 micron, 30%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (1R,2S,7R,8S)—N-{3-[3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-sulfamide (55.7 mg, 0.099 mmol, 58.7% over two steps), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.19-1.24 (2H, m), 1.40-1.60 (4H, m), 2.51-2.54 (1H, m), 2.64-2.65 (1H, m), 3.04 (1H, d, J=9.3 Hz), 3.53 (1H, d, J=9.3 Hz), 4.42 (1H, d, J=15.7 Hz), 4.96 (1H, d, J=15.6 Hz), 7.15 (2H, m), 7.31-7.34 (H, m), 7.43 (1H, dd, J1=9.4 Hz, J2=2.3 Hz), 7.51-7.55 (2H, m), 9.96 (1H, s). LC-MS (ESI) calcd for C24H24FN5O6S 561.12, found 562.5 [M+H+]. Anal. calcd for C24H24FN5O6S.0.5H2O: C, 50.51; H, 4.42; N, 12.27; found: C, 50.42, H, 4.35; N, 11.90.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]Cl)[CH3:34].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:34][CH2:33][N:35]([CH2:39][CH3:40])[CH2:36][CH3:37])=[CH:28][CH:29]=2)=[O:22])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: CCN(CC)CCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCN2S(=O)(=O)c2ccc(C)cc2)C(=O)O)cc1

Procedure:
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride hydrochloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp=105-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[CH2:12]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:15]2[CH2:14][N:13]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:18]1[CH2:17][CH:16]2[CH2:12][N:13]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH:15]2[CH2:19]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Cl)c(Cl)c3)CC2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of acid 3,4-dichlorobenzoic acid (0.45 g, 2.36 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.5 g, 2.36 mmol) and HOBt (0.4 g, 2.83 mmol) in DMF (15 mL), EDCI.HCl (0.54 g, 2.83 mmol) and DIEA (1.5 g, 11.5 mmol) were added. The mixture was stirred at room temperature overnight and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude product which was used directly in the next step.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:30]([N:32]([CH3:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C(C)(C)C)=[CH:13][CH:12]=1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:49]>>[ClH:49].[NH2:8][C@H:9]([C:22]([NH:24][C@@H:25]([C:30]([N:32]([CH3:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:31])[CH2:26][CH2:27][S:28][CH3:29])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)N(C)CCCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CSCC[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N(C)CCCc1ccccc1

Procedure:
A solution of [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-methyl-N-(3-phenylpropyl)-D-methioninamide (601 mg.) in hydrogen chloride-ethyl acetate (3.9 N, 5 ml.) was stirred at room temperature for one hour, then concentrated. The residue was purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel (350 g.) using ammonium acetate (0.15%) in methanol-water (3:2) as the eluant (200 ml./min.). A solution of the product, which appeared in fraction 3 (k'=3.75-5.75), in hydrochloric acid (0.0936N, 20 ml.) and water (20 ml.) was lyophilized. The product was twice more lyophilized, affording as an amorphous white solid L-tyrosyl-N-methyl-N-(3-phenylpropyl)-D-methioninamide monohydrochloride (0.21 g.), whose free base is the compound of Formula II wherein Q is Met, R1 and R2 are each hydrogen, R4 is (CH2)nY wherein n is 3 and Y is phenyl and R5 is methyl.
Reaction SMILES: [CH:1]1([CH3:13])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([C:10]([OH:12])=O)[CH2:2]1.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:28][C:26](=[O:27])[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:10]([CH:3]2[CH2:2][C@H:1]([CH3:13])[CH2:6][CH2:5][C@H:4]2[CH:7]([CH3:8])[CH3:9])=[O:12])=[CH:20][CH:21]=1
Reactant: CC1CCC(C(C)C)C(C(=O)O)C1
Reactant: NC(=O)Cc1ccc(N)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1CC[C@@H](C)CC1C(=O)Nc1ccc(CC(N)=O)cc1
Temperature: 25 °C

Procedure:
The p-Menthane-3-carboxylic acid (obtained according to publication: Desmond Cunningham, Eva T. Gallagher, David H. Grayson, Patrick J. McArdle, Christina B. Storey, Deborah J. Wilcock; J. Chem. Soc., Perkin Trans. 1, 2002, 2692-2698), (2.5 g, 13.5 mmol) was heated under reflux with thionyl chloride (Alfa Aesar) (7 mL) for three hours. Then the excess of thionyl chloride was distilled off in vacuo. Residue was dissolved in CH2Cl2 (30 mL). This solution was added drop wise to the mixture of 4-aminophenylacetamide (2.2 g, 13.5 mmol) and triethylamine (1.8 g, 17.8 mmol) at 0° C. After ten minutes the solution was allowed to warm to room temperature. After 1 hour GC showed that reaction is completed. CH2Cl2 (50 mL) was added to the reaction and this mixture was washed by 0.1 N HCl aq, water, 0.1 N NaOH aq, by brine and dried over MgSO4. The mixture was then filtrated and evaporated give white solid which was crystallized from hot ethyl acetate providing 3 g (65%) product as white solid. C19H28N2O2 (MW 316.22); 1H NMR (500 MHz, DMSO-d6) δ: 9.79 (s, 1H), 7.51 (d, 2H, J=8.41), 7.36 (br s, 1H), 7.15 (d, 2H, J=8.41 Hz), 6.82 (br s, 1H), 3.30 (s, 2H), 2.30 (t, 1H, J=11.43 Hz of d, J=3.19 Hz), 1.70-1.77 (m, 2H), 1.61-1.68 (m, 2H), 1.51 (t, 1H, J=11.5 Hz, of t, J=2.8 Hz), 1.33-1.38 (brs, 1H), 1.17 (q, 1H, J=12.16 Hz), 1.02 (q, 1H, J=12.7 Hz, of d, J=2.7 Hz) 0.89-0.96 (m, 1H), 0.88 (d, 3H, J=6.5 Hz), 0.85 (d, 3H, J=6.9 Hz), 0.79 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH2:1]([NH:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].Cl[CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[CH2:1]([N:10]1[CH2:24][CH2:23][N:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C:11]1=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NC/C=C/c1ccccc1)Nc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
To a solution of 2.51 g of (E)-N-cinnamyl-N'-(3-pyridyl) urea dissolved in 30 ml of dimethylformamide, 990 mg of sodium hydride (60% oily dispersion) was added under ice-cooling and the mixture was stirred for 30 minutes. To the mixture was added 2.8 g of 1-chloro-2-p-toluenesulfonyloxyethane and the mixture was stirred under ice-cooling for 6 hours. After distilling dimethylformamide off under reduced pressure, the residue was diluted with water and extracted with chloroform. The chloroform layer was washed with water, dried and then the solvent was distilled off. The residue was purified by silica gel column chromatography (solvent: chloroform-methanol=30:1) and recrystalliezed from ethanol to give 1.65 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][S:57]([C:60]1[CH:61]=[C:62]2[C:67](=[C:68]([CH3:70])[CH:69]=1)[N:66]=[CH:65][C:64]([C:71]([NH2:73])=[O:72])=[C:63]2[NH:74][C:75]1[CH:80]=[CH:79][CH:78]=[C:77]([O:81][CH3:82])[CH:76]=1)(=[O:59])=[O:58]>>[CH3:82][O:81][C:77]1[CH:76]=[C:75]([NH:74][C:63]2[C:62]3[C:67](=[C:68]([CH3:70])[CH:69]=[C:60]([S:57]([CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH:46]=[O:45])(=[O:58])=[O:59])[CH:61]=3)[N:66]=[CH:65][C:64]=2[C:71]([NH2:73])=[O:72])[CH:80]=[CH:79][CH:78]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCO)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCC=O)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 61 as a substrate. ES/MS calcd. for C29H38N3O5S+ 540.3. Found m/z=540.4 (M+H)+.