Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2].[S:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)(=[O:22])(=[O:21])[NH2:20]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2]
Reactant: CCOc1cc([C@@H]2CCCC[C@@H]2N)ccc1OC
Reactant: NS(=O)(=O)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc([C@H]2CCCC[C@H]2NC(=O)c2ccc(S(N)(=O)=O)cc2)ccc1OC
Reaction time: 8 h
Yield: 23.1 %

Procedure:
3.0 g of (+/-)-cis-2-ethoxy-1-methoxy-4-(2-aminocyclohexyl)benzene (compound B1) are dissolved in 40 ml of methylene chloride and 10 ml of triethylamine. A solution of 3.3 g of p-sulfamoylbenzoyl chloride in 60 ml of methylene chloride is added dropwise at RT, the mixture is extracted after stirring overnight with 100 ml each of water, 2N hydrochloric acid, saturated sodium hydrogencarbonate solution and water again. The organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of ethyl acetate/petroleum ether/methanol in the ratio 6/3/1. After concentration of the product fractions, 1.2 g of the title compound of m.p. 129-133° C. are obtained.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].BrBr.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O.O1CCOCC1>[OH:16][C:10]1[CH:15]=[CH:14][C:13]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: BrBr
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 61 %

Procedure:
A mixture of 4.00 g (40 mmol) of hydantoin, 6.4 g (40 mmol) of bromine, 0.01 g of methanesulfonic acid, and 30 ml of dioxane was heated to a temperature of 100° C. with stirring for 3 minutes. The reaction mixture was further stirred at a temperature of 50° C. until bromine disappeared. To the reaction mixture was then added 7.52 g (80 mmol) of phenol. The reaction mixture was then heated to a temperature of 50° C. with stirring for 4 hours. The reaction mixture was then allowed to cool to room temperature. The reaction mixture was further cooled over an ice bath for 2 hours. The resulting crystal was recovered by filtration, washed thoroughly with water, and then air-dried to obtain 4.69 g (24.4 mmol; yield: 61%) of 5-(p-hydroxyphenyl)-hydantoin in the form of white crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[OH:22])=[O:12])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[I-].[K+]>CN(C)C=O.[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[C:7]([CH3:9])([NH:10][C:11]([C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[O:22][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:12])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1OCCOc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
60 mg 2-[(4-Hydroxy-benzo[b]thiophene-5-carbonyl)-amino]-2-methyl-propionic acid tert-butyl ester, 70 mg cesium carbonate, 36 mg of (2-bromo-ethoxy)-benzene and 6 mg potassium iodide were dissolved in 1 ml of N,N-dimethylformamide and stirred for 2 h at 60° C. 10 ml of ethyl acetate and 10 ml of brine were added to the reaction. The organic layer was separated and washed again with 10 ml of brine. It was then dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting residue was purified by reversed phase HPLC (acetonitrile/water) to afford 58 mg of 2-methyl-2-{[4-(2-phenoxy-ethoxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][CH2:30][CH2:31][CH2:32][N:33]1C(=O)C2C(=CC=CC=2)C1=O)[CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[N:21][C:20]1=2)=O)(C)(C)C.O.NN>C(O)C>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[CH:23][CH:22]=[N:21][C:20]1=2)[CH2:29][CH2:30][CH2:31][CH2:32][NH2:33]
Reactant: CC(C)(C)OC(=O)n1c(CN(CCCCN2C(=O)c3ccccc3C2=O)C2CCCc3nccnc32)nc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2nccnc21
Reaction time: 17 h
Yield: 63.5 %

Procedure:
To a solution of 2-{[[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydroquinoxalin-5-yl)-amino]-methyl}-benzoimidazole-1-carboxylic acid tert-butyl ester (420 mg, 0.723 mmol) in ethanol (20 mL) at room temperature was added hydrazine hydrate (0.20 mL). The mixture was stirred for 17 hours. The mixture was concentrated in vaccuo and the resultant material was purified by column chromatography on silica gel (1:1:10 MeOH:NH4OH:CH2Cl2) to provide COMPOUND 105 as a colourless foam (161 mg, 64%): 1H NMR (CDCl3) δ 1.37-1.48 (m, 5H), 1.70-1.79 (m, 1H), 1.81-1.97 (m, 1H), 2.07-2.16 (m, 1H), 2.18-2.31 (m, 1H), 2.49-2.59 (m, 4H), 2.71-2.78 (m, 1H), 2.90-3.08 (m, 2H), 3.98 (d, 1H, J=16.5 Hz), 4.07 (d, 1H, J=16.5 Hz), 4.06-4.12 (m, 1H), 7.18-7.21 (m, 2H), 7.57-7.59 (m, 2H), 8.41 (s, 1H), 8.54 (s, 1H); 13C NMR (CDCl3) δ 21.2, 22.9, 26.3, 30.5, 32.6, 41.7, 49.8, 51.4, 62.0, 122.3, 142.1, 143.3, 153.8, 155.4, 155.5; ES-MS m/z 351 (M+H). Anal. Calcd. for C20H26N6.0.3CH2Cl2.0.2H2O: C, 64.24; H, 7.17; N, 22.14. Found: C, 64.16; H, 7.41; N, 22.15.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:24]([Cl:25])=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=3[Cl:26])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2].[NH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O>[C:1]([NH:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:13]([C:14]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:20]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[O:22])=[CH:23][C:24]=3[Cl:25])=[O:15])=[CH:12][NH:11][C:10]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)O)cc3Cl)c[nH]c12
Reactant: NCCOCCO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C(=O)NCCOCCO)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichlorobenzoic acid (0.1 g, 0.25 mmol) was taken in a reaction vial. To it 2-(2-aminoethoxyl)ethanol (0.029 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.073 g, 3.8 mmol), 1-hydroxybenzotriazole (0.051 g, 3.8 mmol) and dimethylformamide (2 mL) were added. The whole reaction mixture was stirred at room temperature for overnight. Water (20 mL) was added to the reaction mixture, extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude mass which was purified by flash column chromatography to get 4-{[7-(acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-[2-(2-hydroxyethoxyl)ethyl]benzamide (0.035 g, 29%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1.O.COC(C)(C)C.[CH3:33][N:34](C)C=O>[C-]#N.C([N+](CC)(CC)CC)C>[C:33]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[N:5]2[N:23]=[CH:24][N:25]=[C:4]2[N:3]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(Cl)nc3ncnn23)CC1
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: COC(C)(C)C
Product: CC1CCN(c2c(-c3ccc(F)cc3Cl)c(C#N)nc3ncnn23)CC1
Temperature: 22.5 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-6-(2-chloro-4-fluorophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo-[1,5-a]-pyrimidine (0.1 mol) and tetraethylammonium cyanide (0.25 mol) in 750 ml Dimethylformamide (DMF) was stirred for 16 hours at 20 to 25° C. To this mixture was added water and methyl-tert. butylether (MTBE), the organic phase was separated, washed with water, dried and filtered. The filtrate was evaporated and the residue was purified by column chromatography to yield 5.91 g of the title compound of mp. 247° C.
Reaction SMILES: [CH2:1]([C:4]1([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:26])C=C1>CN(C=O)C.O.[Pd](Cl)Cl>[CH2:16]([C:4]1([CH2:1][C:2](=[O:26])[CH3:3])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15])[CH2:17][CH2:18][CH3:19]
Reactant: C=CCC1(CCCC)Cc2cc(OC)ccc2C1=O
Reactant: O=C1C=CC(=O)C=C1
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC(C)=O)Cc2cc(OC)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.83 h

Procedure:
A solution of 2-allyl-2-butyl-5-methoxy-1-indanone (253 mg, 0.98 mmol) in DMF (1.2 mL) was treated with benzoquinone (108 mg, 0.98 mmol), water (0.026 mL, 1.44 mmol), and palladium(II) chloride (36 mg, 0.2 mmol). The mixture was stirred and heated in an oil bath at 65° C. Additional water was added in 0.026 mL portions after 15, 45, and 130 minutes. After 230 minutes, the mixture was treated with more benzoquinone (10.9 mg, 0.1 mmol) and, after 285 minutes, with more water (0.026 mL). After heating at 65° C. for a total of 345 minutes, the mixture was diluted with water (50 ml) and extracted with Et2O (40 mL) followed by CH2Cl2 (2×50 mL). The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 12M (12 mm×15 cm) silica gel column, eluting with 10:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-5-methoxy-(2-oxopropyl)-1-indanone as an oil.
Reaction SMILES: [F:1][CH:2]([CH2:26][CH2:27][C@H:28]([N:31]([CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:7][C:8]([O:10][CH3:11])=[O:9]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[NH2:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:31]([CH2:44][CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:28]([CH2:29][OH:30])[CH2:27][CH2:26][CH:2]([F:1])[CH2:3][NH:4][C:5](=[O:25])[C@H:6]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:7][C:8]([O:10][CH3:11])=[O:9])(=[O:33])=[O:34])=[CH:40][CH:39]=1
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 70.3 %

Procedure:
A solution of the material from Step 14 (45 mg, 0.065 mmol) in (1:1) in ethyl acetate-ethanol (1 mL) was degassed with nitrogen, then 20% palladium hydroxide on carbon (4.6 mg, 0.007 mmol) was added. The reaction mixture was stirred under hydrogen (1 atm) for 3 hours. The reaction mixture was filtered through celite and washed with dichloromethane to afford 30 mg of the title compound. 1H NMR (DMSO-d6): δ 8.17 (d, J=6.98 Hz, 1H), 7.46-7.38 (m, 3H), 7.35-7.22 (m, 6H), 7.23-7.10 (m, 4H), 6.60 (dd, J=8.50, 3.17 Hz, 2H), 5.94 (s, 2H), 5.03-4.94 (m, 1H), 4.71-4.64 (m, 1H), 4.26 (d, J=11.45 Hz, 1H), 3.94-3.66 (m, 1H), 3.55-3.39 (m, 1H), 3.42 (s, 3H), 3.29-3.22 (m, 2H), 3.13-2.77 (m, 4H), 1.67-1.01 (m, 7H), 0.84 (dd, J=6.31, 3.38 Hz, 6H). The mixture of diastereomers was separated by SFC (AD-H, 4.6×250 mm, 30% i-PrOH in CO2, 2.4 mL/min, 100 bar, 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([Cl:22])=[O:12])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CC(C(=O)O)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CC(C(=O)Cl)c2ccccc2)cc1

Procedure:
3-(4-Methoxyphenyl)-2-phenylpropanoic acid (12.5 g, 0.049 mol) was converted to its acid chloride by treatment with thionyl chloride (8.2 ml) in dry dichloromethane (75 ml) at 40° C. Excess thionyl chloride and dichloromethane were evaporated off. The crude product was used in the next step without purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:36](O)=[O:37])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:36]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]([F:25])=[CH:27][CH:28]=2)=[O:37])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1-propanol (181 mg, 0.53 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (100 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg, 0.79 mmol) and 1-hydroxy-1H-benzotriazole (81 mg, 0.53 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (206 mg, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:27]>CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)=[N:7][C:8]=1[CH:9]=[O:27])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1Nc1cccc(C(F)(F)F)c1
Reactant: O=[Se]=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1Nc1cccc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
69.8 g of 5-cyano-6-methyl-2-[[3-(trifluormethyl)phenyl]amino]-3-pyridine-carboxylic acid, ethyl ester (0.2 mol) are dissolved in 400 ml of diethyleneglycoldimethyl ether. After addition of 24.2 g of selenium dioxide, the mixture is heated at 160° with stirring for 2 hrs. The selenium is filtered off and the filtrate evaporated. The resulting yellow title compound is recrystallized from butanol. Yield 56 g (77%); m.p. 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Clc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccc(Cl)cc4)c[nH]3)C2)n1
Yield: 46.1 %

Procedure:
A solution of 2-[4-(4-chlorophenyl)-1H-imidazol-2-yl]morpholine (322 mg, 1.22 mmol), 4,6-dichloro-2-pyrimidinamine (200 mg, 1.220 mmol) and Hunig's base (531 μL, 3.05 mmol) in ethanol (6.1 mL) was heated at 85° C. overnight. The mixture was evaporated and chromatographed (PE-EtOAc, 2:3) to afford the title compound (220 mg). LC-MS (ES) m/z=391 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[CH:44]1([C:42]([NH:41][C:39]2[N:40]=[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:30]4[CH:29]=[C:28]([NH:27][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([N:3]6[CH2:4][CH2:5][CH2:6][C:2]6=[O:1])[CH:8]=5)[CH:49]=[CH:48][CH:47]=4)=[N:37][N:36]3[CH:38]=2)=[O:43])[CH2:45][CH2:46]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(N2CCCC2=O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(N2CCCC2=O)c1
Yield: 69.9 %

Procedure:
Using 3-(2-oxopyrrolidin-1-yl)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 70%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](O)=[O:18])=[C:11]([Cl:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[C:11]([Cl:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of 3-[4-(benzyloxy)-2-chlorophenyl]propanoic acid (1.00 g) in tetrahydrofuran (20.0 mL) was added 1,1′-carbonyldiimidazole (1.11 g), followed by stirring at room temperature for 2 hours. Subsequently, sodium borohydride (520 mg) and water (4.00 mL) were added thereto, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3-[4-(benzyloxy)-2-chlorophenyl]propan-1-ol (861 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH2:15]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[N:37][NH:36][C:35]3=[O:39])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:36]1[C:35](=[O:39])[N:34]([C:31]2[CH:30]=[CH:29][C:28]([N:25]3[CH2:24][CH2:23][N:22]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:27][CH2:26]3)=[CH:33][CH:32]=2)[CH:38]=[N:37]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ncn1-c1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Product: C[C@@H](n1ncn(-c2ccc(N3CCN(Cc4ccccc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 19 %

Procedure:
In the same manner as in Reference Example 5, starting from 681 mg of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.0 g of 4-[4-(4-benzyl-1-piperazinyl)phenyl]-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(4-benzyl-1-piperazinyl)phenyl]-3(2H,4H)-1,2,4-triazolone (293 mg) was obtained as a colorless powder.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:33]([CH:34]=1)[C:16]1[N:17]([C:26]3[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=3)[C:18](=[O:25])[C:19]3[C:24]([C:15]=1[N:14]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3>CN(C=O)C>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([N:17]2[C:16]3[N:33]4[CH:34]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:11]=[CH:12][C:13]4=[N:14][C:15]=3[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:25])=[CH:31][CH:30]=1
Reactant: Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc2nc3c4ccccc4c(=O)n(-c4ccc(Cl)nc4)c3n2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (10.0 equiv., 1.935 mmol, 0.231 g) was added to a suspension of compound 53 (1.0 equiv., 0.193 mmol, 0.070 g) in DMF (3 ml). The reaction mixture was stirred overnight at 110° C. The solvent was evaporated under reduced pressure. Isopropyl ether was added and the mixture was brought on a filter and washed with isopropyl ether to give 6-(6-chloro-pyridin-3-yl)-9-[[(dimethylamino)-methylene]amino]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (84) (0.050 g, yield=62%, purity (LC)=77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[C:15]1([NH2:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:25][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: Nc1cccc2ccccc12
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc2ccccc12

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 1-naphthaleneamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[N:20]=3)=[CH:13][CH:12]=2)=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1>[CH3:33][CH:32]([CH3:34])[CH2:31][CH2:30][NH:29][C:21]1[N:20]=[C:19]([NH:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: COC(=O)c1ccccc1-c1ccc(CNc2nc(NCCC(C)C)nc3ccccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CCNc1nc(NCc2ccc(-c3ccccc3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 10 mL of dioxane was added 0.159 g of 4'-[[[2-[(3-methylbutyl)amino]-4-quinazolinyl]amino]methyl][1,1'-biphenyl]-2-carboxylic acid methyl ester and 2 mL of 0.5N aqueous sodium hydroxide. The resulting solution was stirred at room temperature for 72 hours. All solvents were moved and the residue was neutralized with 0.1N hydrochloric acid. The resulting precipitate was collected, washed with water and dried. (0.14 g, 93%) (M.P.=195°-205° C., decomp): 1H NMR (DMSO-d6, 300 MHz) δ 8.43 (bs, 1H), 8.03 (m, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.45 (m, 5H), 7.21 (m, 3H), 7.01 (m, 1H), 6.50 (bs, 1H), 4.78 (d, 2H), 3.50 (m, 2H), 1.60 (m, 1H), 1.40 (m, 2H), 0.85 (d, 6H); negative FAB MS m/e 439 (M-H). Anal. Calcd for C27H28N4O2.1/2 HCl: C, 70.69; N, 12.53. Found: C, 70.77; H, 6.20; N, 12.53.