Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19]Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1.Cl>C1COCC1>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCC1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(CCc2ccc(OCc3ccccc3)cc2)CCC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 20.6 %

Procedure:
To a mixture of magnesium (35 mg) and THF (1.5 mL) was added one grain of iodine under nitrogen flow, followed by warming in an oil bath at 50° C. A solution of 1-(benzyloxy)-4-(2-bromoethyl)benzene (400 mg) in THF (3 mL) was added dropwise to the mixture over 20 minutes, and then the reaction liquid was heated under reflux for 4 hours. The reaction liquid was ice-cooled, and a solution of cyclobutanone (100 mg) in THF (4 mL) was added dropwise over 15 minutes, followed by stirring at room temperature for another 6 hours. The reaction liquid was adjusted to an acidic pH by adding 1M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9:1-1/1) to obtain 1-{2-[4-(benzyloxy)phenyl]ethyl}cyclobutanol (80 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11]3=[N:13][N:14]=[C:15]([S:16][CH3:17])[N:10]3[CH:9]=[CH:8][C:7]=2[CH:18]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11]3=[N:13][N:14]=[C:15]([S:16]([CH3:17])=[O:27])[N:10]3[CH:9]=[CH:8][C:7]=2[CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2c(c1)C=Cn1c(nnc1SC)C2
Product: COc1ccc2c(c1)C=Cn1c(nnc1S(C)=O)C2

Procedure:
By a procedure similar to that described in Example 17, 8-methoxy-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 8-methoxy-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from chloroform-methanol), m.p. 241°-242° C.
Reaction SMILES: C([O:8][C:9](=[O:43])[CH2:10][C@@H:11]([C:24]1[CH:28]=[CH:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH:25]=1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:41]([C:38]1[CH:39]=[CH:40][C:35]([C:32]2[CH:31]=[CH:30][C:29]([N:26]3[CH:27]=[CH:28][C:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:43])=[O:8])=[CH:25]3)=[CH:34][CH:33]=2)=[CH:36][CH:37]=1)#[N:42]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)C(C)(C)C
Yield: 87 %

Procedure:
According to the procedure described in Example 1(a), 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester was hydrogenolyzed in EtOH/EtOAc after 6 hours to give in 87% yield 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a colorless amorphous solid. 1H NMR: δ 7.74 (d, 2H, 8.5 Hz), 7.68 (d, 2H, 8.5 Hz), 7.63 (d, 2H, J=8.5 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.08 (t, 1H, J=2.4 Hz), 6.89-6.83 (m, 1H), 6.29 (t, 1H, J=1.8 Hz), 5.77-5.71 (m, 1H), 4 .17 (d, 1H, J=9.2 Hz), 4.06-4.01 (m, 1H), 3.19 (dd, 1H, J=8.6, 16.4 Hz), 2.85 (dd, 1H, J=4.6, 16.4 Hz), 2.78 (d, 3H, J=4.8 Hz), 0.96 (s, 9H). Anal. Calculated for C28H30N4O4•0.25 EtOAc•0.2 C6H14: C, 68.98; H, 6.67; N, 10.66. Found: C, 68.91; H, 6.79; N, 10.64.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20](Cl)=[O:21])=[C:16]([CH3:26])[CH:15]=3)[O:11][C:9]=2[N:10]=1.Cl.C([O:36][C:37](=[O:43])[C@@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)(C)(C)C.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:24]=[C:23]([CH3:25])[C:17]([O:18][CH2:19][C:20]([N:39]4[CH2:40][CH2:41][CH2:42][C@H:38]4[C:37]([OH:43])=[O:36])=[O:21])=[C:16]([CH3:26])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
A solution of 175 mg of {4-[5-(2-fluoro-phenoxy)-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetyl chloride in 2 ml of dichloromethane was added slowly to a suspension of 102 mg of proline tert-butyl ester hydrochloride and 170 μl of triethylamine in 5 ml of dichloromethane. After stirring for 2 h, the solvent was removed in vacuo. 1.6 ml of trifluoroacetic acid were added and the mixture was stirred for 2 h at room temperature. Then 10 ml water were added and the aqueous layer was extracted three times with 15 ml of a dichloromethane/isopropanol mixture (3:1). After drying with sodium sulfate and filtration, the solvents were removed in vacuo and the title compound was isolated via preparative HPLC. Yield: 56 mg of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:44])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([O:18][Si](C(C)(C)C)(C)C)[CH:12]=3)[C:3]=12>Cl.CCO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:26]([C:28]3[O:29][C:30](=[O:44])[C:31]4[C:36]([C:37]=3[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:27])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([F:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(F)cc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
3-(1-(4-amino-3-(3-((tert-butyldimethylsilyl)oxy)-5-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one single enantiomer (intermediate Q.3, second eluted enantiomer under the conditions described above, 0.038 g, 0.063 mmol) was dissolved in a solution of 1M HCl in EtOH (0.2 mL) and stirred at room temperature for 5 hrs. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=97:3) to afford title compound as a white solid (0.025 g, 0.05 mmol, 80%). This compound proved to be the first eluted enantiomer under Chiral HPLC conditions of Method A5: Rt=7.3 min, ee>99%.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1>CO.O.[Pd]>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[N:16]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[N:15]=[CH:14]3)=[CH:5][CH:4]=1
Reactant: CN(C)CCCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)CCCn1ncc2cc(CCc3ccc(O)cc3)ccc2c1=O
Yield: 94.4 %

Procedure:
Trans-6-[2-(4-Hydroxyphenyl)ethenyl]-2-(3-dimethylaminopropyl)-1(2H)-phthalazinone hydrochloride (5 g) in methanol (100 ml) and water (10 ml) was hydrogenated at 50 psi over 10% Pd/C (0.5 g). After 6 hours the catalyst was filtered and the filtrate was diluted with ether (600 ml). The precipitated product was filtered to give 4.3 g of the saturated product as the hydrochloride mp. 234°-236° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([Cl:21])=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(Cl)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a pre-cooled solution (0° C.) of the compound from Step F of Example 2 (140 mg, 0.50 mmol) in DMF (2.5 mL) was added N-chlorosuccinimide (0.075 g, 0.55 mmol) in DMF (0.5 mL) dropwise. The solution was stirred at room temperature for 1 h and the reaction quenched by addition of methanol (4 mL) and evaporated in vacuo. The crude product was purified on silica gel using methanol/dichloromethane (1:9) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (55 mg) as a colorless solid.
Reaction SMILES: [OH-].[Na+].[ClH:3].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:5]1.O>CO>[ClH:3].[O:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:5]1
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCNCCC1COc2ccccc2C1
Reaction time: 0.08 h
Yield: 87.5 %

Procedure:
21 ml (42 mmol) of 2N sodium hydroxide solution are added at room temperature while stirring to a solution of 2.99 g (10 mmol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride in 60 ml of methanol. After 5 minutes, 40 ml of water are added to the reaction mixture which is then stirred for 30 minutes at 50°-60°. After cooling, the mixture is concentrated by evaporation in vacuo. The residue is dissolved in 30 ml of water, and then 10 ml of hydrochloric acid (36% strength) are added and the whole is cooled in an ice bath. The crystals formed are filtered off with suction. 2.5 g (87.5%) of N-[2-(chroman-3-yl)ethyl]-N-(2-carboxyethyl)-amine hydrochloride are obtained (m.p. 186°-188°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:28]([C:22]3[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=3[Cl:20])(=[O:30])=[O:29])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CCCCCC
Product: O=S(=O)(Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1)c1ccc(Cl)cc1Cl
Yield: 21.5 %

Procedure:
Using the method of Example 17.4, 2-(3-chloro-5-pyridyloxy)-5-aminobenzotrifluoride (0.394 g) and 2,4-dichlorobenzenesulfonyl chloride (0.34 g) were combined to provide, after flash chromatography and trituration with hexane/ether the title compound as a crystalline solid (0.146 g). mp 129-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:61][C:62]1[NH:63][CH:64]=[CH:65][N:66]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:61][C:62]2[NH:63][CH:64]=[CH:65][N:66]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ncc[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ncc[nH]2)cc1Br
Yield: 58.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 148A, 100 mg, 0.266 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), triethylamine (115 μL, 1.064 mmol), and 2-aminoimidazole sulfate (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 15 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(1H-imidazol-2-yl)-propionamide (69 mg, 53%) as a white solid: mp >210° C. (dec); EI-HRMS m/e calcd for C18H22BrN3O3S (M+) 439.0565, found 439.0566.
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:15][N:16](C=O)C>Cl.O.C(OCC)(=O)C>[C:15]([C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[N:4][CH:5]=[N:6][CH:7]=1)#[N:16]
Reactant: Cc1ccc(-c2ncncc2Br)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2ncncc2C#N)cc1
Temperature: 50 °C

Procedure:
A mixture of 5-bromo-4-(p-tolyl)pyrimidine (10 g, 40.2 mmol) and cuprous cyanide (4.4 g, 44.2 mmol) in DMF (20 ml) was heated under reflux for 3 hours. To the reaction mixture was added a solution of ferric chloride. 6 hydrate (13 g, 48.2 mmol) in a mixture of hydrochloric acid (7 ml) and water (55 ml) and the mixture was heated at 50° C. for 10 minutes. After the reaction solution was taken up in ethyl acetate and water, the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a crystalline product. Recrystallization from isopropyl ether-hexane afforded colorless needles (5 g, 64%), m.p. 127°-128° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([CH2:41][CH3:42])[C:36]=1[Cl:43]>>[Cl:43][C:36]1[C:37]([CH2:41][CH3:42])=[N:38][CH:39]=[CH:40][C:35]=1[NH:34][C:17](=[O:19])[CH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=2)=[CH:15][CH:14]=1
Reactant: CCc1nccc(N)c1Cl
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Temperature: 25 °C
Yield: 59.9 %

Procedure:
3.6 g (12.1 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 20 ml of 4dioxane, and the solution was stirred at room temperature. Then, 2.4 g (14.8 mmol) of 1,1'-carbonyldiimidazole was gradually added thereto, and the mixture was stirred for one hour at room temperature. Then, 1.8 g (11.5 mmol) of 4-amino-3-chloro-2-ethylpyridine was added thereto, and the mixture was refluxed under heating for 30 minutes. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 3.0 g of the desired product as colorless cotton-like crystals (melting point: 124.5° to 125° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:43][N:44]([CH3:59])[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[C:50]2[S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:55]([C:50]1[C:51]2[C:46](=[C:45]([N:44]([CH3:59])[CH3:43])[CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1)(=[O:57])=[O:56])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a stirring solution of (S)-2(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (100 mg, 0.2 mmol) prepared above dissolved in DCM containing pyridine (31.6 mg, 0.4 mmol), was added 5-Dimethylamino-naphthalene-1-sulfonyl chloride (59.1 mg, 0.0.22 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1M HCl and brine evaporation followed by column chromatography purification (silica, CH2Cl2) giving (2S)-[5-chloro-2-(5-dimethylamino-naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (100 mg) as a light yellow solid which was hydrolyzed according to Procedure C yielding the title compound (93 mg) as a light yellow solid. LC/MS (m/z): 720 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])[N:8]2S(C2C=CC=CN=2)(=O)=O)=[CH:4][CH:3]=1>CO.CCOC(C)=O>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C=Cc1cc2ccc(C)cc2n1S(=O)(=O)c1ccccn1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cc2ccc(C)cc2[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A suspension of 45 (1.86 g, 5.22 mmol) and Mg (2.54 g, 104.4 mmol) in MeOH (40 mL) was stirred at 0° C. for 2 h. The mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with a sat. NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 10% EtOAc-hexanes to provide 0.69 g (60%) of product 46 as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 2.74 (t, J=7 Hz, 2H), 3.06 (t, J=7 Hz, 2H), 3.71 (s, 3H), 6.17 (m, 1H), 6.90 (d, J=8 Hz, 1H), 7.10 (s, 1H), 7.40 (d, J=8 Hz, 1H), 8.36 (brs, 1H). LC-MS (CI): m/z 218.1 [(M+H)+ C13H15NO2 requires 217.11].
Reaction SMILES: [F:1][C@:2]1([CH3:20])[C:6]([OH:8])([CH3:7])[C@@H:5]([CH2:9][OH:10])[O:4][CH:3]1[N:11]1[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]1=[O:19].C(=NC1CCCCC1)=NC1CCCCC1.[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].O>O1CCCC1>[C:36]([O:40][C:41]([NH:43][C@@H:44]([CH3:48])[C:45]([O:10][CH2:9][C@@H:5]1[C:6]([OH:8])([CH3:7])[C@:2]([F:1])([CH3:20])[CH:3]([N:11]2[CH:16]=[C:15]([CH3:17])[C:14](=[O:18])[NH:13][C:12]2=[O:19])[O:4]1)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1cn(C2O[C@H](CO)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cn(C2O[C@H](COC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)(O)[C@@]2(C)F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a stirred solution of 1-((3R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3,4-dimethyltetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (about 0.05 g, 0.17 mmol) in tetrahydrofuran (about 5 ml) was added N,N-dimethyl amino pyridine (about 0.06 g, 0.52 mmol), N,N′-methanediylidenedicyclohexanamine (about 0.071 g, 0.34 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (about 0.09 g, 0.52 mmol) at about 0° C. and stirred at room temperature for about 1 hour. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 1.5% methanol in dichloromethane as eluent furnished title compound (0.03 g) as a colorless solid. Yield: 46.8%; 1H NMR (300 MHz, CDCl3): δ 8.08 (bs, 1H), 7.23-7.22 (m, 1H), 6.37 (d, 1H, J=23.4 Hz), 4.95 (bs, 1H), 4.45-4.25 (m, 3H), 3.40-3.34 (m, 1H), 1.95 (s, 3H), 1.45 (d, 3H, J=22.8 Hz), 1.44 (s, 9H), 1.41 (m, 3H), 1.27 (s, 3H), ES Mass: [M+Na] 482 (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:4][C:3]1=[O:17].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:26][C:4]1[C:3](=[O:17])[C:2]([CH3:18])([CH3:1])[O:6][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([O:15][CH3:16])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C2=CC(=O)C(C)(C)O2)cc1C#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1C#N
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a stirred solution of 5-(5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.9 g, 3.70 mmol) in CHCl3 (10 mL), NBS (1.1 g, 6.29 mmol) was added portionwise at RT. The reaction mixture was then stirred for 1 h and diluted with DCM (50 mL). the combined organic layers were washed with water (20 mL) and brine (15 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.5 g, 42%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[SH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][S:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:10])=[O:9]
Reactant: COC(=O)CS
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 10 h
Yield: 67 %

Procedure:
To a solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (450 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (150 mg) and methyl mercaptoacetate (130 μL), and the mixture was stirred at 50° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (348 mg, yield 67%) as pale-yellow crystals. melting point 126° C.