Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and acetophenone, 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([O:12]C)[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2ccc(OC)cc2s1
Agent: BrB(Br)Br
Product: CCc1cc2ccc(O)cc2s1
Yield: 81.8 %

Procedure:
This material was prepared from 2-ethyl-6-methoxybenzo[b]thiophene 134a (2.30 g, 12 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give a white solid (1.75 g, 82%). 1H NMR (DMSO-d6) δ9.43 (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.16 (1H, d, J=2.2 Hz), 6.95 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.81 (2H, q, J=7.5 Hz), 1.26 (3H, t, J=7.5 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6]2([CH2:11][CH2:10][N:9]([O:12][CH3:13])[CH2:8][CH2:7]2)[C:5]([O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([C:20]2[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=2[CH3:28])[C:3]1=[O:29].C(N(CC)CC)C.Cl[C:38]([O:40][CH3:41])=[O:39]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:13][O:12][N:9]1[CH2:10][CH2:11][C:6]2([N:2]([O:1][C:38]([O:40][CH3:41])=[O:39])[C:3](=[O:29])[C:4]([C:20]3[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[C:5]2[O:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])[CH2:7][CH2:8]1
Reactant: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(O)C12CCN(OC)CC2
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(c2c(C)cc(C)cc2C)C(=O)N(OC(=O)OC)C12CCN(OC)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of carbonic acid ethyl ester 1-hydroxy-8-methoxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (preparation example 13, step 1; compound P1ii.11) (140 mg, 0.33 mmol), triethylamine (93 μl, 68 mg, 0.67 mmol) and 4-dimethylaminopyridine (2 mg) in tetrahydrofuran (3 ml) at 0° C. was added a solution of methyl chloroformate (33 μl, 41 mg, 0.43 mmol) in tetrahydrofuran (2 ml) dropwise. The suspension was stirred at 0° C. for one hour, and at room temperature for one hour. The reaction mixture was evaporated, diluted with ethyl acetate and filtered to remove salts. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2×15 ml) and brine, dried over sodium sulfate and concentrated. The oily residue was purified by chromatography on silica gel (ethyl acetate/hexane 1:2). Yield: 30 mg of carbonic acid ethyl ester 8-methoxy-1-methoxycarbonyloxy-2-oxo-3-(2,4,6-trimethyl-phenyl)-1,8-diaza-spiro[4.5]dec-3-en-4-yl ester (title compound P1ii.13) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][N:25]([C:28](=[O:38])[CH2:29][NH:30]C(=O)OC(C)(C)C)[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][CH2:29][C:28]([N:25]1[CH2:26][CH2:27][CH:23]([N:6]2[C:5]3[CH:39]=[CH:40][C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][N:10]2[C:14]3=[CH:15][N:16]=[CH:17][CH:18]=[C:13]3[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]2)[CH2:24]1)=[O:38]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCN(C(=O)CN)C2)c2cnccc12
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 2-(3-(5-chloro-2-((3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)pyrrolidin-1-yl)-2-oxoethylcarbamate(30 mg, 0.05 mmol) in 6 mL of DCM was added 3 mL of TFA. The mixture was stirred overnight. The solvent was removed in vacuum and purified by prep-HPLC to give product 2-amino-1-[3-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)pyrrolidin-1-yl]ethanone (10 mg, yield: 42%) as a pale solid.
Reaction SMILES: [Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9]O>>[Br:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH3:9])=[O:4]
Reactant: CO
Reactant: CC(C)C(Br)C(=O)O
Product: COC(=O)C(Br)C(C)C
Temperature: 25 °C

Procedure:
2-Bromo-3-methylbutyric acid (3.65 g, 20 mmole) was esterified in refluxing methanol containing 2 mL concentrated sulfuric acid for 22 hours. After cooling to room temperature, volatiles were evaporated and the residue was taken up in 50 mL of water and extracted with Et2O. The ether layer was washed with 5% aq. NaHCO3, water brine, and dried over Na2SO4. The desired material was obtained after filtration and removal of volatiles; homogeneous by TLC in 4/1 hexane/EtOAc.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21](OC)[O:22]C)[N:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1.Cl>O>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:33]([CH:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[N:4][C:5]([NH:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[N:6][CH:7]=1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCC2
Agent: Cl
Solvent: O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(NC(=O)N2CCCc3ccc(C=O)nc32)ncc1Cl

Procedure:
N-(5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2E, 25 mg, 0.045 mmol) was treated with HCl (4 M in dioxane, 2 ml, 8.00 mmol) and some drops of water and stirred at room temperature for 2 h. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was triturated in a hot mixture of EtOAc/heptanes 10:1, the suspension was then centrifuged, the liquid phase was removed, some heptane was added and it was again centrifuged. The liquid phase was removed and the solid was dried under high vacuum to give the title compounds as a colorless powder.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].O=[C:10]1[CH2:16][S:15]C[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11]1>>[CH:2]1[N:11]2[C:10]([CH2:16][S:15][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=32)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:1]=1
Reactant: O=C1CSCc2ccccc2N1
Reactant: [C-]#[N+]CC(=O)OCC
Product: CCOC(=O)c1ncn2c1CSc1ccccc1-2

Procedure:
Ethyl 4H,6H-imidazo(5,1-c)(4,1)benzthiazepine-3-carboxylate, M.p. 171.4°-171.7° C. by reaction between ethyl isocyanoacetate and 1,2,3,4 tetrahydro-2-oxo-4,1-benzthiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)[NH2:5].[CH3:20][N:21]=[C:22]=[O:23].O>C(#N)C.C(N(CC)CC)C>[CH3:20][NH:21][C:22]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[C:2]([Cl:1])[CH:3]=1)=[O:23]
Reactant: CN=C=O
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CNC(=O)Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
18.7 g (0.06 mole) of 3-chloro-4-(3-trifluoromethylphenoxy)-aniline were dissolved in 100 ml of acetonitrile, and 3 drops of triethylamine and 4.3 g (0.078 mole) of methylisocyanate were added at 10° C. The mixture was stirred for a further 4 hours at room temperature and then poured into water, and when the reaction mixture had crystallized throughout the solid was filtered off and recrystallized from toluene. 6 g (29% of theory) of N-methyl-N'-[3-chloro-4-(3-trifluoromethylphenoxy)-phenyl]-urea of melting point 160° C were obtained.
Reaction SMILES: CC[CH2:3][CH2:4][O-:5].[Na+].C(O)C.[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14].C(Cl)(Cl)Cl>C1COCC1.O>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:5][CH2:4][CH3:3])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: CCCC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of sodium 1-butoxide (65 g, 0.642 mol) in THF (1 L), at room temperature under a dry nitrogen atmosphere, ethanol (250 mL, 5.35 mol) was added over a 10 minute period. To the resulting solution, 2-chloro-6-fluorobenzonitrile (100 g, 0.642 mol) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes and then reduced to a volume of approximately 250 mL under reduced pressure. The resulting mixture was poured into chloroform and water and the layers separated. The organic layer was washed with water (twice) and brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to afford a light yellow solid. This material was recrystallized from hexanes to provide the 2-chloro-6-ethoxybenzonitrile, 135, (101 g, 87% yield) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[CH:29]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:25]1[S:26][CH:27]=[CH:28][C:24]=1[CH3:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: Cc1ccsc1C=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1sccc1C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.01 g, 15.1 mmol) and 3-methylthiophene-2-carbaldehyde (7.5:1 mixture with 4-methylthiophene-2-carbaldehyde, 2.48 g, 19.6 mmol) in dry dichloromethane (100 mL), was cooled to 0° C. and treated dropwise with DBU (2.76 g, 18.1 mmol). The mixture was warmed to ambient temperature and stirred overnight. The solution was concentrated, taken up in ethyl acetate (150 mL) and washed with 5% hydrochloric acid (2×75 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×75 mL), water (75 mL), dried (magnesium sulfate), filtered and evaporated. The residue was purified by flash chromatography (20-40% ethyl acetate/hexanes gradient) to afford the title compound (4.07 g, 81%) as an orange oil. The product is a mixture of 3- and 4-methylthiophene isomers (6.8:1). 1H NMR major isomer: (300 MHz, d6-DMSO) δ2.33 (s, 3H), 3.72, (s, 3H), 5.13 (bs, 2H), 7.01 (d, 1H, J=5.3 Hz), 7.18-7.52 (m, 5H), 7.60-7.85 (m, 2H), 8.83 (s, 1H). MS APCI, m/z=354(M+Na). LC/MS: 2.43 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7](C2CCCCO2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([Cl:21])[N:9]=2.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[NH:7][C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[N:11]=[C:10]([Cl:21])[N:9]=2
Reactant: Clc1nc(N2CCOCC2)c2nc(CCCCBr)n(C3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2nc(CCCCBr)[nH]c2n1
Temperature: 50 °C

Procedure:
A suspension of 4-(8-(4-bromobutyl)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.1 g, 2.4 mmol) in methanol (10 mL) was treated with p-toluenesulfonic acid (40 mg, 0.24 mmol) and heated overnight at 50° C. The solvent was removed in vacuo to afford 4-(8-(4-bromobutyl)-2-chloro-9H-purin-6-yl)morpholine as a white solid, which was used in the next step without any further purification (880 mg, quant). LC/MS (ESI+): m/z 375 (M+H)
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][OH:23]>C(OCC)C.O=P(Cl)(Cl)Cl>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:21]=1[CH2:22][O:23][C@@H:15]1[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]1
Reactant: OCc1c(Cl)cccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3c(Cl)cccc3Cl)O2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.1 %

Procedure:
To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.06 g of 2,6-dichlorobenzyl alcohol in 25 ml of diethyl ether was added a catalytic amount (2 drops) of phosphorus oxytrichloride, and then the mixture was stirred at room temperature for 4 days. The colourless crystals which had precipitated were filtered off, giving 1.582 g of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran, melting at 123°-124° C. Triethylamine was then added to the mother liquor and the resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography through silica gel, in essentially the same manner as described in Example 1(a), to give 338 mg of trans-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran and 306 mg of cis-6-(2,6-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[CH:17][CH:16]=[CH:15][C:14]=2[O:28][CH3:29])=[O:9])=[O:5])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])=[CH:17][CH:16]=[CH:15][C:14]=2[O:28][CH3:29])[OH:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCC(O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
A well-stirred suspension consisting of 3.59 g (0.00915 mole) of 3-(3-ethoxycarbonylpropionyl)-8-methoxy-4-(2-methylphenylamino)-quinoline (the product of Example 1) in 200 mL of methanol was cooled to 5° C. and 173 mg. (0.0045 mole) of sodium borohydride (available from the Aldrich Chemical Company, Inc. of Milwaukee, Wis.) was immediately thereafter slowly added in small-divided portions, followed by continued stirring of the reaction mixture at 5° C. for a period of 45 minutes. At this point, a fresh batch of 90 mg of sodium borohydride was added to the stirred reaction mixture and further stirring was then continued at 5° C. for a period of one hour. Upon completion of this step, the pH of the resulting homogeneous solution was next adjusted to a value of pH 7 by the careful addition of glacial acetic acid, followed by filtration and subsequent evaporation of the resulting filtrate under reduced pressure to eventually give a crystalline product as the residue. Recrystallization of the latter material from methanol-water then gave a nearly quantitative yield of pure 3-(3-ethoxycarbonyl-1-hydroxypropyl)-8-methoxy-4-(2-methyl-phenylamino)quinoline as a partial hemihydrate, m.p. 133°-135° C. The pure product was further characterized by means of mass spectrum (MS) analysis and nuclear magnetic resonance (NMR) data, in addition to elemental analysis.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:34]O>>[CH3:34][O:18][C:17](=[O:19])[CH2:16][C:14]1[N:15]=[C:11]([NH:10][C:8](=[O:9])[CH:7]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:12][CH:13]=1
Reactant: O=C(O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Yield: 61 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid (prepared in Example 16, 80 mg, 0.18 mmol) in methanol (10 mL) was treated with concentrated hydrochloric acid (1 mL) and then heated under reflux for 16 h. At this time, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL) and then washed with water (5 mL). The aqueous layer was further extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (50 mg, 61%) as a yellow oil: EI-HRMS m/e calcd for C26H28N2O4S (M+) 464.1770, found 464.1769.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Cl:23])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:24]([NH2:26])=[O:25].FC(F)(F)C(O)=[O:30].OO.[OH-].[Na+]>C(O)(=O)C.O.C(OCC)C>[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([S:15]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:30])=[C:10]([Cl:23])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:24]([NH2:26])=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1nnn(Cc2cc(Cl)c(Sc3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: NC(=O)c1nnn(Cc2cc(Cl)c(S(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95.1 %

Procedure:
A stirred solution of 5-amino-1-(4-[4-chlorophenylthio]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide (176 mg, 0.409 mmol) in glacial acetic acid (10 ml) was treated at ambient temperature with trifluoroacetic acid (94.3 μl, 139 mg, 1.23 mmol) and 30% aqueous hydrogen peroxide (2.72 ml). The mixture was stirred 45 minutes, diluted with glacial acetic acid (3.0 ml), stirred 3.25 hours, and diluted with water (100 ml). The mixture was cooled to 0° C., a small volume of diethyl ether was added, the mixture was carefully basified by addition of 50% (w/v) aqueous sodium hydroxide, and diethyl ether was evaporated under vacuum. The resulting suspension was filtered, and the solid washed well with water and dried at 45° C. under vacuum to provide 173 mg (95%) of 5-amino-1-(4-[4-chlorophenylsulfinyl]-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide. Recrystallization from ethanol provided material of m.p. 195°-197 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[O:27])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CN2CC(C)(C)OCC2C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CC1
Yield: 12 %

Procedure:
The desired compound was prepared using [5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and 1-methyl piperazine following Method F in 12% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12](=[O:15])[NH:13][CH3:14])=[C:6]2[CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:18][CH2:17][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]=1[C:12]([NH:13][CH3:14])=[O:15]
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl {2-[5-methoxy-2-(methylcarbamoyl)-1H-indol-3-yl]ethyl}carbamate (520 mg) and dioxane (5.00 mL) was added hydrogen chloride (4 M dioxane solution, 5.00 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (460 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][CH2:22][CH3:23].S(=O)(=O)(O)[OH:25].OO>CO.C(O)(C)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH2:22][CH3:23])=[O:25]
Reactant: CCSc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(C)O
Solvent: CO
Product: CCS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 302.9 %

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylthiopyrazole (22.25 g) in methanol was added a solution of sulfuric acid (1.5 g) in isopropanol. Hydrogen peroxide (6.95 g of 30% aqueous solution) was added and the temperature raised to 60° C. After two hours, the reaction was filtered and the solid washed with methanol. The filtrate was washed (water), dried and recrystallized (methanol) to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethylsulfinylpyrazole (18.4 g), m.p. 173-174° C.
Reaction SMILES: [CH2:1]([C:8]1[N:13]([CH2:14]C(O)=O)[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:56])[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:35])C=C>>[CH2:1]([C:8]1[N:13]([CH2:14][C:34]([NH:36][CH:37]([C:46](=[O:57])[CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[Cl:56])[CH2:38][C:39]([OH:41])=[O:40])=[O:35])[C:12](=[O:18])[C:11]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc1ccccc1Cl
Reactant: O=C(O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O
Product: O=C(O)CC(NC(=O)Cn1c(Cc2ccccc2)ccc(NC(=O)CCc2ccccc2)c1=O)C(=O)COCc1ccccc1Cl

Procedure:
N-2-(6-Benzyl-1,2-dihydro-2-oxo-3-(3-phenylpropionyl)amino-1-pyridyl)acetyl-3-amino-5-(2-chlorobenzyloxy)-4-oxo-pentanoic acid (90) was prepared from 52b and (3S) t-butyl N-(allyloxycarbonyl)-3-amino-5-(2-chlorophenylmethoxyl)-4-oxo-pentanoate (prepared by a similar method as 82) to give a white solid: 1H NMR(DMSO-d6) δ 9.2(s, 1H), 8.75(d, 1H), 7.7-7.1(m, 14H), 6.4(d, 1H), 4.65(d, 6H), 4.56(s, 1H), 4.6-4.35(dd, 1H), 3.9(s, 2H), 2.9-2.6(m, 6H) ##STR156##