Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])N.N([O-])=O.[Na+].[I-:14].[K+].CCOCC>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([I:14])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [I-]
Reactant: Cc1ccc(N)cc1Br
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(I)cc1Br
Reaction time: 0.75 h
Yield: 53 %

Procedure:
A well stirred solution of 18.6 g (0.10 mol) of 3-bromo-p-toluidine in 80 mL of 6N HCl at 0° C. was treated with a solution of 7.35 g (0.11 mol) of sodium nitrite in 15 mL of water at a rate that maintained the temperature <10° C. The mixture was stirred for 45 minutes then cautiously treated with 33.2 g (0.20 mol) of potassium iodide at 0° C. The mixture was treated with 300 mL of ether and washed (3×) with saturated aqueous sodium bisulfite. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was redissolved in 50 mL of hexane, filtered through 30 g of silica and concentrated under vacuum to afford 15.6 g (0.053 mol,53%) of the product which was determined to be 65% pure by 1H NMR. 1H NMR (200 MHz,CDCl3): 2.33 (s,3H), 6.97 (d,8 Hz,1H), 7.51 (dd;2,8 Hz,1H), 7.86 (d,2 Hz,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Reactant: NCCCO
Product: O=C(NCCCO)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Yield: 60 %

Procedure:
As described for example 346b, 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid (200 mg, 0.6 mmol) was converted, using 3-amino-1-propanol instead of ethanolamine, to the title compound (140 mg, 60%) which was obtained as a white solid. MS: m/e=385.9 [M−H]−.
Reaction SMILES: O1CCCC1.C([Mg]Br)CCCC.C1([SiH2]C2C=CC=CC=2)C=CC=CC=1.[C:26]1([CH2:32][C:33](OCC)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2].CCOCC>[CH2:33]([OH:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Ti+2]
Agent: CCCCC[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.2 %

Procedure:
To a dry Schlenk tube under argon was added 50 mg of titanocene dichloride (0.2 mmol) and 2 mL of tetrahydrofuran. The slurry was cooled to -78° C. in a dry ice/acetone bath and 200 μL of a 2M ether solution of pentylmagnesium bromide (0.4 mmol) was added. After stirring for 15 minutes, 930 μL of diphenylsilane (5.0 mmol) was added and the reaction mixture was allowed to warm to 0° C. Next 637 μL of ethyl 2-phenylethanoate (4.0 mmol) was then added and the reaction mixture was allowed to warm to room temperature. After 2 hours, an additional 200 μL of diphenylsilane was added and the reaction was stirred for 1.5 hours. The catalyst was then quenched by exposure to air until the color changed from dark brown to yellow. 5 mL of tetrahydrofuran and 15 mL of 1N NaOH in MeOH solution were then added. After stirring for 2 hours, the mixture was added to a brine/hexane mixture (150 mL each), shaken vigorously, and the layers were then separated. The aqueous layer was extracted with hexane (2×50 mL), the combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by flash chromatography (ether:hexane=3:7), which afforded 397 mg (81% yield) of phenethyl alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.C1(C)C=C[C:21]([S:24](O)(=O)=O)=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[C:21]2=[S:24])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccc(Cl)cc1NCCCNC(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Cl)cc1N1CCCN(C(C)C)C1=S
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a suspension of the diamine of Step C (6.47 g) in dioxane (100 mL) was added N,N′-thiocarbonyl-di-1,2,4-triazole (4.85 g) and the mixture was stirred at room temperature for 2 hours. Para-toluenesulfonic acid monohydrate (7.07 g) was added and the reaction mixture was heated at reflux under nitrogen until the reaction was complete by TLC (31 hours). Upon cooling the mixture was evaporated to dryness. The solid residue was redissolved in ethyl acetate, the solution was washed with water and brine, dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel packed in hexane. Elution with a gradient of 20-25% ethyl acetate in hexane provided the title compound (5.81 g, 76.4%) as a white solid which was further triturated in hexane, m.p. 176-178° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([C:16]([N:18]([CH2:20][C:21]([OH:23])=O)[CH3:19])=[O:17])=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N:52]1([C:58]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:68])[F:67])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C=O)C.O>[CH3:19][N:18]([CH2:20][C:21](=[O:23])[N:55]1[CH2:56][CH2:57][N:52]([C:58](=[O:59])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[C:66]([F:69])([F:67])[F:68])[CH2:53][CH2:54]1)[C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1)=[O:17]
Reactant: CN(CC(=O)O)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
DIPEA (216 mg, 0.3 mL, 1.6 mmol) was added to a stirred solution of [(biphenyl-4-carbonyl)-methyl-amino]-acetic acid (100 mg, 0.37 mmol) in DMF (3 mL). HOBT (55.2 mg, 0.4 mmol) and EDCI (178 mg, 0.92 mmol) were then added at room temperature. After 2 minutes piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride salt (131 mg, 0.44 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 135 mg (71.3% yield) of biphenyl-4-carboxylic acid methyl-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 96.56%. 1H NMR (DMSO-d6): δ 7.9-7.6 (m, 7H), 7.6-7.45 (q, 4H), δ 7.45-7.3 (q, 2H), 4.5-4.2 (m, 2H), 4.15 (s, 1H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.25-3.1 (m, 2H), 3.0 (s, 3H).
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7](O)=[O:8])=[O:4].C(N(CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH3:10][CH:2]1[S:1][C:7](=[O:8])[CH:6]=[N:5][C:3]1=[O:4]
Reactant: CC(S)C(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1SC(=O)C=NC1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
A solution of N-(2-mercaptopropanoyl)glycine (5 g, 0.031 mole) in methylene chloride (250 ml) was chilled in an ice bath and triethylamine (3.1 g, 0.031 mole) was added. Ethyl chloroformate (3.4 g, 0.031 mole) in methylene chloride (25 ml) was added dropwise over 15 minutes. The resulting solution was then stirred for two and a half hours at room temperature. The methylene chloride was washed with water, saturated aqueous sodium chloride, and dried over magnesium sulfate. Filtration and evaporation of the solvent afforded the crude product as a yellow oil which was chromatographed on silica-gel (CHCl3) to yield colorless crystals of 6-methyl[1,4]thiazine-2,5-dione (1.5 g, 30%) after crystallization from ether-hexane, m.p. 81°-83°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([N+:24]([O-])=O)[CH:4]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:23]=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccc(OC)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(OC)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-methoxy-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-methoxyanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]3[N:15]([C:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)=[O:17])[C:14]([O:28]C)=[N:13][C:12]([CH3:30])=[C:11]3[C:31]([O:33][CH3:34])=[O:32])[CH:8]=[CH:9][C:2]=12.[Br:35]Br>C(Cl)(Cl)Cl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]3[N:15]([C:16]([O:18][C:19]4[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=4)=[O:17])[C:14](=[O:28])[NH:13][C:12]([CH2:30][Br:35])=[C:11]3[C:31]([O:33][CH3:34])=[O:32])[CH:8]=[CH:9][C:2]=12
Reactant: BrBr
Reactant: COC(=O)C1=C(C)N=C(OC)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc2nonc2c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1=C(CBr)NC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc2nonc2c1
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
Into a well-stirred solution of 6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine (0.310 mmol, 0.140 g) in 1.5 mL of chloroform was added a solution of bromine (0.310 mmol, 0.020 mL) in 1.5 mL of chloroform at 0° C. and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3 (10 mL) and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain 0.15 g (88% yield) of 6-(benzofurazan-5-yl)-1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine as a yellow foam. The crude product was used in the next step without purification. 1H NMR (CDCl3) δ 3.79 (s, 3 H), 4.72 (ABq, 2 H), 6.47 (s, 1 H), 7.37 (d, J=9.1 Hz, 2 H), 7.51 (d, J=7.8 Hz, 1 H), 7.80 (s, 1 H), 7.92 (d, J=9.1 Hz, 1 H), 8.30 (d, J=9.1 Hz, 2 H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:26]3[C:31]([F:32])=[C:30]([O:33]C)[CH:29]=[C:28]([O:35][CH3:36])[C:27]=3[F:37])[C:7]2=[O:38])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.O.Cl>CN(C)C=O>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[N:14][CH:15]=[C:10]3[CH2:9][N:8]([C:26]3[C:27]([F:37])=[C:28]([O:35][CH3:36])[CH:29]=[C:30]([OH:33])[C:31]=3[F:32])[C:7]2=[O:38])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(OC)cc(OC)c1F)C2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCCCNc1ncc2c(n1)N(C1CCCC1)C(=O)N(c1c(F)c(O)cc(OC)c1F)C2
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
To a solution of sodium ethylthiolate [generated from sodium hydride (200 mg, 8.32 mmol) and ethanethiol (616 μL, 8.32 mmol) in dimethylformamide (20 mL)], 1-Cyclopentyl-7-(4-diethylamino-butylamino)-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one in dimethylformamide (8 mL) was added. The resulting solution was then stirred at 75° C. for 90 minutes. The solvent was removed under reduced pressure to afford a light brown oil. Dichloromethane (100 mL) and water (20 mL) were added. The bilayer thus afforded was then stirred vigorously while 4 N hydrochloric acid was added. Enough hydrochloric acid was added until the aqueous layer reached pH=5. The layers were separated; the aqueous layer was extracted with dichloromethane (2×80 mL). The organic layers were combined and set aside. Saturated aqueous sodium chloride (20 mL) was to the aqueous layers and was extracted with ethyl acetate (2×80 mL). The organic layers were combined, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. To the yellow oil (794 mg) thus afforded, hexanes were added to remove non-polar impurities. The supernatant was removed, and the remaining residue was placed in vacuo. The oil was purified via reverse phase HPLC to give the title compound (289 mg, 54%) as a clear amber gum: MS (APCI) 519.2, 520.2.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11]O)[CH3:7].CCN(CC)CC.[N-:28]=[N+:29]=[N-:30].[Na+]>C(Cl)Cl.CCOC(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:28]([CH2:11][C@@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][O:8][CH2:6][CH3:7])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Methanesulfonyl chloride (0.851 mL, 10.95 mmol) in DCM (1 mL) was added to a solution of (R)-tert-butyl 1-ethoxy-3-hydroxypropan-2-ylcarbamate (1.6 g, 7.30 mmol) and Et3N (1.538 mL, 10.95 mmol) in DCM (10 mL) at 0° C. After stirring at RT for 1 h, the mixture was diluted with EtOAc. The organic layer was washed with saturated aq NaHCO3 solution, dried, and concentrated in vacuo. The residue was dissolved in DMF (10.00 mL). Sodium azide (2.372 g, 36.5 mmol) and tetrabutylammonium iodide (0.270 g, 0.730 mmol) were added, and the reaction mixture was stirred at 75° C. for 4 h. After cooling to RT, the mixture was diluted with EtOAc. The organic layer was washed with saturated aq NaHCO3, dried, and concentrated in vacuo to give the title compound (1.2 g, 67%). [M+H] calc'd for C10H20N4O3, 245. found, 245.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1.[H-].[Na+]>C1COCC1>[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[N:12]=1
Reactant: OCc1cccc(F)n1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(COc2cncc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.9 %

Procedure:
To a solution of (6-fluoro-pyridin-2-yl)-methanol I-3d (368 mg, 2.89 mmol) and 2,6-dichloro-pyrazine (431.2 mg, 2.89 mM) in THF (14.7 mL) at room temperature was added 60% NaH in mineral oil (174 mg, 4.34 mmol). The resulting mixture was stirred at ambient temperature for 19 h and concentrated. The residue was purified by column chromatography (ethyl acetate/hexanes=1:4)) to afford 560 mg of the title compound (I-3e).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]1=O)=O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]1[C:6]2[CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[C:7]=2[NH:21][N:20]=1
Reactant: O=C(c1ccccc1Br)C1Cc2sccc2C1=O
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccccc1-c1n[nH]c2c1Cc1sccc1-2
Temperature: 25 °C
Yield: 30.5 %

Procedure:
5-(2-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (30 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 2.5 mmol) as white solid in 30% yield.
Reaction SMILES: Cl.[CH3:2][C:3]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C(OCC)=O)[C:4]([O:6]CC)=[O:5]>>[CH3:2][CH:3]([CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(Cc1ccncc1)C(=O)OCC
Agent: Cl
Product: CC(Cc1ccncc1)C(=O)O
Yield: 100.3 %

Procedure:
Next, 6 N hydrochloric acid (96.8 ml, 581 mmol) was added to diethyl 2-methyl-2-(4-pyridylmethyl)malonate (17.2 g, 64.6 mmol), and the mixture was refluxed overnight. The reaction mixture was allowed to stand, then washed with hexane (100 ml) to remove sodium hydride oil contained in diethyl 2-methyl-2-(4-pyridylmethyl)malonate, and concentrated under reduced pressure. The resulting crystals were filtered off with ethyl acetate to give 10.7 g (82%) of 2-methyl-3-(4-pyridyl)propionic acid as pale pink crystals.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7].S(OC)(O[CH3:24])(=O)=O>O>[CH3:24][O:3][C:4]1[C:11]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: Cc1ccccc1Sc1cccc(CO)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(CO)cccc1Sc1ccccc1C
Yield: 96.9 %

Procedure:
A solution of potassium hydroxide (5.8 g) in water (30 ml) was added dropwise to a mixture of 2-hydroxy-3-(o-tolylthio)benzyl alcohol (8.3 g) and dimethyl sulfate (8.5 g) in 10 minutes at temperature below 60° C. with stirring, and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was treated in a similar manner to that of Example 21-(4). The resultant oily residue was purified by column chromatography (silica gel 150 g, benzene) to give oily 2-methoxy-3-(o-tolylthio)benzyl alcohol (8.5 g).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:44])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:20]([CH3:43])[CH:21]=[C:22]([NH:24][C:25]([C:27]4[N:28]([CH3:42])[C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([NH:36][C:37](=[O:41])[C:38]([Br:40])=[CH2:39])=[CH:31][CH:30]=5)=[O:26])[CH:23]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:45]([NH:47][CH2:48][CH2:49][C:50](N)=[NH:51])=[O:46].C(=O)([O-])[O-].[K+].[K+].C1(=O)OC(=O)CC1>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH3:44])[CH:13]=[C:14]([NH:16][C:17]([C:19]3[N:20]([CH3:43])[CH:21]=[C:22]([NH:24][C:25]([C:27]4[N:28]([CH3:42])[C:29]5[C:34]([CH:35]=4)=[CH:33][C:32]([NH:36][C:37](=[O:41])[C:38]([Br:40])=[CH2:39])=[CH:31][CH:30]=5)=[O:26])[CH:23]=3)=[O:18])[CH:15]=2)=[O:10])[CH:5]=[C:4]1[C:45]([NH:47][CH2:48][CH2:49][C:50]#[N:51])=[O:46]
Reactant: C=C(Br)C(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cc(C(=O)Nc3cc(C(=O)Nc4cc(C(=O)NCCC(=N)N)n(C)c4)n(C)c3)n(C)c1)n2C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Product: C=C(Br)C(=O)Nc1ccc2c(c1)cc(C(=O)Nc1cc(C(=O)Nc3cc(C(=O)Nc4cc(C(=O)NCCC#N)n(C)c4)n(C)c3)n(C)c1)n2C
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To a solution of 150 mg of 3-[1-methyl-4[1-methyl-4[1-methyl-4[1-methyl-5(α-bromoacrylamido) indole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride, prepared as described in step I as above, in 10 ml DMF were added 25 mg of potassium carbonate and 20 mg of succinic anhydride. The mixture was heated at 60° C. for 4 hours. The solvent evaporated under vacuum and the crude residue purified by flash chromatography (methylene chloride/methanol:8/2) to yield 100 mg of the title compound as a yellow powder.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6]1[CH:7]=[C:8](/[C:12](/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)#[N:2].C([O-])(=[O:33])C.[Na+]>Cl>[C:1]([N:3]=[C:4]([NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[NH:5][C:6]1[CH:7]=[C:8](/[C:12](/[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)(=[O:33])[NH2:2]
Reactant: CC(=O)[O-]
Reactant: CC(C)CNC(=NC#N)Nc1cccc(/C(=C\CCCC(=O)O)c2cccnc2)c1
Agent: Cl
Agent: [Na+]
Product: CC(C)CNC(=NC(N)=O)Nc1cccc(/C(=C\CCCC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.34 g of 5E-6-(3-(2-cyano-3-(2-methylpropyl)guanidino)phenyl)-6-(3-pyridyl)hex-5-enoic acid are dissolved in 50 ml of 4N hydrochloric acid and stirred for 48 hours at ambient temperature. The solution is adjusted to pH 5-6 by the addition of sodium acetate and extracted with ethyl acetate. The organic extract is evaporated down and the residue is purified over a silica gel column with dichloromethane/ethanol=19:1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][C:3]=1[NH2:10].[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:11]([NH:19][C:20]([NH:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH:10][C:20](=[S:21])[NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:5]=1[CH3:9])=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(N)c(C)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=S)NC(=O)c2ccccc2)c(C)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
2,5-Dimethyl-p-phenylenediamine (0.340 g, 2.5 mM) was dissolved in 30 ml of ethyl acetate, and 2 equivalents of benzoylisothiocyanate (0.816 g, 5 mM) were added. The mixture was stirred at room temperature for 10 minutes. After cooling, the reaction mixture was filtered, and washed with ethyl acetate/n-hexane to obtain 1.14 g (98.6% yield) of a colorless crystal of compound A-26.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[C:11]([O:19]C(=O)C)[CH:10]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:23])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:19])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Oc1ccc(C(=O)N2CCN(C)CC2)cc1OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a solution of 1-methyl-4-(3,4-diacetoxybenzoyl)piperazine (295 mg) in methanol (3 ml) was added a saturated potassium carbonate solution in methanol (6 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was poured into ice water and adjusted to pH 9 with 1N hydrochloric acid. The mixture was extracted several times with a mixture of chloroform and methanol (20:1 V/V) and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized by addition of ethyl acetate to give 1-methyl-4-(3,4-dihydroxybenzoyl)piperazine (71 mg) as white crystal.