Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:10]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)SCCCS2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(#N)C.[OH2:25]>C(OCC)(=O)C>[OH:9][CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:25]
Reactant: OC(Cc1ccccc1)C1(c2ccccc2)SCCCS1
Reactant: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1ccccc1)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74 %

Procedure:
To a solution of 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66) (2.50 g, 7.9 mmol) in 100 mL of a 9:1 mixture of acetonitrile and water was added mercuric perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes and thin layer chromatography indicated that the reaction was completed. The mixture was diluted with ethyl acetate, filtered through a pad of Celite and the filtrate was washed with saturated NaHCO3, brine and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel, (20% ethyl acetate in hexanes) to afford 1.32 g (74%) of the title compound (67).
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39](S(N)(=O)=O)[S:40][CH:41]=1>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:39]3[S:40][CH:41]=[C:37]([Cl:36])[CH:38]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: NS(=O)(=O)c1cc(Cl)cs1
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Product: Nc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4cc(Cl)cs4)cc3)c(=O)c2cc1F

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-chlorothiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-4-chlorothiophene-2-sulfonamide. ES-MS (M+H)+=507.0, 509.0 (Cl).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
1.3 g (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethyl acetate (40 ml) at ambient temperature. 0.3 g of Lindlar Catalyst (ex Aldrich) is added to the mixture. The mixture is then pressurised under a hydrogen atmosphere to 2 bar. The mixture is stirred at ambient temperature and 2 bar hydrogen pressure for 3 days. The mixture is then filtered to remove the catalyst and concentrated under reduced pressure. The residue is then purified by column chromatography (ethyl acetate/hexane, 70:30) to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 99.2:0.8 (3-a, R1=Boc:3-b, R1=Boc) as determined by hplc.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:16]3[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.[OH-:21].[Na+].O.OO>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:12][CH:13]([OH:21])[CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[C:4]([F:20])[CH:3]=1
Reactant: [OH-]
Reactant: O=C1C2=C(CC=CC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1C2=C(CC(O)CC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg(1.61 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,7-dihydro-1H-isoindole-1,3(2H)-dione in 10 mL of tetrahydrofuran (THF) was added 1.94 mL of a 1M solution of BH3 in THF at 0° C. The mixture was then stirred at the same temperature for 1 h. Then, the mixture was warmed to room temperature. A solution of 3.0 mL of 6N aqueous sodium hydroxide, 1.8 mL of water, and 2.1 mL of 30% aqueous hydrogen peroxide were added subsequently. The mixture was stirred at the same temperature for 4 h. The crude product was diluted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel, eluting with a 1:2 v:v mixture of ethyl acetate and n-hexane to give 62 mg of the title product of Step B, a compound of the invention, as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 1.8 (br s, 1H), 1.95 (m, 2H), 2.8-2.4 (m, 4H), 4.4 (m, 1H), 5.85 (br s, 1H), 6.9 (s, 1H), 7.5 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[C:12]([C:11]1[C:6]2[N:7]([C:3]([C:1]#[C:2][C:25]3[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=3)=[CH:4][N:5]=2)[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=2)[CH:10]=1)#[N:13]
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(S(N)(=O)=O)s3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 5-bromothiophene-2-sulfonamide (117 mg, 0.5 mmol) according to general procedure II. Obtained as an off-white solid (80 mg, 35%). MS (ISP) 473.1 [(M+H)+]; mp 267-269° C.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:10]([S:15][CH2:16][CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)(=[O:20])=[O:19])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:10]([S:15][CH2:16][CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)(=[O:20])=[O:19])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[C:4]([OH:33])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of 515 mg (1.0 mmol) 4-fluoro-2-methoxy-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]benzamide (example compound 50) in DCM (5 ml) was cooled to −78° C. 5 ml (1 M in DCM, 5.0 mmol) BBr3 were added at this temperature and the mixture was stirred for 1 h at −78° C. Then the reaction solution was poured into an iced water mixture and it was adjusted to pH 8 with NaHCO3. Then it was extracted with DCM and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 290 mg of 4-fluoro-2-hydroxy-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]benzamide were obtained as residue. MS: m/z 501.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:13].C(N(CC)CC)C.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28].C(=O)([O-])N>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([C:23]([F:22])([F:37])[F:38])[CH:25]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid methyl ester (5.00 g, 25.5 mmol) in methylene chloride (75 mL) was added triethylamine (4.13 g, 40.8 mmol) followed by 3,5-bis-trifluoromethyl-benzoyl chloride (8.46 g, 30.6 mmol). This mixture was allowed to stir overnight at ambient temperature. Work-up of an aliquot of the reaction mixture revealed incomplete reaction. Additional 0.5 equivalents of the acid chloride (2.3 mL) and triethylamine (1.8 mL) were added and the mixture was refluxed overnight. The reaction mixture was allowed to cool and filtered. The filtrate was partitioned against brine, the layers were separated, and the aqueous layer was extracted with one portion of ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The resultant paste was dissolved in methylene chloride (25 mL) and the product was precipitated out by the addition of hexanes (175 mL). The precipitate was isolated by filtration and determined to be a mixture of the desired amide (mono-acylated) product and the carbamate (di-acylated) side product. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (15/85 gradient to 30/70) to give 2-(3,5-bis-trifluoromethyl-benzoylamino)-4-nitro-benzoic acid methyl ester (3.7 g, 33%) as an off-white solid. 1H NMR (400 MHz, CDCl3); δ 12.40 (bs, 1H), 9.78 (d, 1H), 8.50 (s, 2H), 8.31 (d, 1H), 8.11 (s, 1H), 8.00 (dd, 1H), 4.07 (s, 3H). 1H NMR (400 MHz, DMSO-d6); δ 9.04 (d, 1H), 8.43 (dd, 1H), 8.34 (s, 4H), 8.24 (s, 1H), 8.22 (s, 2H), 3.87 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:33][C:34]([F:37])([F:36])[F:35])(=O)=O>C1COCC1>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4][N:3]1[CH2:33][C:34]([F:37])([F:36])[F:35]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)N(CC(F)(F)F)CC2c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Tert-butyl 1-oxo-4-phenyl-2,7-diazaspiro[4.5]decane-7-carboxylate (1 g, 3.03 mmol) in THF (13 ml) cooled to 0° C. was treated with sodium hydride (60% in oil) (4.54 mmol, 0.182 g). The reaction mixture was stirred at 0° C. for 5 minutes and stirred at room temperature for 1 hour. The reaction mixture was cooled back down to 0° C. and treated dropwise with 1,1,1-trifluoroethyl trichloromethanesulfonate (0.547 ml, 3.33 mmol) in THF (2 ml). The reaction mixture was stirred at room temperature for 9 hours. The reaction was quenched with water and extracted with EtOAc. The organic portion was dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica chromatography, eluting with 0-20% ethyl acetate/iso-hexane. The relevant fractions were combined and concentrated in vacuo to give tert-butyl 1-oxo-4-phenyl-2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[4.5]decane-7-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[CH:12]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH:42](=O)[CH2:43][CH:44]([CH3:46])[CH3:45]>>[CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=2)[CH:12]=[C:13]([N:15]([CH2:16][C:17]2[CH:18]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=2)[CH2:42][CH2:43][CH:44]([CH3:46])[CH3:45])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CC=O
Reactant: COC(=O)C(CC(C)C)c1cc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
Following the procedure of Example 39, step (a), reaction of 2-[5-(3,5-Bis-trifluoromethyl-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester, compound 46a with isovaleraldehyde gave the title compound; Calcd. MW 661.66. Found MH+ 662.4.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:19][O:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:18]2[C:27](=[O:26])[C:22]3[C:23](=[CH:29][CH:30]=[CH:31][C:21]=3[O:20][CH3:19])[C:24]2=[O:25])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: COc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(OC)c3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-methoxyisoindoline-1,3-dione was prepared by the procedure of Example 8 from 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethylamine (580 mg, 2.12 mmol) and 3-methoxyphthalic anhydride (380 mg, 2.13 mmol) in acetic acid (15 mL). The product was obtained as a white solid (620 mg, 67% yield): mp, 162.5-164.5° C.; 1H NMR (CDCl3) δ 1.45 (t, J=6.9 Hz, 3H, CH3), 2.85 (s, 3H, CH3), 3.78 (dd, J=4.7, 10.5 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 3.99 (s, 3H, CH3), 4.09 (q, J=6.9 Hz, 2H, CH2), 4.54 (dd, J=10.3, 14.4 Hz, 1H, CHH), 5.87 (dd, J=4.6, 10.7 Hz, 1H, NCH), 6.80-6.83 (m, 1H, Ar), 7.10-7.18 (m, 3H, Ar), 7.38 (d, J=7.3 Hz, 1H, Ar), 7.63 (dd, J=7.5, 8.2 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.57, 41.32, 48.52, 54.62, 55.82, 56.19, 64.38, 111.35, 112.52, 115.56, 116.75, 117.58, 120.40, 129.58, 133.59, 136.30, 148.41, 149.46, 156.74, 166.43, 167.35; Anal Calcd for C21H23NO7S: C, 58.19; H, 5.35; N, 3.23. Found: C, 58.05; H, 5.35; N, 3.24.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(Cl)Cl>[Cl:8][C:6]1[N:7]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:5]=1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: C[C@H]1COCCN1c1nc(Cl)nc(-c2ccccc2S(C)(=O)=O)n1
Temperature: 60 °C

Procedure:
A mixture of (S)-4-(4,6-dichloro-1,3,5-triazin-2-yl)-3-methylmorpholine (1.25 g, 5.0 mmol), 2-methylsulfonylphenyl boronic acid (1.1 g, 5.5 mmol), sodium carbonate (1.6 g, 15.0 mmol) and bis(triphenylphosphene)palladium(II) dichloride (205 mg, 0.25 mmol) in DME/H2O/ (4:1, 10 mL) was heated in the microwave at 60° C. for 25 minutes. The mixture was then diluted with DCM (200 mL), washed with water (200 mL), the organic layer passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a dark orange/brown oil (S)-4-(4-chloro-6-(2-(methylsulfonyl)phenyl)-1,3,5-triazin-2-yl)-3-methylmorpholine, 2.59 g, >100%, crude.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][C:37]=1[S:46](Cl)(=[O:48])=[O:47]>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:46]([C:37]2[CH:38]=[CH:39][C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:36]=2)(=[O:48])=[O:47])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 62 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (500 mg) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 2-naphthalenesulfonyl chloride (463 mg) to obtain (RS)-N-(4-(ethoxycarbonyl-methyl)phenyl)-2-(2-naphthalenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (345.7 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[N+](=[CH2:23])=[N-]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([O:13][CH3:23])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.00 g (3.8 mmole) of 3(S)-t-butoxycarbonylamino-2-hydroxy-5-methylhexanoic acid prepared by the method of R. L. Johnson [J. Med. Chem., 25, 605 (1982)] in 30 ml, of methanol was stirred, whilst cooling with ice, and then a diethyl ether solution of diazomethane was added and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off and the resulting solid was recrystallized from hexane to give 952 mg of the title product as colorless needles, melting at 84°-85° C.; [α]25 -10.2° (C=1.26, methanol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+].[I-].[Na+].O>CN(C)C=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[C:7]3[CH:18]=[C:3]([CH2:2][C:19]#[N:20])[CH:4]=[CH:5][C:6]=3[O:10][N:9]=2)=[CH:12][CH:13]=1
Reactant: Clc1ccc(-c2noc3ccc(CBr)cc23)cc1
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc2onc(-c3ccc(Cl)cc3)c2c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole(6.5g.), sodium cyanide (1.1g) and dry sodium iodide (0.3g) were stirred together in dry dimethylformamide (50ml) for 20 hours at ambient temperature. The mixture was poured into water (500ml.), stirred for one hour and the brown solid filtered off, washed and dried (5.1g). This was recrystallised, with charcoaling, from 50% toluene/60-80 petrol ether (100ml.) To give the title compound as an off-white solid (3.4g) m.p. 118°C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[N:11]([O-])=O.[Na+].[OH:15][C:16]1[CH:21]=[C:20]([CH3:22])[O:19][C:18](=[O:23])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][N:11]=[C:17]2[C:16](=[O:15])[CH:21]=[C:20]([CH3:22])[O:19][C:18]2=[O:23])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=N[O-]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1=CC(=O)C(=NNc2ccc(C#N)cc2)C(=O)O1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a mixture of 5.9 g (0.05 mol) 4-aminobenzonitrile and 20 ml of 12 N hydrochloric acid in 25 ml of water, cooled to 5° C., there is added dropwise a solution of 3.8 g (0.055 mol) sodium nitrite in 10 ml of water. The solution formed is added to an ice cooled solution of 6.3 g (0.05 mol) 4-hydroxy-6-methyl pyr-2-one and 22 g (0.205 ml) of sodium carbonate in 125 ml of water. The suspension formed is stirred at 5° C. for 1 hr., at room temperature for 3 hrs. and is vacuum filtered. The filter cake is air dried to afford 12 g (94% yield) of product, mp 300° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:33][CH2:34][CH2:35]I)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[C:42]1(O)C=CC=CC=1>>[N:37]1([CH2:42][CH2:35][CH2:34][CH2:33][C:25]2[S:24][C:23]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[C:13]([C:11](=[O:12])[NH:10][C:2]5[S:1][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[N:3]=5)[CH:14]=[CH:15][CH:16]=4)[CH2:21]3)=[N:27][C:26]=2[C:28]([OH:30])=[O:29])[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Reactant: Oc1ccccc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCCCn3ccnc3)s1)CC2

Procedure:
The title compound 72 was prepared by substituting compound 42C for compound 2C and imidazole for phenol in step 4 of Example 2. The alkylation intermediate was not isolated prior to ester hydrolysis. After precipitation of the desired product, the solid was purified by HPLC (Preparative reverse phase HPLC was performed on an automated Gilson HPLC system, using a SymmetryPrep Shield RP18 prep cartridge, 250 mm×21.20 mm i.d., 10 um, and a flow rate of 25 mL/min; λ=214, 245 nm; mobile phase A, 0.1% TFA in H2O; mobile phase B, CH3CN; linear gradient 20-90% of B in 40 min) to provide the title compound in 34% yield: 1H NMR (300 MHz, DMSO-d6) δ ppm 12.91 (1H, s), 12.55 (1H, s), 9.06 (1H, s), 8.04 (1H, d), 7.77 (2H, m), 7.66 (2H, m), 7.43 (4H, m), 4.19 (2H, t), 3.73 (2H, t), 3.05 (4H, m), 1.83 (2H, m), 1.53 (2H, m). MS (ESI(+)) m/e 559 (M+H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH:28]([CH3:39])[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].Cl>C(OCC)(=O)C>[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH:28]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH3:39])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: CC(Br)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(OC(=O)CCC(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Triethylamine was added drop-wise to a stirred solution of 5-(Cbz-amino)-4-oxopentanoic acid (4.00 g; 15.0 mmol) and the product of 2a (3.65 g; 15.0 mmol) in ethyl acetate (50 mL). The stirred mixture was refluxed for 2 days under argon. After cooling to ambient temperature, 0.5 M HCl solution (50 mL) was added and the mixture was shaken thoroughly. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solutions were washed with saturated NaHCO3 solution (2×15 mL) and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation an amber oil was obtained that was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL), collecting 8×100 mL fractions. Evaporation of fractions 3-5 resulted in 4.92 g (77%) product (oil).