Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[NH:10][CH3:11].[C:17](OC)(OC)(OC)[CH:18]([CH3:20])[CH3:19]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:17]1[CH:18]([CH3:20])[CH3:19]
Reactant: COC(OC)(OC)C(C)C
Reactant: CNC(Cc1ccccc1N)c1cccs1
Solvent: CC(=O)O
Product: CC(C)C1=Nc2ccccc2CC(c2cccs2)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A stirred solution of 3.45 g of 2-amino-N-methyl-α-(2-thienyl)benzeneethaneamine and 13.34 g of trimethyl orthoisobutyrate was treated rapidly with 3.8 ml of glacial acetic acid. The reaction mixture was refluxed for 8 hours and cooled to room temperature overnight. The mixture was concentrated on a rotary evaporator at 70° C. After standing overnight under refrigeration, the residue was dissolved in 60 ml of 10% hydrochloric acid solution and extracted with diethyl ether (2×50 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×75 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by HPLC (Water's Associates Prep LC/System 500; silica gel; sample applied in dichloromethane; methanol as eluent). Concentration of the appropriate fractions yielded 1.08 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(2-thienyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[C:13]([NH:15][C:16](=[O:25])[C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=1)(O)=[O:2].C([N:28](CC)CC)C.ClC(OCC(C)C)=O.N>ClCCl.CO>[C:1]([C:4]1[CH:14]=[C:13]([NH:15][C:16](=[O:25])[C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=1)(=[O:2])[NH2:28]
Reactant: CCN(CC)CC
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(C(=O)O)cc2c1C
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cc(C(N)=O)cc2c1C
Temperature: -20 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
A solution of 5-carboxy-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (152 mg) and triethylamine (61 mg) in dichloromethane (3 ml) was stirred at -20° C. and to the solution was added isobutyl chloroformate (66 mg). The mixture was stirred at -20° C. for 3 hours and added to cold (-20° C.) solution of 10% ammonia in methanol (3 ml). The reaction mixture was stirred at ambient temperature for 10 minutes and partitioned between dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from ethyl acetate to give 5-carbamoyl-7-(2,6-dichlorobenzoylamino)-2,3-dimethylbenzo[b]furan (70 mg).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCC(=O)NC1CCCc2c(-c3ccc(Cl)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-chlorophenylboronic acid to give the title compound as light yellow foam in 86% yield. MS: 315.5 (M+H+, 1Cl).
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:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:38]([C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]([F:27])=[CH:29][CH:30]=2)=[O:39])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OCC(F)(F)C(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(2,2,3,3-tetrafluoropropyloxy)phenyl)-1-propanol (197 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 (240 mg, 84%).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]#[N:11])[CH2:9][CH2:8]2)[CH:2]=1.[ClH:13].[CH2:14]([OH:16])[CH3:15]>>[ClH:13].[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10](=[NH:11])[O:16][CH2:14][CH3:15])[CH2:8][CH2:9]2)[CH:2]=1
Reactant: Cc1cccc(C2(C#N)CC2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C1(c2cccc(C)c2)CC1
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To 1-(m-tolyl)cyclopropanecarbonitrile (100 mg, 0.64 mmol) was added a saturated solution of hydrogen chloride in ethanol (2 mL). After 16 h at room temperature and 2 h at 70° C. and another 16 h at room temperature, the mixture was concentrated in vacuo and the residue was dried under high vacuum to afford the title compound (147.1 mg, 96.5%) as a colorless solid. MS (ES+) (M+H) 204.1, LCMS retention time: 3.10 minutes (Method L).
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:27]([OH:29])=O)[NH2:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:31]>CN(C=O)C>[C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@@H:25]([C:27]([NH2:31])=[O:29])[NH2:26])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [NH4+]
Reactant: N[C@@H](CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H](N)CCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of compound 2 (1.49 g, 3.71 mmol) in 10 ml DMF was cooled to −78° C. in a pressure tube. Ammonia gas was bubbled though the solution until approximately 1 ml has added. Ammonium hydroxide solution (12 ml, 185.6 mmol, 50+ equivalents) was then added, and the tube allowed to warm to room temperature. The mixture was then sonicated for 20 minutes and heated to 55° C. while stirring. After 24 hours, the solution was golden in color, after which it was removed from the oil bath and cooled to −78° C. for 5 minutes before removing pressure cap. The solution was then allowed to warm to room temperature, and the solvent removed by reduced pressure distillation. The product was purified by flash column chromatography (Silica Gel, 8% methanol/92% CH2Cl2). and isolated as a clear golden oil (0.987 g. Yield: 68%). 1H NMR (CDCl3, 300 MHz) δ1.3-1.6 (m, 4H), 1.76 (m, 2H), 2.13 (t,2H), 3.33 (t, 1H) 7.14-7.52 (m, 15H) 13C NMR (CDCl3) 75 MHz) δ23.8, 30.9, 35.2, 43.6, 55.3, 71.0, 126.3, 127.9, 128.8, 146.4, 178.3; ESI-MS calculated for C25H29N3O 387.52; found 388.4 [M++1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C([O-])([O-])=O.[Na+].[Na+].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH:14]=[CH2:15])=[CH:5][CH:4]=1
Reactant: C=CC(=O)Cl
Reactant: COc1ccc(SCCN)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)NCCSc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 1 (1.83 g) in EtOAc (50 mL) was added acryloyl chloride (1.35 g, 1.5 eq.) and Na2CO3 (2.12 g, 2.0 eq.). The reaction mixture was stirred at r.t. overnight and triethylamine was added. After stirring for 20 min, the mixture was washed with H2O (20 mL), 1N HCl (2×20 mL) and sat. NaHCO3 (2×20 mL). The solvents were removed by evaporation under reduced pressure to give product 32 as white solid (one spot on TLC). Yield: 2.2 g, 92.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:13][NH2:14]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:14][CH3:13])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CN
Reactant: O=C(O)Cc1ccc(O)c(F)c1
Product: CNC(=O)Cc1ccc(O)c(F)c1

Procedure:
was prepared from 3-fluoro-4-hydroxyphenylactic acid and methyl amine following Method A. S1H NMR (300 MHz, CD3OD) δ 7.89 (s, 1H), 6.90 (d, 1H, J=13.37 Hz), 6.82–6.71 (m, 1H), 3.29 (s, 2H), 2.62 (s, 3H). LCMS (ESI+) [M+H]/z Calc'd 184, found 184.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][CH:8]2[CH2:12]OS(=O)(=O)[N:9]2[CH:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([NH:41][CH2:12][CH:8]([NH:9][CH:15]([CH:23]([CH3:25])[CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:7][C:6]1[CH:26]=[CH:27][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(CC2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(CC(CNCc2ccccc2)NC(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
t-Butyl 2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3) oxathiazolidin-3-yl)-3-methylbutyrate (1.0 g; 2.5 mmol) was dissolved in acetonitrile (15 ml). Cs2CO3 (1.63 g; 5 mmol) and benzylamine (0.5 ml; 4.5 mmol) were added, The reaction mixture was stirred at 55° C. for 4 h. It was then allowed to reach RT, and the reaction mixture was filtered through a clarifying layer. The residue was washed with acetonitrile. The filtrate was concentrated and taken up in CH2Cl2 (10 ml). Aqueous H2SO4 (20%; 5 ml) was added, and the mixture was stirred at RT for 1.5 h. The phases were then separated, the aqueous phase was extracted with CH2Cl2 (2×), and the combined organic phases were dried over Na2SO4 and concentrated in a rotary evaporator. The crude product was stirred with CH2Cl2/CH3CN/Et2O and concentrated. t-Butyl 2-(2-benzylamino-1-(4-methoxybenzyl)ethylamino)-3-methylbutyrate (1.15 g; 2.5 mmol) was obtained as a yellowish foam. MS: 427.20 (M+H); Rt: 1.42 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.C[O:20][C:21](=O)/[CH:22]=[C:23](\[NH:25][C:26](=O)[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=1)/[CH3:24]>C(Cl)Cl>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[O:28][CH2:27][C:26]1[N:5]([C:4]2[CH:6]=[CH:7][C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[C:2]([F:1])[CH:3]=2)[C:21](=[O:20])[CH:22]=[C:23]([CH3:24])[N:25]=1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1ccc(F)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2ccc(F)c(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.39 g, 2.00 mmol) in DCM (15 mL) was added trimethylaluminium (3.5 mL, 7.0 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3,4-difluorophenoxy)acetamido)but-2-enoate (0.57 g, 2.00 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred further at rt for 12 h. The mixture was then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale brown solid (0.50 g, 58%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:33](Cl)([CH3:35])=[O:34]>C(Cl)Cl>[C:33]([O:25][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[CH:20][C:21]([F:24])=[CH:22][N:23]=2)[CH2:14][CH2:13]1)(=[O:34])[CH3:35]
Reactant: CC(=O)Cl
Reactant: OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(CCCN1CCN(c2ncc(F)cn2)CC1)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A cold (5° C.) mixture of 1-(4-fluorophenyl)-4-(4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl)-1-butanol monohydrochloride1 (3.0 g, 7.8 mmol) and Et3N (2.38 mL, 17.1 mmol) in CH2Cl2 (55 mL) was treated dropwise (10 min) with AcCl (0.67 mL, 9.4 mmol). The reaction mixture was stirred at 5° C. for 0.25 h and then at 23° C. for 2 h before being diluted with CH2Cl2 (250 mL). The organic solution was washed with water (30 mL), saturated Na2CO3 solution to bring pH to 9, water (20 mL) and brine, dried (MgSO4) and concentrated in vacuo to a solid which was purified on silica gel column using a mixture of 30-40% AcOEt in CH2Cl2. The appropriate fractions were collected and concentrated in vacuo to a white solid, 2.93 g, 96%. Recrystallization from ether-hexane mixture afforded analytical sample, mp 76°-7° C.
Reaction SMILES: C([Mg]Cl)(C)C.Cl[CH2:7][CH2:8][CH2:9][OH:10].[Mg].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[O:19]>O1CCCC1.BrCCBr>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([OH:19])[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: O=Cc1ccccn1
Reactant: OCCCCl
Agent: CC(C)[Mg]Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OCCCC(O)c1ccccn1
Yield: 54.2 %

Procedure:
i-Propyl magnesium chloride (11.6 ml, 2M in tetrahydrofuran) was added dropwise to a solution of 3-chloropropanol (2.1 g) in tetrahydrofuran (20 ml) at 0° C. Magnesium turnings (0.8 g) and 1,2-dibromoethane (1 drop) were added and the mixture was refluxed for 5hand then added at 0° C. to a solution of pyridine-2-carboxaldehyde (1.3 g) in tetrahydrofuran (10 ml). The mixture was quenched with aqueous ammonium chloride and basified to pH 9 with aqueous potassium carbonate. Extraction with ethyl acetate and then extraction of the residual inorganics with methanol, followed by evaporation and purification by chromatography on silica eluting with dichloromethane—2M ammonia gave the sub-title compound as a brown oil (1.1 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH:20]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cccc(-c2ccc(Cl)cc2)c1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc(-c3ccc(Cl)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.9 grams (0.012 mole) of 3-(4-chlorophenyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-(4-chlorophenyl)phenyl]pyridine.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](O)=[O:15].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH2:35])[CH2:27][CH2:26]1.Cl>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH:35][C:14]([C:2]2[CH:1]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)=[O:15])[CH2:29][CH2:30]1
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc3c(c2)Cc2ccccc2-3)CC1
Yield: 61 %

Procedure:
Prepared from 9H-fluorene-2-carboxylic acid and 4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine according to the general procedure. Yield: 61%. Mp. (hydrochloride): 224-226° C. 1H NMR (400 MHz, CDCl3): d 2.68 (s, 4H), 3.09-3.10 (m, 6H), 3.86 (s, 3H), 3.94 (s, 2H), 4.13 (m, 2H), 5.81-5.83 (m, 2H), 6.32 (t, J 5.4, 1H), 6.85 (dd, J 8.2, 1.2, 1H), 6.89-6.96 (m, 2H), 7.00 (m, 1H), 7.35 (td, J 7.3, 1.3, 1H), 7.40 (td, J 7.4, 1.6, 1H), 7.57 (d, J 7.4, 1H), 7.78-7.83 (m, 3H), 7.99 (s, 1H). 13C NMR (101 MHz, CDCl3): d 37.4, 42.0, 51.0, 53.8, 55.8, 60.8, 111.6, 118.7, 120.2, 121.0, 121.4, 123.4, 124.3, 125.7, 126.2, 127.5, 128.1, 129.3, 130.4, 133.1, 141.1, 141.7, 143.9, 144.5, 145.4, 152.7, 168.0. Anal. (C29H31N3O2.3HCl) C, H, N.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13]>>[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH:19][CH2:8][C:7]2[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CC(C)c1ccc(C=O)cc1
Product: CC(C)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Yield: 96.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-isopropylbenzaldehyde (1.5 g) and 4-isopropylaniline (1.4 g) as starting materials, (4-isopropylphenyl)[(4-isopropylphenyl)methyl]amine (2.6 g) was obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH2:3]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:12]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN[C@@H]2CCNC2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CC[C@@H](NCc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 73.8 %

Procedure:
A solution of (R)-benzylpyrrolidin-3-yl-amine dihydrochloride (3.0 g, 12 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (2.6 g, 12 mmol), and triethylamine (6 g, 60 mmol) in tetrahydrofuran (40 ml) was stirred for 12 hours at 95° C. The solvent was evaporated off under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 2-((R)-3-benzylaminopyrrolidin-1-yl)-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (3.2 g, 75%) as pale yellow oil.
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:32]([O:34]CC)=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br.Br[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:1]1([O:11][CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[C:25]([CH3:31])=[N:26][N:27]([CH3:30])[C:28]=4[CH3:29])[CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[C:16]=2[C:32]([OH:34])=[O:33])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1[nH]c2c(-c3c(C)nn(C)c3C)cccc2c1CCCOc1cccc2ccccc12
Reactant: BrCc1cccnc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(C)c1-c1cccc2c(CCCOc3cccc4ccccc34)c(C(=O)O)n(Cc3cccnc3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 580A (90 mg), 3-(bromomethyl)pyridine hydrobromide (47.3 mg) and cesium carbonate (183 mg) in N,N-dimethylformamide (3.5 ml) was stirred at room temperature overnight. The insoluble material was filtered off and the filtrate was concentrated. The residue was suspended in tetrahydrofuran-methanol, and 10% NaOH was added. The resulting mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in a mixture of DMSO and methanol. The solution was purified by reverse phase HPLC (mobile phase: 10%-100% acetonitrile in 0.1% TFA aqueous solution during 60 minutes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=5.22 Hz, 1 H), 8.23-8.28 (m, 1 H), 7.85-7.90 (m, 1 H), 7.80-7.85 (m, 2 H), 7.49-7.57 (m, 3 H), 7.45-7.49 (m, 1 H), 7.38-7.43 (m, 1 H), 7.19 (d, J=7.67 Hz, 1 H), 7.10-7.15 (m, 1 H), 6.92 (t, J=7.67 Hz, 2 H), 5.65 (d, J=17.49 Hz, 1 H), 5.44 (d, J=17.80 Hz, 1 H), 4.26 (t, J=5.98 Hz, 2 H), 3.62 (s, 3 H), 3.35-3.49 (m, 2 H), 2.24-2.32 (m, 2 H), 1.67 (s, 3 H), 1.59 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:39])[CH3:38])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 41 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.6 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.043 ml) and acetyl chloride (0.011 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.3 mg, 41%) as white powder.