Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[S:10]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11]1.Cl>O1CCCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:15]([C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)[OH:16])=[CH:3][CH:4]=1
Reactant: O=Cc1ccsc1
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)c1ccsc1
Yield: 47.4 %

Procedure:
To a stirred Grignard complex, previously prepared from 7.80 g (0.0446 mol) 1-bromo-4-fluorobenzene and 1.10 g (0.045 mol) magnesium turnings in 50 ml tetrahydrofuran, 5.00 g (0.0446 mol) thiophene-3-carboxaldehyde, dissolved in 50 ml tetrahydrofuran, was added dropwise. Upon completion of the addition, the reaction mixture was refluxed for 1 h and then poured on a mixture of ice and 6N hydrochloric acid. Subsequent extraction with dichloromethane, washing of the organic layer with water and evaporation in vacuo, left 8.50 g of crude (4-fluorophenyl)(3-thienyl)methanol as an oil. Chromatography on silica gel (THF/n-heptane 1:2 as eluent) gave 4.4 g of the pure (4-fluorophenyl)(3-thienyl)methanol, which was directly converted to the (4-fluorophenyl) (3-thienylmethyl chloride with thionyl chloride by a known procedure.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:5]=1[OH:14].C1N2CN3CN(C2)CN1C3.Cl.[OH:26]C(C)=O.O>O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:26])=[C:5]([OH:14])[CH:6]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1ccc(CN)c(O)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 130 °C

Procedure:
To a solution of 1.5 g (6.9 mmol) of the product of Example 1 in 15 mL of HOAc-H2O (11:3) was added 1.17 g (8.3 mmol) of hexamethylenetetramine dissolved in 3 mL water. The reaction mixture was magnetically stirred and heated at 130° C. for 3 h at which point 13.5 mL of a 2:1 solution of conc. hydrochloric acid and water was added. The reaction mixture was heated for an additional 10 min at 130° C., then cooled to room temperature and the acetic acid was removed on a rotary evaporator. The residue was partitioned between EtOAc and water, then extracted and the organic layers were combined and dried (Na2SO4). The filtrate was passed through a layer of Celite filter aid mixed with silica gel to remove polar impurities, then evaporated. The residual oil was dried in vacuo and subsequently used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N:11]1([C:2]2[C:3]([CH3:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=2[CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cc1ccc(N)c(C)c1Br
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N)c(C)c1N1CCCC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of the 3-bromo-2,4-dimethylphenylamine (0.6 g, 3.0 mmol) in toluene (10 mL) and pyrrolidine (1.25 mL, 15 mmol) was added sodium-t-butoxide (0.86 g, 9 mmol, 3eq). The suspension was deoxygenated by passing a stream of N2 gas through the mixture for approximately 5–10 minutes before introducing the tris(dibenzilidene)dipalladium(0) (Pd2(dba)3) (27 mg) and rac-2,2′Bis(diphenylphosphino)-1,1′binaphthyl (BINAP) (25 mg). The nitrogen stream continued 10 minutes before heating at 100° C. overnight. The reaction mixture was cooled, acidified with HCl (2N) and extracted with diethyl ether. The aqueous layer was adjusted basic and re-extracted with ethyl acetate. The organic layer was dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, gradient elution with 6:1 to 4:1 hexanes to ethyl acetate) to give the desired 2-(pyrrolidin-1-yl)-4-amino-m-xylene.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]([C:34]1[CH:39]=[CH:38][C:37]([S:40][CH3:41])=[CH:36][CH:35]=1)([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:32])=[O:31])([CH3:29])[CH3:28])[CH:20]=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)[CH:12]=1)C#N)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[OH-].[Na+].C(OCC)(=O)C>[CH3:33][S:30]([C:27]([C:19]1[CH:20]=[C:21]2[C:26](=[C:17]([C:13]3[CH:12]=[C:11]([CH2:10][C:7]([C:34]4[CH:35]=[CH:36][C:37]([S:40][CH3:41])=[CH:38][CH:39]=4)=[O:6])[CH:16]=[CH:15][CH:14]=3)[CH:18]=1)[N:25]=[CH:24][CH:23]=[CH:22]2)([CH3:28])[CH3:29])(=[O:31])=[O:32]
Reactant: CSc1ccc(C(C#N)(Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)Cc2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)cc1
Temperature: 21 °C
Reaction time: 0.5 h

Procedure:
To a solution of crude cyanohydrin from Step 2 above in THF (25 mL) was added tetrabutylammonium fluoride (1M, THF, 6.5 mL, 6.5 mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for 30 min and diluted with a sodium hydroxide solution and ethyl acetate. The organic extracts were washed (1N NaOH 2×), (brine), dried (MgSO4), filtered and concentrated.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[O:28]CC=C)[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:32])[N:5]([CH3:33])[C:4]1=[O:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CO.[Pd]>[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[OH:28])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:32])[N:5]([CH3:33])[C:4]1=[O:34]
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3O)CC2)cc(=O)n(C)c1=O
Yield: 78.8 %

Procedure:
0.6 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 161--free form) was dissolved in 10 ml of methanol, followed by the addition of 0.1 g of 10% Pd/activated carbon, 0.1 g of p-toluenesulfonic acid monohydrate and 2 ml of water. The resultant mixture was heated for 15 hours under stirring and reflux. After allowing the reaction mixture to cool down, insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=50/1, by volume), thereby thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16]([NH:18][C:19]([O:21][CH3:22])=[O:20])=[S:17])[CH2:3][CH3:4].[OH-].[Na+].[CH3:25]I>CC(C)=O.O>[NH:1]=[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16](=[N:18][C:19]([O:21][CH3:22])=[O:20])[S:17][CH3:25])[CH2:3][CH3:4]
Reactant: CI
Reactant: CCCSc1ccc(C(=N)CC)c(NC(=S)NC(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCSc1ccc(C(=N)CC)c(NC(=NC(=O)OC)SC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a suspension of 1-iminopropyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (1 g.; 0.00295 mole) in acetone (30 ml.) and water (15 ml.) there is added 50.8% aqueous sodium hydroxide (0.23 g.; 0.00295 mole). The solution that forms is stirred at room temperature for one hour and to it there is added methyl iodide (0.42 g.; 0.00295 mole). The turbid solution formed is stirred at room temperature for 30 minutes and is poured into water (500 ml.). The suspension formed is stirred at room temperature for one hour and is vacuum filtered. The filter cake is dried to afford 1-iminopropyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (0.85 g.; 81.5%), m.p. 85°-90° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[N:3]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.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>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[N:10]([CH3:9])[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: Clc1cccc(I)n1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(-c2cccc(Cl)n2)cc2ccccc21
Yield: 100.2 %

Procedure:
2-Chloro-6-iodopyridine (400 mg, 1.67 mmol), N-methylindole-2-boronic acid (292 mg, 1.67 mmol), tetrakis(triphenylphosphine)palladium (0) (154 mg, 0.13 mmol) and Na2CO3 (442 mg, 4.18 mmol) were dissolved in water (10 mL) and dioxane (10 mL) and heated using a microwave (110° C., absorption high) for 1 h. The solvents were removed in vacuo and the residue was partitioned between DCM (50 mL) and water (30 mL). The aq fraction was extracted with DCM (30 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound (406 mg) as a brown gum. LCMS (ES+): 243.2 [MH]+.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5][CH2:6][CH2:7][C:8]([CH3:10])=[CH2:9])=[CH2:3].OP(O)(O)=O>C(O)(C)C>[CH3:10][C:8]([CH2:7][CH:6]=[CH:5][CH:4]=[C:2]([CH3:3])[CH3:1])=[CH2:9]
Reactant: C=C(C)C=CCCC(=C)C
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: C=C(C)CC=CC=C(C)C
Yield: 75.3 %

Procedure:
10 g of 2,7-dimethyl-1,3,7-octatriene are kept at reflux temperature under argon atmosphere for 24 hours together with 25 ml of isopropanol and 0.384 g of (PhCN)2PdCl2 and 0,1 g of H3PO4. After this period 75.3% of 2,7-dimethyl-1,4,6-octatriene have been formed (GC-analysis).
Reaction SMILES: [C:1]([C:3]1[C:15]([C:16](OCC)=O)=[C:14]2[C:6]([NH:7][C:8]3[C:13]2=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH2:21][CH2:22][CH2:23][C:4]=12)#[N:2].CN(C=[O:28])C>[Ni]>[CH:16]1[C:15]2[C:3]([C:4]3[C:5]([CH2:21][C:22](=[O:28])[CH:23]=3)=[C:6]3[C:14]=2[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:7]3)=[CH:1][N:2]=1
Reactant: CCOC(=O)c1c(C#N)c2c(c3[nH]c4ccccc4c13)CCC2
Reactant: CN(C)C=O
Agent: [Ni]
Product: O=C1C=c2c(c3[nH]c4c(c3c3c2=CN=C3)CCCC4)C1
Yield: 100 %

Procedure:
Ethyl 4-Cyano-1,2,3,10-tetrahydrocyclopenta[a]carbazole-5-carboxylate (14 mg) in DMF (1.6 mL) was hydrogenated at 55 psi over W2 Raney nickel (150 mg) for 2.5 days. The catalyst was removed by filtration and the DMF was evaporated in vacuo to give the product (12 mg, 100% yield) as light brown crystals. A sample was recrystallized from DMF, boiled with ethanol, cooled, and filtered to give the product as an off-white solid, mp>300° C. NMR (DMSO-d6) δ 11.45 (s, 1H), 9.06 (d, 1H), 8.47 (s, 1H), 7.51 (d, 1H), 7.40 (t, 1H), 7.16 (t, 1H), 4.41 (s, 2H), 3.21 (t, 2H), 3.04 (t, 2H), 2.30 (quintet, 2H). Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.40; H, 5.66; N, 10.49.
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:14][C:13]3[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: Fc1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 98 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-fluorobenzyl bromide to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 98% yield: 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 2H), 7.07-6.97 (m, 2H), 4.45 (s, 2H), 4.10-4.04 (m, 2H), 3.48-3.37 (m, 2H), 2.67 (s, 3H), 2.38 (s, 3H); MS (ES+) m/z 334.1 (M+1).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1)C#N.[OH-].[K+].Cl>CO.O>[SH:1][C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)c2c[nH]c(S)c2)cc(C(C)(C)C)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2-Thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (10.0 g) was dissolved in methanol (80 ml) and cooled to -10° C. Potassium hydroxide (3.2 g) in methanol (20.0 ml) and water (20.0 ml) was added at such a rate that the temperature did not exceed 0° C. After stirring for 1 hour at the same temperature, one half of the resulting solution was converted to the title compound by acidification with 20% HCl. The product was filtered, dissolved in methylene chlorede, dried and the solvent evaporated to dryness. The residue was chromatographed on silica gel (500 g) and the product eluted with hexane:ethyl acetate (1:1) to yield 1.56 g of the purified title compound, 2-mercapto-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole, after recrystalization from ethyl acetate-hexane [mp 213°-215° C.; 1H nmr: 1.46s (18H), 5.46s (OH), 6.93m (1H), 7.46m (1H), 7.76s (2H), 7.91 (NH); MS m/e 331 (M+)].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: COc1cccc(N)c1C(N)=O
Product: COc1cccc(Nc2nc(Cl)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1C(N)=O

Procedure:
Using General Protocol II with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 8.8 mmol) and 2-amino-6-(methyloxy)benzamide (3.10 g, 18.7 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-(methyloxy)benzamide was isolated as white solid (1.15 g, 28% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (s, 3 H), 3.81 (s, 3 H), 6.55 (s, 1 H), 6.94 (d, J=7.87 Hz, 1 H), 7.37-7.49 (m, 4 H), 7.63 (d, J=4.03 Hz, 3 H), 7.94 (d, J=8.24 Hz, 2 H), 10.98 (s, 1 H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[NH:3][CH:2]=1.C(N(CC)CC)C.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:21]([N:3]1[C:4]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[CH:2]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc2nc[nH]c12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 1.12 g of methyl 3H-benzimidazole-4-carboxylate in 25 ml of dichloromethane is admixed with 0.97 ml of triethylamine and a solution of 2.010 g of trityl chloride in 25 ml of dichloromethane. The reaction mixture is stirred at room temperature over 16 hours and subsequently poured onto a 100 ml of semisaturated aqueous sodium hydrogencarbonate solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow solid from the residue by flash chromatography (SiO2 60F). Rf (1:2 EtOAc-heptane)=0.25; Rt=4.31;
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]2[C:21]([N:23]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=1)[C:24]1[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH:16]2[C:21]([N:23]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=1)=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc(N(Cc2ccc(C(=O)O)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Temperature: 55 °C
Yield: 80.2 %

Procedure:
Methanol (14 mL) and 1 mol/L-aqueous sodium hydroxide solution (7 mL) were added to methyl 4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoate (2.56 g), and the mixture was stirred with heating at 50-60° C. After the completion of the reaction, the reaction mixture was neutralized with conc. hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoic acid (2 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([NH2:22])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:23]=[C:24]1[NH:28][C@@H:27]([C:29](O)=[O:30])[CH2:26][NH:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH2:1]([C:5]1[CH:6]=[C:7]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[C:13]([NH:22][C:29]([C@H:27]3[CH2:26][NH:25][C:24](=[O:23])[NH:28]3)=[O:30])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC[C@H](C(=O)O)N1
Reactant: CCCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cccc(-c2cc(NC(=O)[C@H]3CNC(=O)N3)nn2-c2ccccc2)c1
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a solution of 5-(3-butylphenyl)-1-phenyl-1H-pyrazol-3-ylamine (40 mg) in N,N-dimethylformamide (0.4 ml) were sequentially added (R)-2-oxoimidazolidine-4-carboxylic acid (21 mg) prepared by the same procedures as Preparation 20, HATU (63 mg), diisopropylethylamine (29 μL) at room temperature, and the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/acetone=1/5). To the resulting solid was added diisopropyl ether, and the mixture was stirred. A solid was collected from this suspension by filtration, and was dried under reduced pressure to give the titled compound (12 mg).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([I:32])[CH:23]=2)[C:10]=1[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[C:35]([CH2:34][CH2:33][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[C:24]([I:32])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])([OH:37])=[O:36]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(I)cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.2 %

Procedure:
To a solution of 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (0.9 g, 1.31 mmol) in hot ethanol (40 mL) was added aqueous 1.0 N sodium hydroxide (10 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 805 mg (97%) of title compound as a light yellow oil. HR-ES(+) m/e calcd for C26H33O8SI (M+H)+ 633.1014, found 633.1008.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[Br:10]C1CC(C(C)C)CCC1=O>>[Br:10][CH:4]1[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8]
Reactant: CC1(C)CCC(=O)CC1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CC1(C)CCC(=O)C(Br)C1

Procedure:
The bromination of 4,4-dimethylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:52]=[CH:51][C:16]2[NH:17][C:18]([C@@H:20]([NH:25][C:26](=[O:50])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][C@H:36]4[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34])=[C:29]([Cl:49])[CH:28]=3)[CH2:21][CH2:22][S:23][CH3:24])=[N:19][C:15]=2[CH:14]=1>ClCCl.C(O)(=O)C>[Cl:12][C:13]1[CH:52]=[CH:51][C:16]2[NH:17][C:18]([C@@H:20]([NH:25][C:26](=[O:50])[C:27]3[CH:32]=[CH:31][C:30]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][C@H:36]4[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34])=[C:29]([Cl:49])[CH:28]=3)[CH2:21][CH2:22][S:23]([CH3:24])=[O:6])=[N:19][C:15]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
0.1 g (0.4 mmol) of 3-chloroperoxybenzoic acid is added at −10° C. to a solution of 0.3 g (0.4 mmol) of N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfanylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide in 10 mL of dichloromethane and 1 mL of glacial acetic acid and stirred for 30 minutes. Then the mixture is stirred for 4 hours at ambient temperature and washed with 5% sodium carbonate solution. The combined organic phases are dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel, eluting with dichloromethane/methanol (0%-10%). Yield: 0.1 g (59%); Rf value: 0.42 (silica gel; dichloromethane/methanol=9:1); C29H35Cl2N5O5S (636.60); mass spectrum: (M+H)+=636/638/640 (chlorine isotope) and (M−H)−=634/636/638 (chlorine isotope).