Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:28])=[O:27])[C:7]([C:36]#[N:37])=[C:6]([CH3:38])[NH:5][C:4]=1[CH3:39])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[NH:25][S:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[O:28])=[O:27])[C:7]([C:36]#[N:37])=[C:6]([CH3:38])[NH:5][C:4]=1[CH3:39])#[N:2]
Reactant: CCOC(=O)CCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCS(=O)(=O)Nc1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
41 mg (0.073 mmol) tert-butyl 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-3-{[(3-ethoxy-3-oxopropyl)sulfonyl]amino}-1H-indazole-1-carboxylate (Example 19A) were dissolved in dichloromethane (4 ml) and treated with 0.062 ml (0.8 mmol) trifluoroacetic acid. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 33 mg (98% of th.) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH:15]([CH3:25])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:17].O>CN(C)C=O>[CH2:12]([O:11][C:3]([CH:4]([CH:15]([C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:25])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Cl)C(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)C(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (50% oil dispersion, 3.5 g) was added with caution to a cooled solution of diethyl malonate (11.85 ml) in dimethylformamide (10 ml). The reaction mixture was stirred at room temperature for 30 minutes before a solution of 2-chloro-1-(4-fluorophenyl)-1-propanone (12.13 g) in dimethylformamide (50 ml) was added in small aliquots. The resulting reaction mixture was stirred for 2 hours at room temperature and then water (35 ml) was added. The mixture was extracted with petroleum ether (b.p. 40°-60° C.) (3×50 ml) and the combined organic extracts were evaporated under reduced pressure to afford ethyl 2-ethoxycarbonyl-3-(4-fluorobenzoyl)butanoate (15.92 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 1.35 g (5.233 mmol) of the product of Example 50 dissolved in 20 mL of chloroform and 1.5 mL of pyridine was added 1.02 g (5.233 mmol) of 4-fluorobenzenesulfonyl chloride and the resulting mixture was stirred overnight at room temperature. The chloroform was removed in vacuo and the residue was diluted with ether and washed with water, 5% HCl solution and saturated sodium bicarbonate solution and then dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether/hexanes (1:1) and the solid was collected by filtration and dried in vacuo to provide 1.50 g (69%) of the sulfonamide as a white solid. Electrospray Mass Spec: 416.9 (M+H)+
Reaction SMILES: [B:1]([OH:4])([OH:3])[OH:2].[CH3:5][C:6](O)([CH2:8][CH:9](O)[CH3:10])[CH3:7]>CCCCCCC>[OH:2][B:1]1[O:4][C:6]([CH3:7])([CH3:5])[CH2:8][CH:9]([CH3:10])[O:3]1
Reactant: CC(O)CC(C)(C)O
Reactant: OB(O)O
Solvent: CCCCCCC
Product: CC1CC(C)(C)OB(O)O1
Temperature: 95 °C

Procedure:
61.2 g of boric acid (1 mol) and 118.2 g of 2-methyl-2,4-pentanediol (1 mol) and 200 ml of heptane are charged to a reaction flask equipped with stirrer, Marcusson apparatus and reflux condenser. The reaction mixture is heated up to its reflux temperature (about 95° C.), with stirring, and is kept at that temperature for a 4-hour period.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21]>CCO>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Sodium hydroxide (5M; 10.2 mL; 51 mmol; 3 eq.) was added to a solution of methyl 2′-methyl-2-(trifluoromethyl)biphenyl-4-carboxylate (5 g; 17 mmol; 1 eq.) in EtOH (150 mL) and the reaction mixture was stirred at 60° C. for 2 hours. After concentration in vacuo, the residue was taken up in water (300 mL) and the aqueous phase was washed with ethyl acetate (2×100 mL). The pH was adjusted to 2 with conc. HCl and the solution was concentrated to ca. 150 mL. The precipitate was filtered off and dried to afford the title compound (3.33 g, 70%) as a beige solid. HPLC (Method A): Rt 4.57 min (purity 98.7%). LC/MS: 278.9 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]\[OH:21])/[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N/O)c2ccc(Cl)cc2)c(O)c1

Procedure:
A mixture of 382 g of 4'-chloro-2-hydroxy-4-methoxybenzophenone, 230 g hydroxylamine hydrochloride and 1.5 liters of pyridine is heated under reflux for 3 hr. The solvent is evaporated and the residue is partitioned between hydrochloric acid and ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution. The solvent is removed to afford a mixture of E- and Z-oxime isomers which is separated on a Waters Prep IC System 500 using 5% ethyl acetate/toluene as the eluting system to afford E-4'-chloro-2-hydroxy-4-methoxybenzophenone oxime, mp 159° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[CH3:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([NH:17][C:18]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])=[S:19])=[O:16]
Reactant: CNC(=O)c1ccccc1N
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1C
Yield: 93.4 %

Procedure:
To a stirred mixture of 5.4 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 6.67 g of 2-methylbenzoyl isothiocyanate in 100 ml of ether over 15 minutes. After several hours the solid was collected, giving 11 g of 2-methyl-N-[[[2-[(methylamino)carbonyl]phenyl]amino]thioxomethyl]benzamide
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)=O.[CH3:16][NH2:17]>>[CH3:16][NH:17][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)=[O:3]
Reactant: CN
Reactant: COC(=O)c1ccc2c(c1)CNCC2
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)CNCC2
Temperature: 100 °C

Procedure:
1,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid methyl ester hydrochloride (113 mg, 0.5 mmol) is dissolved in aqueous methylamine (40%, 5.0 ml)) and heated at 100° C. overnight. Upon cooling to rt, the reaction mixture is evaporated to dryness under reduced pressure. The residue is taken up in water (1.0 ml), and treated with sodium hydroxide solution (1.0 N, 1.0 ml). The mixture is extracted with DCM (10 ml×3). The combined organic phase is dried over sodium sulfate, and concentrated to give the title compound. MS (+VE) m/z 191.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), dry potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were stirred in refluxing dry acetone (600 mL) for 12 h. After cooling, the acetone was evaporated, and the solution was dissolved in water (250 mL). The water phase was extracted with diethyl ether (4×100 mL), the organic phase was washed with brine (2×50 mL), dried (MgSO4) and the solvent was removed in vacuo. Recrystallisation from petroleum ether and ethyl acetate gave the titled compound as white crystals, m.p. 102-103° C. Yield: 121.4 g (89%). Spectroscopic data were in accordance with the literature (J. Barbera, R. Iglesias, J. L. Serrano, T. Sierra, M. R. de la Fuente, B. Palacios, M. A. Perez-Jubindo, J. T. Vazquez, J. Am. Chem. Soc. 1998, 120, 2908).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([OH:19])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:20][C:21]1[C:26]([O:27][Si](C(C)(C)C)(C)C)=[CH:25][CH:24]=[CH:23][C:22]=1[C@@H:35](O)[CH3:36]>>[N:1]1([C:10]2[S:14][C:13]([C:15]([O:17][CH3:18])=[O:16])=[C:12]([O:19][C@@H:35]([C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([OH:27])[C:21]=3[Cl:20])[CH3:36])[CH:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1sc(-n2cnc3ccccc32)cc1O
Reactant: C[C@H](O)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Product: COC(=O)c1sc(-n2cnc3ccccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Yield: 73.3 %

Procedure:
Title compound (2.2 g) was prepared from methyl 5-(1H-benzimidazol-1-yl)-3-hydroxy-2-thiophenecarboxylate (J. Heterocyclic Chem., 1987, 24, 1301-1303) (1.9 g, 7.0 mmol) and (1S)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethanol (Intermediate 17, 2.0 g, 7.0 mmol) using a procedure analogous to Intermediate 2, Step C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1.CN(C)C(=O)C.[H-].[Na+].[ClH:29].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O>[ClH:30].[ClH:29].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of 167 parts of ethyl 3-(1H-benzimidazol-2-ylamino)-1-pyrrolidinecarboxylate and 2790 parts of N,N-dimethylacetamide were added portionwise 61.0 parts of a sodium hydride dispersion 50% Upon completion, stirring was continued for 1 hour at 50° C. 127.2 Parts of 2-(chloromethyl)pyridine hydrochloride were added portionwise at 80° C. After complete addition, the whole was stirred for 2 hours at 80° C. After cooling, the reaction mixture was poured into 1000 parts of water. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 and 99:1 by volume) as eluents. The first and second fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt was filtered off and dried, yielding 69.5 (24%) parts of ethyl 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidinecarboxylate dihydrochloride; mp. >140° C. (compound 23).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:42])[C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4([NH:34]C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:42])[C:23]#[C:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4([NH2:34])[CH2:32][CH2:33]4)=[CH:27][CH:26]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1
Reaction time: 24 h

Procedure:
1 mL (12.92 mmol) of trifluoroacetic acid is added to a solution of 0.24 g (0.49 mmol) of 3-[4-(1-tert-butoxycarbonylaminocyclopropyl)phenyl]propynoic acid-(4′-chlorobiphenyl-4-yl)amide in 20 mL dichloromethane and stirred for 24 hours. Then the solvent is eliminated by rotary evaporation and the residue is combined with toluene and again subjected to rotary evaporation. This residue is then triturated with dichloromethane, suction filtered and dried in the air. Yield: 0.22 g (89% of theory); C24H19ClN2O*C2HF3O2 (M=500.90); calc.: molecular ion peak (M+H)+: 387 (Cl); found: molecular ion peak (M+H)+: 387 (Cl); melting point: 160° C.-164° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:38]#[N:39])[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]4=[N:4][CH:3]=3)[CH:24]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 53.5 %

Procedure:
3-Bromo-8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridine (0.10 g, 0.36 mmol) and 4-fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (0.15 g, 0.47 mmol) were coupled following the procedure in Example 1 to afford 4-fluoro-3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as a white amorphous solid (75 mg, 53%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.09 (1H, s), 7.19 (1H, dd, J 7 and 7), 7.30 (1H, ddd,J 8, 8 and 3), 7.49-7.58 (3H, m), 7.64-7.66 (2H, m), 7.73-7.75 (2H, m), 8.33 (1H, d, J 7); m/z (ES+) 390 (M++H).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>>[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:11]([C:10]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:9]=2[NH:8][CH:7]=[CH:6]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(O)c1c(F)ccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2c(F)ccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a solution of 59 mg (0.33 mmol) of 6-fluoro-1H-indole-7-carboxylic acid and 86 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine in 3 ml DCM 63 mg (0.33 mmol) of EDC.HCl were added and the reaction mixture was stirred over night at rt. The product was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 51 mg (38%) product as a colorless viscous oil. MS (ISP) 447.4 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[O:18]=[C:19]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]3[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=3)[CH:32]=2)[O:27][C:21]2([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:20]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[C:10]([C:13]([N:24]4[CH2:23][CH2:22][C:21]5([CH2:20][C:19](=[O:18])[C:33]6[C:28](=[CH:29][CH:30]=[C:31]([C:34]7[NH:35][C:36]([C:39]([NH2:41])=[O:40])=[N:37][N:38]=7)[CH:32]=6)[O:27]5)[CH2:26][CH2:25]4)=[O:15])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: NC(=O)c1nnc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnc(C(N)=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylic acid (54 mg) and 5-[4-oxo-spiro(chroman-2,4′-piperidin)-6-yl]-4H-1,2,4-triazole-3-carboxamide (102 mg) in DMF (4 mL) were added TEA (77 uL), HOBT (42 mg), and WSC (53 mg) at room temperature and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into H2O, extracted with CHCl3, dried over sodium sulfate, filtered, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of CHCl3/MeOH (1:0-10:1) as eluent to give the title compound as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ: 8.78-8.60 (1H, m), 8.40-8.25 (1H, m), 7.29 (1H, s), 7.15 (1H, d, J=8.0 Hz), 7.09 (1H, d, J=4.0 Hz), 6.57 (1H, s), 6.52 (1H, d, J=4.0 Hz), 4.30-4.17 (1H, m), 3.95 (3H, s), 3.62-3.38 (3H, m), 3.38-3.32 (1H, m), 2.85 (2H, s), 2.28-1.70 (4H, m), 1.06-1.04 (2H, m), 1.00-0.97 (2H, m); MS [M+H]+=541.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(F)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(F)cc3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 28.3 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2,4-difluoro aniline (0.047 g, 0.364 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.035 g of the desired product. 1HNMR (DMSO-d6): δ 1.56 (s, 6H), 3.09 (s, 2H), 7.11 (t, J=8.4 Hz, 1H), 7.30 (s, 1H), 7.41 (t, J=8.7 Hz, 1H), 8.39-8.45 (m, 3H), 9.91 (s, 1H), 11.01 (br s, 1H), 11.55 (br s, 1H); MS [M]+: 504.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][N:10]1C(OC)=O.Br>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][C@H:13]([C:15]2[O:19][NH:18][C:17](=[O:20])[CH:16]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)cc1Cl
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(F)cc3Cl)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
Trans-methyl 2-(2-chloro-4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (130 mg, 0.37 mmol) (from example 47, step 3) was dissolved in hydrogen bromide (33% in acetic acid, 2.9 mL, 16.49 mmol) and stirred at room temperature for 16 h. The solvent was removed and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(Trans-2-(2-chloro-4-fluorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (94 mg, 86%). 1H NMR (600 MHz, dmso) δ 1.50-1.60 (m, 1H), 1.79-1.88 (m, 1H), 1.95-2.01 (m, 1H), 2.06-2.12 (m, 1H), 2.70 (t, 1H), 2.88-2.96 (m, 1H), 3.20-3.24 (m, 1H), 4.01 (d, 1H), 5.95 (d, 1H), 7.21 (dt, 1H), 7.37 (dd, 1H), 7.68 (dd, 1H). HRMS Calculated for [C14H14ClFN2O2+H]+: 297.0806. Found: 297.0823
Reaction SMILES: Cl[O-:2].[Na+].[C:4]1([S:10]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CN(C=O)C>[C:4]1([S:10]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:2])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [O-]Cl
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 5 mL sodium hypochlorite and 4-benzenesulfinyl-benzoic acid (0.14 gm, 0.57 mmol) in DMF (5 mL) was stirred at room temperature overnight. A further 5 mL of sodium hypochlorite was then added and the mixture stirred at room temperature overnight. After acidification using 10% HCl, the resulting solid was filtered to afford 105 mg (70% yield) of 4-benzenesulfonyl-benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[CH2:17]1[O:21][C:20]2[CH:22]=[C:23]([CH2:26][C:27](O)=[O:28])[CH:24]=[CH:25][C:19]=2[O:18]1>>[O:18]1[C:19]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[O:28])=[CH:22][C:20]=2[O:21][CH2:17]1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Product: O=C(Cc1ccc2c(c1)OCO2)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 55 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and 3,4-(methylenedioxy) phenylacetic acid in 55% yield. The product was purified by crystallization from acetonitrile. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=371, 1H NMR (MeOH-d4): 3.61 s (2H), 5.82 s (2H), 6.20 s (1H), 6.66 d, 8 Hz (1H), 6.74 dd, 8.1 Hz (1H), 6.76 d, 1 Hz (1H), 7.03 t, 8 Hz (1H), 7.12 t, 8 Hz (1H), 7.25 t, 8 Hz (1H), 7.33–7.36 m (2H), 7.48 d, 8 Hz (1H), 7.52 d, 8 Hz (1H), 7.99 d, 8 Hz (1H).