Azzindani/Open_Reaction_Data huggingface dataset:
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]([C:32]#[C:33][CH2:34][OH:35])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]>CCOC(C)=O.O=[Pt]=O>[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]([CH2:32][CH2:33][CH2:34][OH:35])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1C#CCO
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxyprop-1-ynyl)thiazole-4-carboxylate (8D) (1.2 g, 2.31 mmol) in EtOAc (20 mL) was added PtO2 (120 mg, 0.53 mmol). The mixture was stirred at rt under a hydrogen balloon overnight. After this time the mixture was filtered and the filtrate was concentrated to provide the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-hydroxypropyl)thiazole-4-carboxylate (8E): LC/MS (APCI): m/z 509.2 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([CH3:29])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])[C:4]([CH3:29])=[CH:3][C:2]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C
Yield: 56.5 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (307 mg, 0.642 mmol), (3-fluorophenyl)boronic acid (117 mg, 0.834 mmol), potassium carbonate (266 mg, 1.926 mmol), and Pd(PPh3)4 (37.1 mg, 0.032 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (2407 μl) and water (802 μl) were added. The vial was sealed and heated to 90° C. for 19 h. The reaction was cooled down to rt. The whole was extracted with EtOAc (3×25-mL). The organic layer was separated, combined, dried over MgSO4, filtered, and concentrated to afford colorless residue. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 70% EtOAc in heptane, to provide 1-(2,3′-difluoro-5-methyl-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (179 mg, 56.5% yield) as off-white solid. m/z (ESI) [M+H]+=493.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.91 (s, 3 H) 6.44 (d, J=1.87 Hz, 1 H) 6.80 (d, J=9.02 Hz, 1 H) 6.85 (d, J=9.64 Hz, 1 H) 7.26-7.37 (m, 1 H) 7.44-7.54 (m, 3 H) 7.54-7.64 (m, 1 H) 7.75 (d, J=8.40 Hz, 1 H) 7.88 (dd, J=8.97, 2.23 Hz, 1 H) 8.28 (d, J=9.64 Hz, 1 H) 8.41 (d, J=2.18 Hz, 1 H) 8.71 (d, J=1.76 Hz, 1 H) 11.68 (s, 1 H).
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH:7]=[C:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)C(=O)C(=CC1CCCCC1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)C(O)C(=CC1CCCCC1)n1cncn1
Yield: 55.1 %

Procedure:
26 g (0.1 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (Example 1) were taken up in 200 ml of methanol, and 4.5 g of sodium borohydride were added in portions, whilst stirring and cooling. When the reaction had ended, the reaction mixture was adjusted to pH 6 and concentrated. The residue was taken up in 200 ml of methylene chloride, the methylene chloride mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulphate and filtered and the filtrate was concentrated. The residue was recrystallised from petroleum ether. 14.5 g (55% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-ol of melting point 131° C. were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:2].[OH-].[Na+].O.C(O)(=O)C>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([N:15]2[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])#[N:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCCC(C)C)c(C#N)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCOc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 80 °C
Yield: 66.3 %

Procedure:
To a solution (15 ml) of ethyl 1-(3-cyano-4-(3-methylbutoxy)phenyl)pyrazole-4-carboxylate (1.6 g) in ethanol was added 1.5 N aqueous sodium hydroxide solution (4 ml) with stirring, and the mixture was heated at 80° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into water and neutralized with acetic acid. The precipitated crystals were recrystallized from ethyl acetate to give 0.97 g of 1-(3-cyano-4-(3-methylbutoxy)phenyl)pyrazole-4-carboxylic acid, melting point 210-211° C.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5]([N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH2:8]1)=[O:6].C([NH:20][C:21]([NH2:23])=[NH:22])(OC(C)(C)C)=O.[ClH:24]>CN(C=O)C.CO.CC#N>[ClH:24].[CH3:3][O:4][C:5]([N:7]1[CH2:8][CH:9]=[CH:10][C@H:11]2[NH:22][C:21]([NH2:23])=[N:20][C@@H:12]12)=[O:6]
Reactant: COC(=O)N1C=CC=CC1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Agent: BrBr
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)N1CC=C[C@H]2NC(N)=N[C@H]21
Yield: 71 %

Procedure:
A solution of Br2 (0.73 ml, 14.3 mmol, 1 equiv.) in DMF (5 ml) is added over 15 min to a solution of N-methoxycarbonyl-1,2-dihydropyridine 1 (2 g, 14.3 mmol, 1 equiv.) and of Boc-guanidine (9.15 g, 57.5 mmol, 4 equiv.) in a mixture of DMF (10 ml) and of CH3CN (5 ml) under cold conditions (0-5° C.) and under argon. The reaction being complete from the end of the addition of bromine, the reaction mixture is poured onto ice-cold water (600 ml). The aqueous phase is subsequently extracted with DCM (3×200 ml). The crude product obtained (3.5 g) is dissolved in the minimum amount of methanol, followed by addition of a 2N hydrochloric acid solution (10 ml). The solution is brought to reflux in [illegible] for 5 min. After cooling, the reaction mixture is washed with ether and then evaporated to dryness to give 2.4 g of the deprotected compound 4 with a yield of 71% over the two stages.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].[CH3:25][S-:26].[Na+]>CN(C)C=O>[CH3:25][S:26][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: C[S-]
Reactant: O=C(O)C(CC1CCCCO1)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.20 g, 16.24 mmol) in dry N,N-dimethylformamide (90 mL) at 25° C. under argon was carefully treated with 95% sodium hydride (410 mg, 17.05 mmol). The reaction mixture was stirred at 25° C. for 30 min and then was treated with sodium thiomethoxide (2.40 g, 32.48 mmol). This mixture was heated at 100° C. for 4.5 h and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with water (100 mL) and then was acidified to pH=2 using a 1N aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×600 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 chloroform/methanol to 9/1 chloroform/methanol) afforded 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.70 g, 100%) as a yellow gum: EI-HRMS m/e calcd for C16H19F3O3S (M+Na)+ 371.0899. found 371.0902.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Br:10]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:10])=[C:4]([CH3:9])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)nc(N)c1
Solvent: CC#N
Product: Cc1cc(N)nc(C)c1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution containing 2.00 g (16.32 mmol) of 2-amino-4,6-dimethylpyridine in 25 mL of acetonitrile were added 2.90 g (16.32 mmol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature under argon atmosphere for 5 h. The formed precipitate was filtered and dried to afford the expected product as a white solid: yield 2.76 g (84%). 1H-NMR (CDCl3) δ 6.22 (s, 1H), 4.39 (br, 2H), 2.48 (s, 3H), 2.25 (s, 3H); 13C-NMR (CDCl3) δ156.34, 155.23, 148.64, 112.26, 108.10, 25.10, 23.30.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]=[S:10]([C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)([CH2:12][CH2:13][CH2:14][CH2:15][O:16]CC2C=CC=CC=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([CH2:7][CH2:8][N:9]=[S:10]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(CCCCOCc2ccccc2)=NCCN2CCOCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(CCCCO)=NCCN2CCOCC2)cc1

Procedure:
A solution of N-[2-(4-morpholinyl)ethyl]-S-(4-nitrophenyl)-S-[4-(phenylmethoxy)butyl]sulfoximine in ethanol is treated under nitrogen with 5% palladium on carbon catalyst and the mixture is subjected to catalytic hydrogenation on a Parr apparatus at 70° C. When hydrogen uptake ceases, the catalyst is removed by filtration and the filtrate concentrated to obtain the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([CH3:16])=[CH:13][CH:14]=3)[O:9][C:8](=[O:17])[CH:7]=2)=[CH:2]1.C1C(=O)N([Br:25])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:16][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)=[CH:7][C:8](=[O:17])[O:9]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1cc(-c2ccoc2)c2ccc(CBr)cc2o1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 4-(furan-3-yl)-7-methylcoumarin (1.2 g, 5.3 mmol) in CCl4 (40 mL) was added NBS(1 g, 5.8 mmol) followed by AIBN (87 mg, 0.53 mmol). The resulting mixture was refluxed for 4 h, then cooled to r.t. filtered and evaporated. Purification by chromatrography on silica gel gave 682 mg (42%) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:29].[OH-].[Na+]>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:16][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)=[O:29]
Reactant: O=C(c1ccc(O)cc1)c1ccccc1Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3Cl)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (2-Chloro-phenyl)-(4-hydroxy-phenyl)-methanone from Step B under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25ClO6 [M+NH4]+: 491, [M+H]+: 469.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:18]=[C:17]4[C:19]5([CH2:25][CH2:26][CH2:27][CH2:28][N:16]4[N:15]=3)SCCCS5)=[CH:9][C:8]=2[O:29][CH3:30])[CH:6]=1.C(=O)([O-])[O-:32].[Ca+2]>C(#N)C.O.CCOC(C)=O.[Hg](Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:18]=[C:17]4[C:19](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:29][CH3:30])[CH:6]=1
Reactant: COc1cc(Nc2nc3n(n2)CCCCC32SCCCS2)ccc1-n1cnc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: Cl[Hg]Cl
Agent: [Ca+2]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3=O)ccc1-n1cnc(Cl)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 43.4 %

Procedure:
To a suspension of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-5,6,7,8-tetrahydrospiro[[1,2,4]triazolo[1,5-a]azepine-9,2′-[1,3]dithian]-2-amine (80 mg, 0.173 mmol) in acetonitrile (1.5 mL) and water (0.4 mL) was added calcium carbonate (51.9 mg, 0.518 mmol) and mercury(II) chloride (141 mg, 0.518 mmol). The mixture was stirred at 80° C. for 5 h and at 100° C. for 6 h. The crude reaction was diluted with EtOAc (150 mL) and washed with aqueous solution of ammonium acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7,8-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-9(6H)-one (28 mg, 0.075 mmol, 44% yield). LC-MS (M+H)+ =373.1. The crude product was used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH:23](C(OCC)=O)[C:24]([O:26]CC)=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2>Cl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CCOC(=O)C(Cc1c(-c2c(-c3ccccc3)noc2C)[nH]c2ccccc12)C(=O)OCC
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1-c1[nH]c2ccccc2c1CCC(=O)O

Procedure:
A mixture of 22.8 g (0.05 mole) of [[2-(5-methyl-3-phenyl-4-isoxazolyl)-1H-indol-3-yl]methyl]propanedioic acid, diethyl ester and 150 ml of 12N hydrochloric acid is refluxed for 65 hours. The mixture is cooled and extracted with ether. The ether is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. The solid residue is then decolorized with charcoal and recrystallized from ether hexane to give 2-(5-methyl-3-phenyl-4-isoxazolyl)-3-indole propionic acid m.p. 170° to 172° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38]>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:40][CH2:39][C:37]([OH:41])([CH3:38])[CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C=CC(C)(C)O
Product: CC(C)(O)CCc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.15 g, 0.278 mmol) and 2-Methyl-3-buten-2-ol (0.087 ml, 0.835 mmol), the title compound was obtained as a solid (86 mg, 52% yield). 1H NMR (400 MHz, DMSO-d6) ppm 10.88 (s, 1H), 8.47 (dd, J=5.31, 1.46 Hz, 1H), 7.67 (m, 1H), 7.43 (m, 2H), 7.31 (t, J=8.15 Hz, 1H), 7.23 (t, J=9.61 Hz, 2H), 6.63 (d, J=4.94 Hz, 1H), 4.29 (s, 1H), 2.87 (m, 2H), 1.78 (d, J=8.42 Hz, 2H), 1.43 (d, J=1.46 Hz, 9H), 1.13 (d, J=1.28 Hz, 6H); MS (ESI): 591 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([NH:14][CH2:15][CH3:16])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].Cl[CH:23]([CH2:29][CH2:30][C:31]([O-:33])=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[C:8]([N:14]([CH2:15][CH3:16])[C:31]([CH2:30][CH2:29][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:33])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: CCNc1nc(C)ccc1C(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC(=O)N(CC)c1nc(C)ccc1C(=O)c1cccc(Cl)c1

Procedure:
A DMF solution of 3-(3-chlorobenzoyl)-2-ethylamino-6-methylpyridine was treated with 60% sodium hydride and then reacted with monoethyl chloroglutarate under heating. Thereafter, the whole was worked up and purified in a usual manner to obtain ethyl 4-{N-[3-(3-chlorobenzoyl)-6-methylpyridin-2-yl]-N-ethylcarbamoyl}butanoate. The resulting compound was reacted with sodium methoxide in ethanol under heating, then concentrated sulfuric acid was added to the reaction mixture, followed by reaction under heating for 2 days. Thereafter, the reaction mixture was worked up and purified in a usual manner to obtain ethyl 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate. MS: 399.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1.N(C(OC(C)(C)C)=O)[C@H](C(NCC(NCC(N[C@H](C([NH:66][C@H:67]([C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70])=O)CC1C=CC=CC=1)=O)=O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1.N[C@H](C(O)=O)CC1C=CC(OCC2C=CC=CC=2)=CC=1>>[NH2:66][C@H:67]([C:72]([O:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)=[O:73])[CH2:68][CH:69]([CH3:71])[CH3:70]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
The pH of the aqueous layer obtained by the washing procedure with 5% aqueous sodium carbonate solution and saturated brine one more time was 9.6, and the content of Boc-Tyr(Bn)-OBt in the obtained organic layer was 0.2% and the content of Boc-Tyr(Bn) was 0.1%. Subsequently, the obtained organic layer was washed once with saturated brine (15 ml) and then washed by adding 5% aqueous potassium hydrogen sulfate solution (5 ml) and saturated brine (15 ml) thereto. Then, saturated brine (15 ml), water (15 ml) and chlorobenzene (8 ml) were added to the organic layer, and the resulting mixture was condensed under reduced pressure, thereby distilling off chlorobenzene until the total amount of the solution was 7.29 g. As a result, a solid was deposited. When chlorobenzene (10 ml) and water (15 ml) were added thereto, and the resulting mixture was allowed to mature at room temperature for 1 hour, a homogenous slurry was formed. Then, after the slurry was allowed to mature by stirring for 1 hour under ice-cooling, the deposited solid was filtered, and sequentially washed with chlorobenzene (2 ml) and water (2 ml), and then dried under vacuum, thereby a white solid was obtained. The purity of the target Boc-Tyr(Bn)-Gly-Gly-Phe-Leu-OBn (SEQ ID NO: 4) was 92%, and the content of Tyr(Bn) was 2.1%. Further, the crystallization yield was 93%, and the acquisition yield relative to the Leu-OBn.TsOH salt was 64%.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:10]1OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:52].[Li+]>C(#N)C>[CH2:1]([O:8][C@@H:9]1[C:13]([CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])([CH2:14][O:15][S:16]([CH3:19])(=[O:18])=[O:17])[O:12][C@@H:11]([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][CH:29]=[N:30][C:31]=3[NH:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]1[I:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](OS(=O)(=O)C(F)(F)F)[C@@H]1OCc1ccccc1
Agent: [Li+]
Solvent: CC#N
Product: CS(=O)(=O)OCC1(COS(C)(=O)=O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H](I)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 89.9 %

Procedure:
9-(3-O-Benzyl-5-O-methanesulfonyl-4-C-(methanesulfonyloxymethyl)-2-O-trifluoromethanesulfonyl-β-D-erythro-pentofuranosyl)-6-N-benzoyladenine (589 mg, 0.755 mmol) was dissolved in dry acetonitrile (15 ml), added lithiumiodide (202 mg, 2 equiv.) and heated to reflux. After 2 hrs, LCMS shows full conversion. Solvent was removed in vacuo and the residue was partitioned between DCM (50 ml) and water (50 ml). Layers were separated and the organic layer was washed with brine (50 ml), dried (Na2SO4), filtered and the solvent removed in vacuo to afford an orange foam (514 mg, 90% yield)
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])([O-])=[O:7].[K+].[Br:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:6]([O-:9])=[O:7])=[C:14]([OH:18])[CH:13]=1
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)cc1O
Temperature: 10 °C
Reaction time: 0.08 h
Yield: 18.2 %

Procedure:
To a solution of concentrated sulfuric acid (32.6 mL) in water (105 mL) was added potassium nitrate (51.5 g, 509 mmol) at 10° C. The reaction mixture was stirred for 5 min before adding 3-bromophenol (49.35 g, 285 mmol) dropwise so that the temperature of the reaction was maintained around 10° C. The reaction mixture was stirred at ambient temperature for an additional 2 h, diluted with water (350 mL) and extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (SiO2, 19:1 hexanes/ethyl acetate) to give 5-bromo-2-nitrophenol (11.3 g, 18%) as a yellow-green solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.44 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H), 7.18 (dd, J=8.7, 2.1 Hz, 1H).