Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)[OH:4].[C:13]1([S:27](Cl)(=[O:29])=[O:28])[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][CH:14]=1.[OH-:31].[Na+]>O.C(OCC)(=O)C>[C:13]1([S:27]([OH:29])(=[O:4])=[O:28])[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23]([OH:25])(=[O:24])=[O:31])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: [OH-]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 14.5 g of D-glucamine in 120 ml of water was covered with a solution of 11.4 g of naphthalene-1,5-disulfonyl chloride in 300 ml of ethyl acetate. 80 ml of a 1.0N sodium hydroxide solution were added dropwise to the vigorously stirred mixture during 4 hours. After stirring at room temperature for 20 hours the aqueous phase was separated, washed once with 100 ml of ethyl acetate and concentrated at 50° C. on a rotary evaporator. The viscous residue was evaporated azeotropically three times with 50 ml of toluene each time, subsequently taken up in a solution of 300 ml of pyridine and 100 ml of acetic anhydride and heated to reflux for 8 hours. The reaction mixture was again concentrated to dryness and partitioned between water and ethyl acetate. The organic phase was washed with water and sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel in hexane/ethyl acetate as the eluent. 5.6 g of the purified product were dissolved in 100 ml of methanol and treated with 2 mg of sodium. After stirring for 16 hours. the insoluble precipitate was filtered off. This was dried at 50° C. in a high vacuum and gave naphthalene-1,5-disulfonic acid bis-D-glucit-1-ylamide, MS: m/z 615 ([M+H]+); 637 ([M+Na]+).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CO>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:11]2[C:10]3[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=3)[N:4]=[C:3]([CH2:2][N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: C1CNCCN1
Solvent: CO
Product: CCOC(=O)c1c(CN2CCNCC2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 38.7 %

Procedure:
A mixture of ethyl 2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate (1.0 g), piperazine (1.15 g) and methanol (15 ml) was stirred at room temperature for 36 hours. The reaction mixture was concentrated under reduced pressure, and 6N HCl (30 ml) was added to the residue. The resulting mixture was washed with dichloromethane. The aqueous layer was neutralized with 2N NaOH and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The crystals were collected by filtration and recrystallized from dichloromethane-hexane to give ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-piperazinomethylquinoline-3-carboxylate (0.43 g, 39%). Colorless prisms. mp. 192°-193° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([CH2:10][C:11]#[N:12])=[CH:8][CH:7]=1)[CH3:4].[CH2:15]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CO>[CH2:3]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=2)[C:11]#[N:12])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOc1ccc(CC#N)cc1
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCOc1ccc(C=C(C#N)c2ccc(OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 g of KOH were dissolved in 30 ml of methanol whilst being heated. The solution was cooled down to room temperature, after which 3.3 g of p-ethoxybenzylcyanide and 4 g of p-hexyloxybenzaldehyde were added. The mixture was stirred and subsequently stored at room temperature for 1 hour and then at -25° C for 2 hours. The crystallisate was filtered off and subsequently recrystallized from methanol and petroleum ether (60-80). Melting point 53.5°-54° C. Transition point nematic-isotropic 80° C. In a similar way the following compounds were obtained:
Reaction SMILES: C(OC([N:11]1[C@@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[C:22]3[C:27]([CH:28]=[CH:29][C:19]=2[N:18]=1)=[CH:26][C:25]1[C:30]2[C:35]([CH2:36][O:37][C:24]=1[CH:23]=3)=[CH:34][C:33]([C:38]1[NH:42][C:41]([C@@H:43]3[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]3[C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[N:40][CH:39]=1)=[CH:32][CH:31]=2)=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(O)C.[Pd]>[CH3:50][O:49][CH2:48][C@@H:46]1[CH2:45][N:44]([C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[C@H:43]([C:41]2[NH:42][C:38]([C:33]3[CH:34]=[C:35]4[CH2:36][O:37][C:24]5[CH:23]=[C:22]6[C:27]([CH:28]=[CH:29][C:19]7[N:18]=[C:17]([C@@H:12]8[CH2:13][CH2:14][C@H:15]([CH3:16])[NH:11]8)[NH:21][C:20]=76)=[CH:26][C:25]=5[C:30]4=[CH:31][CH:32]=3)=[CH:39][N:40]=2)[CH2:47]1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)OCc7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[(benzyloxy)carbonyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (830 mg, 1.08 mmol) and 100 mg 10% Pd/C in 20 mL ethanol was hydrogenated at latm overnight. Additional 10% Pd/C (300 mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 722 mg. Purification by reverse phase HPLC gave 100 mg purified product.
Reaction SMILES: [N+:1]([CH2:4][C:5](=O)[CH3:6])([O-:3])=[O:2].[NH2:8]/[C:9](/[CH3:15])=[CH:10]\[C:11]([O:13][CH3:14])=[O:12].C(O)(=O)C.[C:20]1([C:26]2[CH:27]=[N:28][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([CH:36]=O)[C:34]=3[CH:35]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH3:6][C:5]1[NH:8][C:9]([CH3:15])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:36]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:34]=2[CH:35]=[C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:27]=[N:28]3)[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1cccc2ncc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
0.9 g (8.75 of nitroacetone, 0.58 g (5 mmol) of methyl 3-aminocrotonate and 0.3 ml (5 mmol) of acetic acid are added to 1.17 g (5 mmol) of 3-phenylquinoline-5-aldehyde in 10 ml of ethanol and the mixture is boiled for 1 hour. It is cooled and concentrated. The evaporation residue is purified by means of a silica gel column using chloroform/methanol mixtures. The clean fractions are concentrated, and the evaporation residue is recrystallized from ethyl acetate. 0.6 g of orange-colored crystals of melting point 262° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1I.[C:14]([Cu])#[N:15]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:14]#[N:15]
Reactant: FC(F)(F)c1cc(Cl)c(I)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(Cl)cc(C(F)(F)F)cc1Br
Temperature: 100 °C

Procedure:
1-bromo-3-chloro-2-iodo-5-(trifluoromethyl)benzene (8.0 g, 20.6 mmol) and CuCN (1.9 g, 20.6 mmol) were dissolved in DMF (20 mL) and heated 100° C. After 2 h the temperature was increased to 110° C. After 3 h the reaction was cooled to room temperature, diluted with DCM, filtered, concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:8]([NH:7][CH:4]1[CH2:3][CH2:2][N:1]([C:16]2[S:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COC(=O)c1cnc(Br)s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)s1
Temperature: 130 °C

Procedure:
tert-Butyl piperidin-4-ylcarbamate (4.5 g, 22 mmol), methyl 2-bromo-1,3-thiazole-5-carboxylate (5.0 g, 22 mmol), and diisopropylethylamine (3.8 ml, 22 mmol) were suspended in anhydrous DMF and heated to an external temperature of 130° C. for 1.5 hours. The DMF was removed and the solid was partitioned with EtOAc and water. The combined organic extracts were washed with brine, dried with MgSO4 and concentrated to a yellow solid (7.05 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Yield: 78.3 %

Procedure:
Add, at 0° C., 1 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde, then 0.27 g of sodium hydride to 10 cm3 of anhydrous tetrahydrofuran. Stir the reaction mixture for fifteen minutes at 0° C. before adding 1.87 g of tosyl chloride in solution in 1.7 cm3 of tetrahydrofuran. Continue stirring the reaction mixture for two hours, allowing it to return to room temperature. Pour the reaction mixture into 100 cm3 of iced water. Extract the mixture obtained with two times 100 cm3 of ethyl acetate. Dry the organic phases over magnesium sulphate and then evaporate to dryness under vacuum in a rotary evaporator. 1.32 g of 5-bromo-1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde is obtained in the form of a beige powder with the following physical characteristics:
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:14][C:11]1([CH3:15])[CH2:10][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([S:2]([NH:1][C:18](=[O:19])[CH:17]([Br:16])[CH3:21])(=[O:4])=[O:3])[C:13]=2[O:12]1
Reactant: CC(Br)C(=O)Cl
Reactant: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Product: CC(Br)C(=O)NS(=O)(=O)c1cccc2c1OC(C)(C)C2
Temperature: 25 °C

Procedure:
A stirred slurry of 0.39 gram (0.0017 mole) of 7-aminosulfonyl-2,3-dihydro-2,2-dimethylbenzofuran and 1 ml of 2-bromopropionyl chloride was heated at 96° for 35 minutes, then at reflux for 30 minutes. The reaction mixture was cooled to ambient temperature and washed repeatedly with petroleum ether to remove excess acid chloride. The residue was 0.53 gram of N-(2,3-dihydro-2,2-dimethylbenzofuran-7-yl)sulfonyl-2-bromopropionamide; m.p. 224°-226° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Zn]>[C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(SCCc3ccccc3)cc2)S1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(SCCc3ccccc3)cc2)S1
Yield: 16.3 %

Procedure:
Title product of Example 5 (4.1 mmol, 1.4 g) and zinc dust (40 mmol, 2.6 g) were heated to reflux in acetic acid (50 ml) for 15 minutes. The reaction mixture was filtered and the solvent was removed in vauco. The residue was purified on silica gel using hexane:ethyl acetate (2:1) plus 5% acetic acid as eluant to afford 230 mg of present title product; m.p. 58°-65° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(Cl)(=O)OC(Cl)(Cl)Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[NH:23][NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N:23]1[N:24]=[C:25]([C:26]([CH3:27])([CH3:29])[CH3:28])[O:30][C:1]1=[O:2]
Reactant: CC(C)(C)C(=O)NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)Cl
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)o1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A toluene solution of phosgene prepared by adding active carbon and toluene (500 ml) to trichloromethyl chlorocarbonate (82.5 g) was added to 1-(2-chloro-5-nitrophenyl) -2-(2,2-dimethylpropionyl)hydrazine (42.23 g), and the resultant mixture was heated under reflux for 2 hours. Active carbon was further added thereto, and heating under reflux was continued for 15 hours. After removal of active carbon by filtration, the filtrate was concentrated. To the concentrated solution, a solution of triethylamine (23.54 g) in toluene (155 ml) was added, and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was combined with water. The toluene layer was separated, washed with water, dried and concentrated under reduced pressure to give 3-(2-chloro-5-nitrophenyl)-5-(1,1-dimethylethyl) -1,3,4-oxadiazol-2(3H)-one (47.51 g). m.p., 130.4° C..
Reaction SMILES: S(O[CH:12]1[CH2:16][CH2:15][O:14][CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:39]3[C:38]([NH2:40])=[N:37][CH:36]=[N:35][C:34]=3[NH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:39]3[C:38]([NH2:40])=[N:37][CH:36]=[N:35][C:34]=3[N:33]([CH:12]3[CH2:16][CH2:15][O:14][CH2:13]3)[CH:32]=2)=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(OCc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCOC1

Procedure:
In a similar manner to Example 2, 3-tosyloxytetrahydrofuran (1.84 g) was reacted with 5-(4-benzyloxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (2.9 g) using sodium hydride (0.30 g, of a 60% dispersion in mineral oil) and dimethylformamide (40 ml) except that the mixture was heated for 4.5 hours at 90° C. to give 5-(4-benzyloxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine as a solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]C)#[N:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+].[Cl:34]CCl>>[ClH:34].[C:1]([CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:7][C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])#[N:2]
Reactant: ClCCl
Reactant: COc1ccccc1-c1nc(-c2ccc(F)cc2)[nH]c1CCC#N
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Cl
Product: N#CCCc1[nH]c(-c2ccc(F)cc2)nc1-c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-cyanoethyl)-2-(4-fluorophenyl)-4-(2-methoxyphenyl)imidazole (40 mg) in dichloromethane (10 ml) was added dropwise boron tribromide (94 mg) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise a saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and then, the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative TLC (solvent: hexane:ethyl acetate=1:1), and further purified by NH silica gel column chromatography (solvent: hexane:ethyl acetate=1:1). To the product was added hydrogen chloride-ethanol solution and the mixture was concentrated to obtain 5-(2-cyanoethyl)-2-(4-fluorophenyl)-4-(2-hydroxyphenyl)-imidazole hydrochloride (6 mg) as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[CH:7]2.O=P(Cl)(Cl)[Cl:25].[Cl-].C([NH+](CC)CC)C>C(#N)C>[Cl:25][C:9]1[C:8]([CH3:13])=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:10]=1
Reactant: Cc1cc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Cc1cc2c(OCCN3CCCCC3)ccc(Cl)c2nc1Cl
Temperature: 120 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
8-chloro-3-methyl-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (160 mg, 0.5 mmol, 1 eq.) was placed in acetonitrile (1.2 mL) in the presence of POCl3 (233 μL, 2.5 mmol, 5 eq.) and triethylammonium chloride (570 mg, 2.5 mmol, 5 eq.). The reaction mixture was stirred at 120° C. during 3 hours. The mixture was then concentrated under reduced pressure and, after adding water to the residue (5 mL), was stirred at room temperature during 30 minutes. Then the resulting precipitate was washed with water and filtered to give 2,8-dichloro-3-methyl-5-(2-(piperidin-1-yl)ethoxy)quinoline (170 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[O:12][C:11]2=[O:21])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]1.CN1CC[O:36][CH2:35]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>ClCCl>[F:20][C:16]1[C:17]([F:19])=[CH:18][C:13]2[O:12][C:11](=[O:21])[N:10]([CH:8]([C:4]3[CH:3]=[C:2]([NH:1][C:35](=[O:36])[O:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)[CH:7]=[CH:6][CH:5]=3)[CH3:9])[C:14]=2[CH:15]=1
Reactant: CN1CCOCC1
Reactant: CC(c1cccc(N)c1)n1c(=O)oc2cc(F)c(F)cc21
Reactant: CN1CCN(CCO)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(c1cccc(NC(=O)OCCN2CCN(C)CC2)c1)n1c(=O)oc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
250 mg (0.86 mmol) of 3-[1-(3-aminophenyl)ethyl]-5,6-difluoro-3H-benzoxazol-2-one, 137 mg (0.95 mmol) of 2-(4-methylpiperazin-1-yl)ethanol and 200 μl (1.81 mmol) of N-methylmorpholine are suspended in 10 ml of dichloromethane, the mixture is stirred at room temperature for 10 min, and 128 mg (0.43 mmol) of bis(trichloromethyl) carbonate are added. The reaction mixture is stirred at room temperature for 16 h. The mixture is subsequently diluted with 30 ml of dichloromethane, washed with 2×20 ml of saturated sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography on silica gel, dissolved in acetone, warmed with HCl in ether and, when crystallisation is complete, filtered off with suction and dried. Product (“A27”): 95 mg, product is in the form of the hydrochloride;
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:7])#[N:3].[N:16]([O-])=O.[Na+]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:7][NH2:16])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])#[N:3]
Reactant: O=N[O-]
Reactant: CC(C)COc1ccc(N)cc1C#N
Agent: Cl
Agent: [Na+]
Product: CC(C)COc1ccc(NN)cc1C#N
Yield: 82.8 %

Procedure:
To an aqueous solution (34 ml) of 3-cyano-4-isobutoxyaniline hydrochloride (20 g) were added sodium nitrite (6.8 g), stannous chloride dihydrate (61 g) and con. hydrochloric add (100 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration. The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 15 g of 3-cyano-4-isobutoxy-phenylhydrazine.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]2[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=2[CH3:19])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Reactant: OB(O)c1ccccc1Cl
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2Cl)cc1

Procedure:
Compound (99) was prepared from compound (20) and (2-chlorophenyl)-boronic acid by adapting the procedure of Example 5(b). LC/MS System B; Rt=1.86 mins, m/z (ES−)=341 and 343 (M−H for C19H15ClO4).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].Cl.[NH2:31][CH:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][CH2:35]2.C(N(CC)CC)C>CN(C=O)C>[CH:33]12[CH2:38][CH:36]([CH2:35][CH2:34]1)[CH2:37][CH:32]2[NH:31][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NC1CC2CCC1C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccc(NC2CC3CCC2C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of Example 1D (50 mg, 0.12 mmol), 2-aminonorbornane hydrochloride (106 mg, 0.58 mmol), and triethylamine (0.08 ml, 0.58 mmol) in DMF (2 mL) were heated to 120° C. in a sealed vial with shaking for 16 hours, then concentrated. The concentrate was dissolved in 1:1/DMSO:methanol (1.0 ml) and purified by reverse phase preparative HPLC with 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 510 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ12.45 (br s, 1H), 8.67 (d, 1H), 8.48 (d, 1H), 7.99 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H), 7.32 (t, 2H), 7.24 (d, 1H), 4.04 (m, 1H), 2.58 (m, 1H), 2.27 (m, 1H), 2.24-2.21 (m, 1H), 1.59-1.29 (m, 6H), 0.97 (dt, 1H).