Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32]>>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:22]([C:11]1[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:8]2[C:4]([CH:1]([CH3:2])[CH3:3])=[N:5][CH:6]=[N:7]2)[CH:10]=1)=[O:24])[CH3:32]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3ncnc3C(C)C)c2)cc1
Reactant: CC(N)c1cnccn1
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(-n3ncnc3C(C)C)c2)cc1

Procedure:
5-(5-Isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid was subject to the amide coupling reaction described in step 4 of Example 6, but replacing 2-amino-propan-1-ol with 1-pyrazin-2-yl-ethylamine, to give 5-(5-isopropyl-[1,2,4]triazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide, MS (M+H)=427.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[C:23][Si](C)(C)C)[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:22]#[CH:23])[CH:11]=[C:12]2[C:17]=1[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]2([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(=O)OC(C)(C)C)c2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A solution of 2,2,4,4-tetramethyl-6-trimethylsilanylethynylchroman-8-carboxylic acid tert-butyl ester (Intermediate 51, 0.064 g, 0.17 mmol) in methanol (5 mL) was treated with potassium carbonate (0.23 g, 1.7 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown oil (0.051 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C.O>C1COCC1>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 5-bromo-2-methoxy-pyridine (1.453 g, 7.73 mmol) in THF (50 mL) at −78° C. under N2 was added n-BuLi (3.4 mL, 2.5 M in hexanes, 8.5 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes, then 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.4 mL, 11.60 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour, then poured into water and extracted with EtOAc. The combined extracts were washed with water and brine, dried (MgSO4), filtered and concentrated to give 2A (1.221 g, 67.5%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]([OH:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.[C:33](OC=C)(=[O:35])[CH3:34]>>[C:33]([O:11][C@@H:9]([C@H:8]([C:6]1[CH:5]=[CH:4][C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:2]([F:1])[CH:7]=1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:10])(=[O:35])[CH3:34]
Reactant: CC(O)C(CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1
Reactant: C=COC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)[C@@H](CCc1ccccc1)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
10.4 g of (2RS,3SR)-3-(2-fluoro-4-biphenylyl)-5-phenylpentan-2-ol was dissolved in 100 ml of vinyl acetate, and 4.3 ml of triethylamine was added. Then, 518 mg of immobilized lipase (Toyothium LIP) was added, followed by stirring at room temperature for 5 days. The enzyme was filtered off and washed with ethyl acetate. The filtrate and the washing liquid were put together, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1) to obtain 5.47 g of (2R,3S)-2-acetoxy-3-(2-fluoro-4-biphenylyl)-5-phenylpentane and 4.79 g of the above identified compound, respectively, as colorless oily substances. The absolute configuration of the above identified compound was determined by Mosher method (J. Am. Chem. Soc., vol. 113, p. 4092 (1991)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NC1CC1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1
Yield: 27.9 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylamine (0.27 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclopropylbenzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 276. HPLC purity 100.0% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:36])[CH2:12][C:13]1[CH:22]=[C:21]([C:23](=[O:34])[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:35])[CH:19]=2)[CH:14]=1.CI>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:36])[CH:12]([C:13]1[CH:22]=[C:21]([C:23](=[O:34])[C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([F:35])[CH:19]=2)[CH:14]=1)[CH3:1]
Reactant: COC(=O)Cc1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1cc(C(=O)c2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To in situ generated lithium diisopropylamide (LDA) (0.33 mmol) [from diisopropylamine (0.33 mmol) and n-butyllithium (0.36 mmol)] in tetrahydrofuran (1.5 mL) at −78° C. under nitrogen was added a solution of [6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-acetic acid methyl ester (0.120 g, 0.30 mmol, prepared in an analogous manner to the precursor of example 2-1 according to Scheme 2) in tetrahydrofuran (1.0 mL) drop-wise. The reaction mixture was stirred for 30 minutes at −78° C. Methyl iodide (0.051 g, 0.36 mmol) in hexamethylphosphoramide (HMPA) (2.4 mL) was then added drop-wise. The resulting mixture was stirred at −78° C. for 20 minutes, then warmed to −30° C. and stirred for an additional 2 hours. The reaction was quenched with an aqueous solution of saturated ammonium chloride (2 mL), and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Flash chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in hexane) gave 2-[6-fluoro-4-(4-methanesulfonyl-benzoyl)-naphthalen-2-yl]-propionic acid methyl ester (0.070 g, 56.4%) as an off-white solid. MS cald. for C22H19FO5S [(M+H)+] 415, obsd. 415.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][CH2:14][C@H:15]3[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Br-].[C:32]([Zn+])([CH3:35])([CH3:34])[CH3:33]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:32]([C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:30]=[CH:29][C:12]([CH2:13][CH2:14][C@H:15]3[CH2:19][O:18][C:17]([CH3:21])([CH3:20])[N:16]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:11][CH:10]=2)=[N:6][CH:7]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(Br)cn3)cc2)COC1(C)C
Reactant: CC(C)(C)[Zn+]
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(Nc3ncc(C(C)(C)C)cn3)cc2)COC1(C)C
Temperature: 22 °C
Reaction time: 1 h
Yield: 9 %

Procedure:
To (S)-tert-butyl 4-(4-(5-bromopyrimidin-2-ylamino)phenethyl)-2,2-dimethyloxazolidine-3-carboxylate (100 mg) and bis(tri-t-butylphosphine)palladium(0) (21.4 mg) in THF (10 ml) under argon was added tert-butylzinc(II) bromide (1.26 ml, 0.5 M solution in THF). The reaction mixture was stirred at 22° C. for 1 hour. The reaction was quenched by addition of EtOAc then washed sequentially with saturated aqueous ammonium chloride solution and 1 N aqueous sodium bicarbonate solution. The phases were separated and the organic phase was dried over MgSO4, filtered and then concentrated in vacuo. The crude material was purified by preparative HPLC (Column: Zorbax 5 micron C18 50×20, flow rate: 30 ml/min; eluant gradient: water (+0.1% formic acid)/acetonitrile (80%-20% to 5%-95%)) to afford (S)-tert-butyl 4-(4-(5-tert-butylpyrimidin-2-ylamino)phenethyl)-2,2-dimethyloxazolidine-3-carboxylate (8.4 mg, 9%) as a yellow oil. MS (ISP): 455.5 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][C:31]=5[CH3:40])[CH:25]=[N:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:17]=3)[C@H:10]2[CH3:46])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[Li+]>O1CCOCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[C:21]([C:22]4[CH:23]=[C:24]([C:30]5[CH:39]=[CH:38][C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]=5[CH3:40])[CH:25]=[N:26][C:27]=4[O:28][CH3:29])=[CH:20][N:19]=[C:18]([N:41]4[CH2:42][CH:43]([F:45])[CH2:44]4)[N:17]=3)[C@H:10]2[CH3:46])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(F)cc(F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl 4-{5-[4-{[(4S,5R)-5-(3,5-difluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 65 mg, 0.103 mmol) was dissolved in 1,4-dioxane (2 mL). Added 0.5N lithium hydroxide (1.0 mL, 0.50 mmol) and stirred at room temperature for 2.5 hours at which time LCMS shows complete hydrolysis. The reaction was quenched by adding 0.50 mL of 1N HCl, followed by water. The reaction was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The crude isolate was purified on a BIOTAGE SNAP C18 column, eluting with 40-100% CH3CN/water (0.05% TFA). The purified fractions were partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous was extracted a second time with ethyl acetate, then washed with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the title compound. LCMS (M+H)+: 620.2. 1H NMR (CDCl3, 500 MHz): δ 8.21 (br, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.97 (d, 1H), 7.47 (s, 1H), 7.33 (d, 1H), 6.81 (m, 3H), 5.50 (d, 1.5H), 5.40 (m, 0.5H), 4.69 (d, 1H), 4.47 (m, 2H), 4.33 (m, 3H), 4.00 (d, s, 4H), 2.38 (s, 3H), 0.76 (d, 3H). RTA IC50: 35 nM
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19]N(C=O)C.C([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:19])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(thioxo)pyrazolo[3,4-d]pyrimidin-4-one (5.2 g, 19.6 mmol), DMF (50 mL) and K2CO3 (2.76 g, 20 mmol) was stirred at ambient temperature for 25 minutes and then dimethyl sulfate (3.88 mL, 40 mmol) was added. The reaction mixture was stirred for 2 hours, then was poured into cold water. The product was collected by filtration, washed with water, recrystallized from cyclohexane/ether and dried at 70°-75° C. in vacuo to afford 4.6 g of 1-cyclopentyl-3-ethyl-6-(methylthio)pyrazolo[3,4-d]pyrimidin-4-one, m.p.200°-202° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([CH3:32])([CH3:31])[C:20]([N:22]2[CH2:29][CH2:28][C:25]3([CH2:27][CH2:26]3)[C@H:24]([OH:30])[CH2:23]2)=[O:21])[C:13](=[O:33])[C@@H:12]1[CH3:34])=O)C1C=CC=CC=1.Cl>>[OH:30][C@@H:24]1[CH2:23][N:22]([C:20](=[O:21])[C:19]([CH3:32])([CH3:31])[CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][NH:11][C@@H:12]([CH3:34])[C:13]2=[O:33])[CH2:29][CH2:28][C:25]21[CH2:27][CH2:26]2
Reactant: C[C@H]1C(=O)N(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)OCc1ccccc1
Agent: Cl
Product: C[C@@H]1NCCN(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Yield: 99 %

Procedure:
In analogy to intermediate 12E, (S)-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3,3-dimethyl-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was hydrogenated without aqueous HCl to give the titled compound in 99% yield as light yellow oil. MS: 338.24 (MH+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15](OC)[C:14]([Br:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC(CSC2C=CC=CC=2)=C(C=1)C(OC)=O>>[C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Br:24])=[CH:15][C:16]=2[C:17]([O:19][CH3:20])=[O:18])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: COC(=O)c1cc(Br)ccc1CSc1ccccc1
Product: COC(=O)c1cc(Br)ccc1CS(=O)(=O)c1ccccc1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 61, starting from methyl 5-bromo-2-(phenylthiomethyl)benzoate (Intermediate 78).
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=O.S(Cl)(Cl)=O.[NH2:21][C:22]1[C:23](=[O:32])[N:24]([CH3:31])[C:25](=[O:30])[N:26]([CH3:29])[C:27]=1[NH2:28].Cl>N1C=CC=CC=1.[OH-].[Na+].O1CCOCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[CH:9][C:3]=1/[CH:4]=[CH:5]/[C:6]1[NH:21][C:22]2[C:23](=[O:32])[N:24]([CH3:31])[C:25](=[O:30])[N:26]([CH3:29])[C:27]=2[N:28]=1
Reactant: COc1ccc(C=CC(=O)O)c(Cl)c1OC
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(C)c(=O)n3C)c(Cl)c1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 28 %

Procedure:
2-Chloro-3,4-dimethoxycinnamic acid (3.93 g, 16.2 mmol) was dissolved in 57 ml of pyridine. To the solution was added 1.26 ml (17.6 mmol) of thionyl chloride under ice cooling, and the mixture was stirred at 60° C. for 1.5 hours. Methylene chloride (58 ml) containing 2.50 g (14.7 mmol) of 5,6-diamino-1,3-dimethyluracil was added dropwise to the solution under ice cooling, and the reaction solution was stirred at room temperature for further 40 minutes. The deposited crystals were collected by filtration and the obtained crude crystals were dissolved in a mixture of 68 ml of an aqueous 2N sodium hydroxide solution, 68 ml of dioxane, and 34 ml of water, followed by heating under reflux for 30 minutes. After cooling, the solution was neutralized with a concentrated aqueous solution of hydrochloric acid, and the deposited crystals were collected by filtration. The collected crystals were washed with water, dried, and recrystallized from dimethylformamide/water to give 1.55 g (yield 30%) of Compound 107 as pale yellow needles.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1)[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH2:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH3:2].I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:29])[C@H:5]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1)[NH:6][S:7]([C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([CH:31]([CH3:33])[CH3:32])[CH2:17]2)=[CH:12][CH:11]=1)(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CNCC2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@H](Cc1cccc(C#N)c1)NS(=O)(=O)c1ccc2c(c1)CN(C(C)C)CC2
Reaction time: 1 h
Yield: 74.8 %

Procedure:
A stirred mixture of N-(1,2,3,4-tetrahydroisoquinoline-7-sulphonyl)-3-cyano-(S)-phenylalanine ethyl ester (Preparation 23; 1.3 g, 3.14 mmol), 2-iodopropane (641 mg, 377 μl, 3.77 mmol), potassium carbonate (650 mg, 4.7 mmol) and acetonitrile (50 ml) was heated under reflux for 9 hours, more 2-iodopropane (35 μl) added and heating under reflux continued for 1 hour. The solvent was evaporated under reduced pressure and the residue purified by chromatography on silica gel, using a 0-5% methanol in dichloromethane elution gradient, followed by trituration with diisopropyl ether, to afford the title compound (1.07 g) as a white solid, m.p. 110° C. Rf 0.49 (SS 6). Found: C,63.19; H,6.34; N,8.89. C24H29N3 O4S requires C,63.27; H,6.41; N,9.22%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br.O>CN(C=O)C>[F:1][C:2]1[C:3]2[O:9][CH2:18][CH2:17][O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(F)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 3-fluoro-1,2-benzenediol (5.278 g, 41.2 mmol) in DMF (50 ml) was treated with potassium carbonate (17.08 g, 124 mmol) and 1,2-dibromoethane (3.91 ml, 45.3 mmol) and stirred at rt for 72 h. The reaction was treated with water (200 ml) and extracted 3×200 ml (EtOAc). The combined organic extracts were washed with water (200 ml), brine (200 ml), dried (MgSO4), evaporated and chromatographed (0-20% EtOAc-Cyclohexane) to give product as a clear oil. (2.437 g, 38%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18]C)[C:13]=1[O:20][CH3:21])([OH:11])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[I-].[K+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([OH:11])([C:12]1[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=1[O:20][CH3:21])[CH2:9][CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1OC
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCC(O)(CC(=O)OC(C)(C)C)c1cc[nH]c(=O)c1OC
Temperature: 60 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
The mixture of 3-(2,3-dimethoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid tert-butyl ester (6) (3.6 g; 11.56 mmol) and potassium iodide (8 g) in acetic acid (10 mL) was stirred at 60° C. for 16 hours. Reaction was checked by TLC and was not completed. The mixture was then heated at 73° C. for 2 days. The acetic acid was removed by evaporation under reduced pressure and dichloromethane (50 mL) was added. The solution was then washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatograph over silica gel (10 to 50% ethyl acetate/hexanes) provided 1.9 g of the ester, 3-hydroxy-3-(3-methoxy-2-oxo-1,2-dihydro-pyridin-4-yl)-pentanoic acid tert-butyl ester (7), as a white solid.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].Cl.[C:18]1([CH:24]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:25]([NH2:48])[CH:26]=[CH:27][S:28]([CH:31]=[CH:32][C@@H:33]([NH2:47])[CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:30])=[O:29])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:49]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:25]([NH:48][C:4](=[O:5])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:26]=[CH:27][S:28]([CH:31]=[CH:32][C@@H:33]([NH:47][C:4](=[O:5])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:30])=[O:29])[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H](C=CS(=O)(=O)C=C[C@@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Agent: Cl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C=CS(=O)(=O)C=C[C@@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Cbz-Ala-Phe-VS-Ph was prepared from Cbz-Ala-OH and Phe-VS-Ph.HCl using standard mixed anhydride coupling method, yield 88%. 1H-NMR (CDCl3) δ 1.25 (d, 3H, Ala-CH3), 2.91 (dq, 2H, CH2-Phe), 4.10 (m, 1H, α-H), 4.80-4.90 (m, 1H, α-H), 5.10 (s, 2H, Cbz), 6.34 (b, 1H, NH), 6.39 (d, 1H, CH═), 6.90-6.98 (dd, 1H, CH═), 7.10-7.39 (m, 10H, 2×Ph), 7.55 (t, 2H, SO2-Ph), 7.65 (t, 1H, SO2-Ph), 7.91 (d, 2H, SO2-Ph). 13C NMR (400 MHz, CDCl3) δ 172.1, 156.3, 144.4, 140.8, 135.7, 134.2, 133.6, 131.2, 129.5, 129.4×3, 129.3, 128.8×2, 128.7, 128.6, 128.4, 128.3, 127.8, 127.3, 126.9, 67.6, 51.7, 51.6, 40.2, 19.4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14].OS(O)(=O)=O.[CH3:25][CH2:26]O>>[CH2:25]([O:14][C:13](=[O:15])[CH:12]([C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:26]
Reactant: CCO
Reactant: CC(C)CC(C(=O)O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(CC(C)C)c1cc(F)c([N+](=O)[O-])cc1F

Procedure:
2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid (29.0 g, 0.11 mol) was dissolved in EtOH (200 mL) and H2SO4 (96%) 10 mL added. The reaction mixture was refluxed for 3 h and the solvent evaporated to an oil which was dissolved in EtOAc. Water (150 mL) added and the reaction mixture was extracted with EtOAc (3×100 mL). Organic phases washed with saturated NaHCO3 (50 mL), water (100 mL) and brine (100 mL) then dried under MgSO4. The evaporation of solvent under reduced pressure gave 2-(2,5-difluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester as yellow oil 32.0 g, (97%), which was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 7.81 (dd, J=8.8, 6.2 Hz, 1H), 7.41 (dd, J=11.1, 5.6 Hz, 1H), 4.23-4.05 (m, 3H), 2.04-1.94 (m, 1H), 1.71-1.62 (m, 1H), 1.51-1.42 (m, 1H), 1.25 (t, J=7.1 Hz, 3H), 0.95-0.92 (m, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 171.6, 155.0 (d, 1JCF=246.0 Hz), 151.5 (d, 1JCF=261.3 Hz), 145.5, 135.7, 118.8 (dd, 2JCF=24.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=20.0 Hz), 61.6, 41.8, 26.1, 22.5, 22.0, 14.1.