Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[CH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[CH2:1]([NH:4][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: O=C(O)CCCl
Product: C=CCNCCC(=O)O
Reaction time: 0.08 h

Procedure:
To a cooled solution of 125 mL aqueous allylamine (60%), 3-chloropropionic acid (20 g) was added portionwise while stirring over 5 minutes. The mixture was stirred at ambient temperature for 72 hours. The mixture was then evaporated to a viscous oily residue (40 g). The product consisted of a 1:1 mixture of 3-allylaminopropionic acid and allylamine hydrochloride. This product mixture was used without further purification for the preparation of the title compound in step 2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([C:26]#[N:27])[CH:3]=1.C(C1C=C([N+]([O-])=O)C=CC=1N1CC[CH:42]([CH:45]([C:51]2C=CC=C[CH:52]=2)[C:46](NCC)=[O:47])[CH2:41]C1)#N>>[C:26]([C:4]1[CH:3]=[C:2]([NH:1][C:46](=[O:47])[CH:45]([CH2:51][CH3:52])[CH2:42][CH3:41])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([C:15](=[O:16])[NH:17][CH2:18][CH3:19])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:12][CH2:13]1)#[N:27]
Reactant: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2C#N)CC1
Product: CCNC(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)C(CC)CC)cc2C#N)CC1
Yield: 95 %

Procedure:
2-[1-(4-Amino-2-cyano-phenyl)-piperidin-4-yl]-N-ethyl-2-phenyl-acetamide. 2-[1-(2-Cyano-4-nitro-phenyl)-piperidin-4-yl]-N-ethyl-2-phenyl-acetamide was subjected to reaction conditions similar to those described in Step C to provide the title compound as a yellow powder (600 mg, 95%). MS (ESI): mass calcd. for C22H26N4O, 362.47. m/z found, 363.2 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[F:5][CH:6]([F:12])[C:7](OCC)=[O:8].[CH3:13][CH2:14][OH:15]>CCOC(C)=O>[F:5][CH:6]([F:12])[C:7](=[O:8])[CH2:3][C:2]([O:15][CH2:14][CH3:13])=[O:1]
Reactant: CCOC(=O)C(F)F
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 65 °C

Procedure:
To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.11 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65° C. for 2 h. Then the reaction mixture was quenched with 1N HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.5 g, 33.11 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100° C. for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[NH:16]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:17]([C:25]([OH:27])=O)[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23].Cl.[NH2:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[NH:16]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:17]([C:25]([NH:39][CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:27])[CH2:18][CH2:19][CH2:20][NH:21][C:22](=[NH:24])[NH2:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
39.6 g of DCC are added at 0° C. to a solution of 55 g of Z-Arg-OH, 30.18 g of HCl.H-Gly-OtBu and 24.3 g of HOBt in 400 ml of dimethylformamide. The mixture is left to stir at 0° C. for 1 hour and at room temperature for 3 hours and to stand at room temperature overnight. The DC-urea is filtered off with suction and the filtrate is concentrated. The residue is subjected to countercurrent partition between ethyl acetate and saturated NaHCO3 solution (400 ml each). This results in the required substance precipitating in the first separating funnel after the 3rd stage.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)[CH:5]=O.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[NH2:30]>>[CH3:21][C:22]1[C:23]2[N:30]=[C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)=[C:2]([CH3:1])[CH:3]=3)[NH:29][C:24]=2[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)ccc1OCCCN1CCN(C)CC1
Reactant: Cc1ccc(N)c(N)c1C
Product: Cc1cc(-c2nc3c(C)c(C)ccc3[nH]2)ccc1OCCCN1CCN(C)CC1
Yield: 75.3 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-methyl-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-benzaldehyde (180 mg, 0.65 mmol, 1.0 equiv), 3,4-dimethyl-benzene-1,2-diamine (89 mg, 0.65 mmol, 1.0 equiv), and Na2S2O5 (161 mg, 0.85 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 192 mg (75%) of the title compound. MS (electrospray): mass calculated for C24H32N4O, 392.26. m/z found, 393.5 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.95-7.85 (m, 2H), 7.35-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.12 (t, J=6.0 Hz, 2H), 2.64-2.37 (m, 16H), 2.29 (s, 6H), 2.10-2.00 (m, 2H).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]=[O:22])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[CH2:4]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([OH:22])[CH3:1])[CH2:16][CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=CCC1CCC(C(=O)OCc2ccccc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CC1CCC(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
Methylmagnesium bromide (1 M solution in THF, 0.526 ml, 0.526 mmol) was added dropwise to 4-(2-oxo-ethyl)-cyclohexanecarboxylic acid benzyl ester (114 mg, 0.439 mmol) in THF (2.2 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture at the same temperature and extracted with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous ammonium chloride solution, water and saturated brine and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-(2-hydroxy-propyl)-cyclohexanecarboxylic acid benzyl ester (80.7 mg, 67%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].[Br:20][C:21]1[C:22](Cl)=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1.[Na+].[Cl-]>CN(C=O)C>[Br:20][C:21]1[C:22]([O:1][CH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)(=[O:7])=[O:8])=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCO)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCCCOc2nc(Cl)ncc2Br)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 272 mg (1.05 mmol) of N-(3-hydroxy-propyl)-3-nitro-benzenesulfonamid in 5 ml DMF is mixed with 49 mg of a 60% dispersion of sodium hydride in mineral oil (1.22 mmol) and stirred for 5 minutes at room temperature. It is mixed with a solution of 220 mg (0.97 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 5 ml of DMF and stirred for another 2 hours. The batch is mixed with saturated NaCl solution and then extracted with ethyl acetate (2×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1, Flashmaster II). 75 mg (0.16 mmol, corresponding to 16% of theory) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](SC)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O[O:14][S:15]([O-:17])=O.[K+].[CH3:19]O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:15]([CH3:19])(=[O:17])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-5-(methylthio)benzoic acid (25 g, 123 mmol) dissolved in methanol (500 ml) is cooled to 0°-5° C. and then OXONE™ (227.6 g, 370 mol) in water (500 ml) is added. The reaction mixture is stirred for 30 minutes at 0°-5° C. and then at room temperature for 4 hours. The reaction mixture is diluted with water, extracted with CHCl3 (3×200 ml) and the CHCl3 extracts are combined, washed with water, then brine and then are dried over MgSO4, filtered and evaporated to afford 5.13 g of 2-chloro-5-(methylsulfonyl)benzoic acid, m.p. 187°-188° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([CH:19]=1)[NH2:18].N1C=CC=CC=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C(#N)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[C:17]([NH:18][C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[CH:19]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(N)c3)c(Br)n2n1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Br)n2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
A solution of 5-(3-bromo-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylaniline (0.165 g, 0.495 mmol) in acetonitrile (25 mL) containing pyridine (1.48 mmol) is added trimethylacetylchloride (0.495 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford 0.200 g (97%) of the title compound as a white solid: Rf 0.41 (1:1 EtOAc:hexanes); LCMS (m/z)=417.3, 419.3 [M+H]+, tR=2.76 min.
Reaction SMILES: [C:1]([C:4]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[NH:9][C:8]=2[CH:7]=[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=1)(=[O:3])[CH3:2].[Se](=O)=[O:26].C.[O:29]1CCO[CH2:31][CH2:30]1>O>[CH2:18]([O:17][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[CH:2]([O:29][CH2:30][CH3:31])[OH:26])[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[NH:9][C:8]=2[CH:7]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2
Reactant: C1COCCO1
Reactant: O=[Se]=O
Solvent: O
Product: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2
Temperature: -18 °C

Procedure:
50.12 g (154 mmol) is 8-acetyl-6-benzyloxy-2,2-dimethylbenzo[1,4]oxazin-3-one is reacted with selenium dioxide as oxidizing agent and activated charcoal in refluxing dioxane and some water. After cooling, the solid is filtered off and washed with dioxane. The filtrate is evaporated down and the residue is dissolved in 550 mL of ethanol and refluxed for 30 minutes. It is filtered and the mother liquor is cooled to −18° C., during which time a solid is precipitated which is suction filtered. After recrystallization from ethanol, the product is obtained in the form of a beige solid. Yield: 8.95 g (15%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([OH:20])(=[O:19])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].[CH2:21]=[O:22].[Li][Li].Cl>O1CCCC1>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([CH2:21][OH:22])[C:13]([OH:20])=[O:19]
Reactant: CC(C)CCC(=O)O
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)CC(CO)C(=O)O
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
Diisopropylamine (20.6 g) is dissolved in 80 ml of dry tetrahydrofuran. This solution is cooled to -30° C. n-Butyllithium (77 ml of 2.6 M in hexane) is added dropwise in a nitrogen atmosphere at a rate that maintains the reaction at -30° to -20° C., and this solution is stirred at -20° C. for 30 minutes. Isocaproic acid (11.6 g) in 10 ml of tetrahydrofuran is added dropwise at -20° to -10° C., then stirred at -10° C. for 30 minutes. In a separate flask, paraformaldehyde (28 g) is heated to about 200° C. and the vapors are carried in a stream of nitrogen over the surface of the tetrahydrofuran solution of the dilithium salt of isocaproic acid. During this procedure the temperature is kept between -10° and +10° C. After all of the paraformaldehyde has vaporized the reaction mixture is cooled to 0° C. and 10% hydrochloric acid is added dropwise until the reaction mixture becomes acidic. Product is extracted with 2 portions of ether (400 ml each). The ether is dried with magnesium sulfate, filtered and concentrated in vacuo to yield 13.2 g of crude material. Product is vacuum distilled to yield 9.0 g, boiling point 135°-142° C./9 mm of Hg.
Reaction SMILES: [F:1][C:2]([F:7])([CH3:6])[C:3](O)=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.ClC1C=C(C=CC=1OC)C[N:34]1[CH2:39][CH2:38][CH:37]([NH:40][C:41]([N:43]2[CH2:48][CH2:47][C:46](=[CH:49][C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[F:57])[CH2:45][CH2:44]2)=[O:42])[CH2:36][CH2:35]1.CCN(CC)CC>C(#N)C.O>[F:57][C:51]1[CH:52]=[CH:53][C:54]([F:56])=[CH:55][C:50]=1[CH:49]=[C:46]1[CH2:47][CH2:48][N:43]([C:41]([NH:40][CH:37]2[CH2:36][CH2:35][N:34]([C:3](=[O:4])[C:2]([F:7])([F:1])[CH3:6])[CH2:39][CH2:38]2)=[O:42])[CH2:44][CH2:45]1
Reactant: COc1ccc(CN2CCC(NC(=O)N3CCC(=Cc4cc(F)ccc4F)CC3)CC2)cc1Cl
Reactant: CC(F)(F)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(F)(F)C(=O)N1CCC(NC(=O)N2CCC(=Cc3cc(F)ccc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.7 %

Procedure:
2,2-Difluoropropionic acid (66.0 mg, 0.60 mmol) was dissolved in acetonitrile (2.0 mL), and then HOBt (75.0 mg, 0.60 mmol), WSC (115 mg, 0.60 mmol), the compound (150 mg, 0.40 mmol) obtained in Example 36 (1), and Et3N (167 μL, 1.2 mmol) were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction mixture, and after extraction with chloroform, the extract was washed with water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:30), thereby giving the title compound (20.0 mg, 12%) as a white solid.
Reaction SMILES: S.[Na].[CH2:3]([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([F:19])[CH:15]=2)[N:10]([CH:21]2[CH2:23][CH2:22]2)[C:9]=1[S:24]C)=[O:7])[CH3:4].Cl>C1COCC1.O.CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Br:20])=[C:14]([F:19])[CH:15]=2)[N:10]([CH:21]2[CH2:22][CH2:23]2)[C:9]=1[SH:24])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(SC)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Agent: Cl
Agent: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(S)n(C2CC2)c2cc(Br)c(F)cc2c1=O
Temperature: 45 °C

Procedure:
Sodium hydrogen sulfide (5 mg, 0.09 mmole, 1.5 equiv.) is added to a stirred solution of 7-Bromo-1-cyclopropyl-6-fluoro-2-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (5, 24 mg, 0.06 mmole) in THF (tetrahydrofuran, 2 ml) under argon at room temperature. The reaction is then stirred at 45° C. until TLC indicated completion. The reaction mixture is diluted with water and washed with diethyl ether. The aqueous layer is acidified by 1N HCl to a pH of approximately 2, and extracted with EtOAc. The resulting organics are washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by PTLC (20% CH3OH in CHCl3) to give 6. Alternatively, sodium hydrogen sulfide (20 mg, 0.36 mmole, 1.5 equiv.) is added to a stirred solution of 5 (crude, 96 mg, 0.24 mmole) in DMF (6 ml) under argon at room temperature. The reaction is then stirred at 40° C. until TLC indicates completion. The reaction mixture is diluted with water, acidified by 1N HCl to a pH of approximately 2, and extracted with EtOAc. The resulting organics are washed with brine, dried over Na2SO4, and concentrated. The crude is purified by PTLC (20% CH3OH in CHCl3) to yield 6. 1H NMR (CDCl3) δ: 8.40 (d, 1H), 8.06 (d, 1H), 4.71 (q, 2H), 3.46 (m, 1H), 1.68 (m, 7H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([C:15](=[O:31])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])C.[OH-].[Na+]>CO>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([C:15](=[O:31])[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:5][C:4]([OH:32])=[O:3])([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)CC(CC(=O)OC(C)(C)C)C(=O)NCCc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CC(=O)O)C(=O)NCCc1ccc(-c2ccccc2)cc1
Reaction time: 24 h

Procedure:
To a solution of the compound of example 71 (1.09 g, 2.48 mmol) in methanol (50 mL) was added drop wise a sodium hydroxide solution (1N, 5 mL, 5 mmol). After stirring the reaction mixture for 24 h, the solvent was evaporated. The residue was partitioned between water and ether. The aqueous phase was acidified with concentrated HCl, and then extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated to give the product as a white solid. 1H-NMR(CDCl3, 400 MH: 1.37(s, 9H); 2.28–2.61(m, 4H); 2.79(t, J=7.3 Hz, 2H); 3.08(m, 1H); 3.27(m, 1H); 3.39 (m, 2H); 6.25(m, t, 5.1 Hz, 1H); 7.26(m, 3H); 7.36(m, 2H); 7.52(m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH3:16])[C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[N:13][CH:12]=3)[S:10][C:3]=12.[CH3:21][C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([NH2:31])=[CH:26][CH:25]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:27]3[CH:28]=[C:29]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22]([CH3:21])=[CH:30]4)[CH:8]=2)=[CH:12][N:13]=[C:14]1[C:17]([OH:20])([CH3:19])[CH3:18]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Solvent: CC(Cl)Cl
Solvent: CC(C)(C)O
Product: Cc1cc2cc(Nc3ccnc4cc(-c5cnc(C(C)(C)O)n5C)sc34)ccc2[nH]1
Yield: 64.1 %

Procedure:
2-[5-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol (190 mg, 0.62 mmol) and 2-methyl-5-aminoindole (108 mg, 0.714 mmol) were dissolved in 3 mL of t-butyl alcohol and 3 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight solvent was added along with an additional 45 mg of the indole an the solution was heated an additional 18 hours. Chromatography of the residue with 20% methanol:methylene chloride afforded 166 mg (66%) of 2-{1-methyl-5-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-1H-imidazol-2-yl}-propan-2-ol. 1H NMR (400 MHz, CD3OD) δ8.17 (d, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.40 (d, 1H), 7.02 (d, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 3.33 (s, 3H), 2.44 (s, 3H), 1.64 (s, 6H). LC-MS: 418, 419 (MH+); HPLC RT: 3.98 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([NH:12][C:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:16]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]#N)=[CH:28][CH:27]=2)[NH:15][N:14]=1)(=[O:11])=[O:10].[OH2:38].[OH-:39].[K+].[Cl-].[NH4+]>C(O)COCCO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([NH:12][C:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[C:16]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][C:36]([OH:39])=[O:38])=[CH:28][CH:27]=2)[NH:15][N:14]=1)(=[O:10])=[O:11]
Reactant: N#CCCCOc1ccc(CSc2[nH]nc(NS(=O)(=O)c3c(Cl)cccc3Cl)c2-c2ccccn2)cc1
Reactant: [OH-]
Reactant: O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: OCCOCCO
Product: O=C(O)CCCOc1ccc(CSc2[nH]nc(NS(=O)(=O)c3c(Cl)cccc3Cl)c2-c2ccccn2)cc1
Yield: 66 %

Procedure:
The 3-(2,6-dichlorophenyl)sulfonylamino-4-(2-pyridyl)-5-(4-(3-cyanopropoxy)benzylthio)-(1H)-pyrazole (0.19 g), prepared as described in Example 7, above, in 2 ml of diethylene glycol and 0.2 ml of water with 0.1 g of potassium hydroxide was heated at 100° C. overnight. After cooling, the reaction was poured into a saturated solution of ammonium chloride, extracted in tetrahydrofuran/ethyl acetate 1:1, and washed with water and then brine. The organic phase was dried over MgSO4, filtered and concentrated to dryness. The residue was treated with ethanol/ether 2:1 to precipitate a yellow solid (0.130 g, 66% yield) isolated by filtration.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[OH:22])=[O:5].[H][H]>CO.[Pd]>[CH3:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[OH:22])=[O:5]
Reactant: COC(=O)c1cc2c(C(=O)CNC(C)C)ccc(O)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2c(C(O)CNC(C)C)ccc(O)c2[nH]1
Temperature: 0 °C
Yield: 98.5 %

Procedure:
A solution of 1.6 g of 7-hydroxy-4-isopropylaminoacetylindole-2-carboxylic acid methyl ester hydrochloride in 80 ml of methanol is combined with 300 mg of 10% palladium-animal charcoal and shaken for 21/4 hours under normal pressure with hydrogen. The reaction mixture is then filtered and the filtrate evaporated to dryness under vacuum. The residue is triturated with acetonitrile, cooled to 0° C., and filtered, thus obtaining 1.41 g of 4-(1-hydroxy-2-isopropylaminoethyl)-7-hydroxyindole-2-carboxylic acid methyl ester, decomposition point 137°-139° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][OH:11].Cl.[OH-].[K+].O>CO.C1COCC1>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:10][OH:11]
Reactant: O=Cc1ccccc1I
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: ONCc1ccccc1I

Procedure:
2-Iodobenzaldehyde prepared above (10.3 g, 44.4 mmol) was dissolved in 50 mL MeOH and 10 mL THF. After addition of H2NOH.HCl (10 mL H2O) and 6N KOH, an additional 50 mL THF, 30 mL H2O, and 30 mL MeOH were added. The product was recovered as a cloudy orange oil (9.46 g, 85.6%, 90% desired product). IR (film): 3256, 3057, 2872, 1564, 1466, 1435, 1013, 748. 1H-NMR (400 MHz, CDCl3): δ 7.92 (dd, 1H, J=7.8, 1.2, C4-H), 7.58 (dd, 1H, J=7.4, 1.8, C7-H), 7.34 (td, 1H, J=7.4, 1.2, C6-H), 7.00 (td, 1H, J=7.6, 1.8, C5-H), 5.5 (br s, 1H, C1-NHOH), 5.0 (br s, 1H, C1-NHOH), 4.13 (s, 2H, C1-H2). 13C-NMR (100 MHz, CDCl3): δ 139.5, 139.1, 131.0, 129.4, 128.3, 100.1, 62.0. EI-MS m/z (rel int): 249 (M+, 36), 217 ([M−NHOH]+, 100), 122 ([M−I], 30). CI-MS (NH3) m/z (rel int): 284 ([M+2NH3+H]+, 30), 267 ([M+NH4]+, 100), 250 ([M+H]+, 27).