Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH:11]3[C:13](=[O:14])[CH:8]([CH2:9][CH2:10]3)[CH2:7][C:6]=2[CH:15]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1C2CCC1Cc1cc(O)ccc1C2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CCC1Cc1cc(OCc3ccccc3)ccc1C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5,6,7,8,9,10-hexahydro-6,9-methanobenzo[a][8]annulen-11-one (15 g; J. Org. Chem 1982, 47, 4329), K2CO3 (20.5 g) and benzyl bromide (10.6 ml) in DMF (100 ml) was stirred for 48 hrs at room temperature. The reaction was diluted with water (500 ml) and extracted with EtOAc (3×150 ml). The combined organic phases were washed with water (2×300 ml), brine (150 ml), dried and concentrated to give a gummy oil which crystallized on standing and after trituration with ether the title benzyl ether (19.5 g, 90%) as a white solid (360 MHz 1H, δ-CDCl3) 1.32 (2H, m), 1.85 (2H, m), 2.57 (2H, m), 2.87 (4H, m), 5.05 (2H, s), 6.82 (2H, m), 7.11 (1H, d, J=8.2), 7.37 (5H, m).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=O)C.[CH:26](=O)[CH2:27][CH2:28][CH3:29].C([BH3-])#N.[Na+].Cl>CN(C)C=O.O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[C:20]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 1.52 g of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 600 ml of dimethylformamide, 40 g of butyraldehyde and 1.60 g of molecular sieves [Na12 (AlSiO4)12. 27 H2O], 36 g of sodium cyanoborohydride are added while stirring under nitrogen and keeping the temperature between about 20° and 30° for 1 hour. After stirring the mixture for 68 hours at room temperature, 6 lt of water are added, followed by 110 ml of concentrated hydrochloric acid and stirring is continued for 1 hour. The precipitate formed is filtered off, washed with water, dissolved in 1.2 lt of 2N aqueous sodium hydroxide and the solution refluxed for 2 hours under nitrogen. After cooling to room temperature it is filtered and the filtrate combined with 250 ml of glacial acetic acid. The precipitate formed is collected, 333 g thereof are dissolved in 2.8 lt of hot, 80% aqueous acetonitrile, the solution filtered, the filter washed with 500 ml more of said acetonitrile and the filtrate diluted with 3.3 lt of hot water. The precipitate formed at 14° is filtered off, taken up in 2.15 lt of hot, 90% aqueous ethanol and the solution diluted with 2.5 lt of hot water. The solids separated after cooling are collected and washed with water, to yield the 4-(4-aminophenylmercapto)-3-n-butylamino-5-sulfamoylbenzoic acid melting at 232°-234°, it is identical with that obtained according to Example 3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=O.CSC.B>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2
Reactant: O=C1NCc2c(Br)cccc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: Brc1cccc2c1CNC2
Temperature: 0 °C

Procedure:
To a solution of 4-bromoisoindolin-1-one (4 mmol) in THF (8 mL) was added borane-dimethyl sulfide complex (2M in THF, 14 mL) at 0° C. The reaction mixture was allowed to stir at reflux overnight and was then cooled to 0° C. The reaction mixture was quenched by the slow addition of MeOH (2 mL) and then 3N HCl. The reaction mixture was allowed to stir at reflux for 3 hr and then concentrated. Water was added to the residue and the pH of the solution was adjusted to >9 with 4N NaOH. The solution was extracted with diethyl ether. The organic solutions from this basic extraction were combined, dried over Na2SO4, filtered and concentrated to give 4-bromoisoindoline, which was dissolved in THF (5 mL). To this solution was added potassium carbonate (4 mmol) in water (0.5 mL), and BOC2O (2 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl 4-bromo-1,3-dihydro-2H-isoindole-2-carboxylate (0.8 mmol, 20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:16])=[O:15])[CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 77.7 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (619 mg, 1.43 mmol, 78%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O>CO.Cl.[Fe]>[NH2:1][C:4]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[C:9]([O:16][CH2:17][C:18]([F:19])([F:20])[F:21])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Temperature: 30 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Iron powder (15.80 g, 283.0 mmol) was added in small portions over 5 min to a stirred suspension of finely grinded 2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzonitrile from step 3 (19.93 g, 63.4 mmol) in MeOH (32 mL) and conc. HCl (40 mL) with water bath cooling keeping the internal temperature at 25–35° C. The resulting mixture was stirred for further 1 h at ca. 30° C. and then poured into ice cold H2O (400 mL). The precipitate was filtered, washed with water, dried, and dissolved in boiling EtOH (400 mL), activated carbon (ca. 10 g) was added, the mixture was refluxed for 45 min, the hot solution was filtered and evaporated to dryness to leave a dark green solid (15.96 g, 84%), which was further purified by silica gel column chromatography with heptane/EtOAc 4:1 to give the title compound as a yellow solid (14.56 g, 81%). MS (ISN) 283 [M−H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH3:28]>CO>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH2:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 48 h

Procedure:
A solution of the product of Example 1 (200 mg) in methanol (10 ml), prepared under argon, was cooled to 4° C.and saturated with dry ammonia gas, then sealed in a pressure bottle and kept for 2 days. The orange crystals which formed, after filtration and washing with a little methanol, gave the title compound, 140 mg: m.p. 247° to 248° C.; NMR (d6DMSO) δ 8.16 (2H, d), 7.99 (2H, d), 7.55 (1H, bs), 7.37 (1H, bs), 7.02 (2H, d), 6.81 (2H, d), 4.54 (2H, s), 3.85 (2H, s), 3.33 (4H, t), 2.60 (4H, t); m/e 355 (M+H)+ ; calculated for C19 H22N4O3 : C, 64.4; H, 6.3; N, 15.8. found: C, 64.4; H, 6.4; N, 15.6%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.Cl.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][NH2:41])=[CH:35][CH:34]=1)[CH3:31].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[NH:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:30]([CH3:31])[CH3:29])=[CH:34][CH:35]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: CN(C)Cc1ccc(CCN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(CN(C)C)cc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a stirred suspension of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.10 g, 0.28 mmol), 2-(4-((dimethylamino)methyl)phenyl)ethanamine dihydrochloride (0.056 g, 0.31 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) in N,N-dimethylformamide (1.4 mL) at ambient temperature was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol). The resulting solution was stirred at ambient temperature for 60 minutes, then partitioned between water (15 mL) and ethyl acetate (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 chloroform/(90/10 methanol/concentrated ammonium hydroxide), to afford methyl 6-cyano-7-(4-(4-((dimethylamino)methyl)phenethylcarbamoyl)phenoxy)chroman-4-carboxylate as a colorless film (0.083 g, 57% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](Cl)=[O:8].[C:10]1([CH3:29])[CH:15]=[CH:14][C:13]([S:16]([NH:19][CH:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>C(Cl)CCl>[Cl:5][CH2:6][C:7]([C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[CH2:28][CH:20]([NH:19][S:16]([C:13]1[CH:12]=[CH:11][C:10]([CH3:29])=[CH:15][CH:14]=1)(=[O:17])=[O:18])[CH2:21]2)=[O:8]
Reactant: Cc1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)NC2Cc3ccc(C(=O)CCl)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.4 g (0.19 mol) of anhydrous aluminium chloride are suspended in 80 ml of ethylene chloride and 11.1 g (0.095 mol) of chloroacetyl chloride are added. 22.8 g (0.079 mol) of 2-p-toluenesulphonamido-indane are then added and the mixture is stirred for 2 hours at room temperature. The product is then decomposed by means of ice and hydrochloric acid and the reaction product is isolated from the organic phase and recrystallised from ethyl acetate/cyclohexane.
Reaction SMILES: Cl.[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N:32]#CBr>C(Cl)(Cl)Cl>[C:2]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]#[N:32])[CH2:21][CH2:20]2)=[N:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CBr
Reactant: CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(c2nn(C(=O)c3ccccc3)c3ccccc23)CC1
Yield: 28.2 %

Procedure:
A sample of 8.4 g of 1-benzoyl-3-(1-methyl-4-piperidinyl)-1H-indazole hydrochloride was converted to its free base and the base was dissolved in 135 ml of chloroform. The solution was stirred and 4.0 g of potassium carbonate was added followed by 2.7 g of cyanogen bromide. The reaction mixture was stirred under reflux for 16 hrs. The mixture was filtered, and the solvent was removed in vacuo. The mixture was chromatographed on a high-pressure column chromatography apparatus (silica gel), eluting with 0.3% methanol/dichloromethane. Evaporation of the appropriate fraction followed by recrystallization from toluene hexane yielded 2.2 g (28%) of the product, mp 144°-146° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:4]3[N:3]=[C:2]([F:1])[C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=3)=[CH:22][CH:21]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)nc1F
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)cc2)nc1F

Procedure:
1.11 g (3.50 mmol) of 2-fluoro-6-(4-hydroxyphenyl)-3-octyloxypyridine, 0.72 g (3.50 mmol) of dicyclohexylcarbodiimide, 0.69 g (3.50 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.02 g of 4-(N,N-dimethylamino)pyridine are stirred in 20 ml of dichloromethane at room temperature for 3 hours. After filtration of the mixture, evaporation of the filtrate to dryness, purification of the residue by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallization from n-hexane, 1.00 g of 4-(2-fluoro-3-octyloxypyridine-6-yl)phenyl trans-4-pentylcyclohexanecarboxylate is obtained. ##STR48##
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=1)=O)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[F:27][C:22]1[CH:21]=[C:20]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][CH2:17]2)[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: COC(=O)[C@@H](CCCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2ccc(F)c(F)c2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (820 mg) in THF (12 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in THF, 7.0 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (850 mg). A solution of 4 N hydrochloric acid in ethyl acetate (25 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(3,4-difluorophenyl)-6-oxohexanoate (2.45 g) in ethyl acetate (25 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (150 mg) was added to a solution of the residue in methanol (30 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for two hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.25 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[CH:6]3)[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCCn1cnc2ccccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc(N2CCN(CCCn3cnc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
1-(3-chloropropyl)-1H-benzimidazole (6.98 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, phenyl piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.1 g compound (I-7) with a yield of 63.2%. ESI-MS [M+H]+: m/z 321.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) in DMF (3 mL) was added CDI (40 mg, 0.244 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (320 μL, 2.03 mmol) was added and reaction mixture was stirred for 30 min and then evaporated. Purification by chromatography (reverse phase HPLC) afforded the title compound (58 mg, 74%) as a white solid. MS: m/e=364.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=1.[C:12]1([C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]2[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:24]([C:22]3[N:21]=[CH:20][N:19]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[OH:25])=[CH:3][C:4]=2[CH2:9][O:8][CH2:7]1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1ccc2c(c1)COCO2
Product: OC(c1ccc2c(c1)COCO2)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 53 %

Procedure:
This compound is prepared like the preceding compound but starting from 6-bromo-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. After decomposing the reaction mixture, the reaction product is extracted with dichloromethane and recrystallized from isopropyl alcohol. By chromatography of the residue obtained after evaporation of the mother liquors, there is obtained a second crop of product. Yield: 53% of theory; M.P.: 165°-167° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([F:16])=[CH:11][CH:10]=3)=[CH:5][N:6]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=1>CC(O)C>[F:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]([C:4]1[O:3][C:2]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:26]=3)=[N:6][CH:5]=1)=[CH:15]2
Reactant: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2cc(F)ccc21
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Nc3cccc(NS(C)(=O)=O)c3)o2)cc2cc(F)ccc21
Temperature: 80 °C
Yield: 24.2 %

Procedure:
A mixture of tert-butyl 2-(2-chlorooxazol-5-yl)-5-fluoro-1H-indole-1-carboxylate 50 (0.314 g, 0.934 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.174 g, 0.934 mmol) in 2-propanol (20 mL) was heated to 80° C. for 18 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide tert-butyl 5-fluoro-2-(2-((3-(methylsulfonamido)phenyl)amino)oxazol-5-yl)-1H-indole-1-carboxylate 52 (0.11 g, 25% yield) as solid. MS (ES) m/z 487 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:6]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)=[N:5]2.C(N(CC)CC)C.[C:33]1([CH3:43])[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:7]2[C:6]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([CH3:43])=[CH:34][CH:35]=4)(=[O:41])=[O:40])[CH:3]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2nc3ccc(N)cc3nc2N2CCN(C)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc3nc(N4CCN(C)CC4)c(N4CCN(C)CC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 6.41 g. (.020 mole) portion of 6-amino-2,3-bis-(4-methyl-1-piperazinyl)quinoxaline (prepared as in Example 1) is dissolved in 200 ml. of chloroform. Then 3.0 ml. (0.021 mole) of triethylamine is added plus 3.81 g. (0.020 mole) of p-toluenesulfonyl chloride. The resulting solution is stirred at room temperature for three hours and is left standing in a sealed flask for 18 hours. It is washed with two 50 ml. portions of distilled water and is dried over anhydrous sodium sulfate and anhydrous calcium sulfate. The solution is stripped of solvent by water pump evacuation to give a yellow solid which is dissolved in 100 ml. of hot benzene and filtered. A 200 ml. portion of cyclohexane is added to the filtrate and the resulting suspension is cooled at 4° C. and then is filtered. The collected solid is dried in vacuo at 78° C. over phosphorous pentoxide, dissolved in 475 ml. of hot acetonitrile and is filtered hot. The filtrate is cooled at -10° C. to recrystallize 3.2 g. of the final product which is collected by filtration, m.p. 234°-237° C.