Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C([Li])(C)(C)C.C(=O)=O.CC(C)=O.[N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[N:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>O1CCCC1.C1CCCCC1>[CH2:11]([CH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:25]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:10]=2)[CH2:6][CH2:7]1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CCC1CCc2ccc(Br)cc21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCC1CCc2ccc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Upon cooling by a dry ice-acetone bath, a solution of 6-bromo-1-ethyl-indan 41b (2.52 g, 11.2 mmol) in 15 mL of tetrahydrofuran was added dropwise to a solution of t-butyllithium in cyclohexane (18.1 mL, 1.3 N) under argon atmosphere. Upon completion of the addition, the mixture was stirred for 2 hours in the dry ice-acetone bath. A solution of di-tert-butyl azodicarboxylate in 15 mL of tetrahydrofuran was added dropwise to the above mixture at the same temperature. Upon completion of the addition, the reaction mixture was stirred for another 1.5 hours in the dry ice-acetone bath. Then the dry ice-ethanol bath was removed. The mixture was warmed up to room temperature and stirred for 18 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched by addition of 25 mL of saturated ammonium chloride. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3-ethyl-2,3-dihydro-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 41c (3.43 g, 81.5%) as a brown oil.
Reaction SMILES: C(OC([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1nc2ccc(OS(=O)(=O)c3cccs3)cc2s1
Yield: 79.4 %

Procedure:
A solution of thiophene-2-sulfonic acid 2-tert-butoxycarbonylaminobenzo-thiazol-6-yl ester (intermediate 30) (1.5 g, 3.63 mmol) and trifluoroacetic acid (15 ml, 196 mmol) in 15 ml of dichloromethane and 600 μl of water is stirred for 2 hours at room temperature. The reaction medium is concentrated to dryness to give 900 mg of thiophene-2-sulfonic acid 2-aminobenzothiazol-6-yl ester in the form of the trifluoroacetic acid salt (oil) in a yield of 76%.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[C:39]([NH2:43])[CH:40]=[CH:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:26])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cccc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.95 g, 1.9 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (0.34 g, 1.1 mmol), Na2CO3 (2 M, 4.6 mL), and Pd(PPh3)2Cl2 (226 mg, 0.1 mmol) in toluene/ethanol (1:1, 16 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 3-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-phenylamine as brown solid in 67% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=O)CCC1=O.C(OCC)(=O)C.ClCCl>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[N:14]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)C1COC(c2ccc([N+](=O)[O-])cc2)=N1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1coc(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
α,α-Bisisobutyronitrile (66 mg, 0.4 mmol) was added to a solution of methyl 2-(4-nitrophenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate (described in Kline, Toni; Andersen, Niels H.; Harwood, Eric A.; Bowman, Jason; Malanda, Andre; Endsley, Stephanie; Erwin, Alice L.; Doyle, Michael; Fong, Susan; Harris, Alex L.; Mendelsohn, Brian; et al., J. Med. Chem., 45, 14, 2002, 3112-3129, 1.95 g, 7.8 mmol) in benzene (30 mL). The mixture was heated to 80° C. and N-bromosuccinimide (1.53 g, 8.58 mmol) was added. The mixture was stirred at the same temperature for 1.5 hours and then ethyl acetate and dichloromethane were added, followed by sequentially washing with water and brine. This was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: chloroform/methanol=100/0, 20/1, 10/1) to obtain 1.29 g of the title compound as a colorless solid (67%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:21])[C:9]([C:22]([O:24]CC)=[O:23])=[CH:8]1)(=O)C.Cl>C(O)(=O)C>[OH:4][CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[C:12]([CH3:20])[C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]1
Reactant: CCOC(=O)c1cn(CCOC(C)=O)c2c(F)c(F)c(F)c(C)c2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2CCO
Yield: 85.9 %

Procedure:
Employing ethyl 1-(2-acetyloxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3-carboxylate (5.80 g) and conc. hydrochloric acid: 90% acetic acid (1:4) (100 ml), the procedure of Reference Example 23 is repeated to give 1-(2-hydroxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3-carboxylic acid (4.04 g), as pale yellow flakes (recrystallized from ethanol), m.p. 244.5°-247° C.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[O:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([C:19]2[O:20][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:22][C:23]=2[CH3:24])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC(c2oc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methanol (271 mg) obtained by the above-mentioned reaction and methyl 4-hydroxybenzoate (146 mg) in tetrahydrofuran (20 mL) were added tributylphosphine (0.4 mL) and 1,1′-(azodicarbonyl)dipiperidine (404 mg), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methoxy)benzoate as an oil. The obtained methyl 4-(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methoxy)benzoate was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL). 2N Lithium hydroxide (1.0 mL) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (138 mg, 39%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
440 mg (1.5 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 15 ml CH2Cl2 were treated with 0.15 ml (1.8 mmol) methane sulfonyl chloride and 0.63 ml (4.5 mmol) triethyl amine at 0° C. for 10 min. The solution was stirred at RT for 2 h and was diluted with CH2Cl2. The organic phase was extracted with 1M HCl and water, and dried over Na2SO4. Evaporation yielded 400 mg (71%) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as light yellow viscous oil, MS: 372 (MH+).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6]1.[C:16]([NH:20][C:21](=[O:30])[CH:22](Cl)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+].[Na+].[I-].[OH-].[Na+]>C1S(=O)(=O)CCC1.O>[C:16]([NH:20][C:21](=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:6]1[CH2:7][CH2:8][C:9](=[O:10])[N:5]1[CH2:4][CH2:3][CH:2]([OH:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCCCC(O)CCN1NCCC1=O
Reactant: CC(C)(C)NC(=O)C(Cl)CCCCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CCCCCC(O)CCN1C(=O)CCN1CCCCCCC(=O)NC(C)(C)C

Procedure:
The 2(3-hydroxy-n-octyl)-3-pyrazolidinone (6) used in this and subsequent examples is prepared according to the General Synthetic Scheme (Ic) shown above and described in more detail in U.S. Pat. No. 3,873,566. A mixture of 3.85 g (18 mmoles) of pyrazolidinone alcohol 6 and 4.90 g (about 18 mmoles) of the N(tert-butyl)-7-bromo(chloro)heptanamide (Example 1a), 5.0g NaHCO3, and 0.25 g NaI in 25 ml of tetramethylene sulfone was heated at 70° for about 56 hrs. The mixture was cooled, poured into 300 ml of H2O and 5% NaOH was added to adjust the pH to 9. The mixture was extracted with ether twice. The combined ether extracts were washed with water and with saturated NaCl solution and dried over anhy. Na2SO4. The dry solution was filtered and treated with HCl gas until no more of the hydrochloride salt (8) separated (as a oil). The oil 8 was run into a separatory funnel, mixed with 50 ml of 5% Na2CO3 solution and extracted into ether. Evaporation of the ether after drying over Na2SO4 gave 3.01 g of N(tert-butyl)7[3-oxo-2(3-hydroxy-n-octyl)pyrazolidin-1-yl]heptanamide 7 which, according to TLC on silica gel (2:1 acetone-toluene; iodine; Rf 0.37) was about 95% pure. The pmr spectrum (CDCl3, TMS) agreed with the assigned structure (tert-butyl 1.33 ppm), as did the IR spectrum [λmax 3320, 3070 (weak, sharp), 1670-1650 (broad, strong) cm-1 ]. A portion of this sample was further purified by preparative scale HPLC (6% MeOH/EtOAc) and analyzed by HRMS:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:3]=1.[NH:20]1[C:28]2[C:23](=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:20]1[C:28]2[C:23](=[C:24]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][NH:8]4)=[C:4]([NH:11][C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)=[O:13])[CH:3]=3)[CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ccccn1
Temperature: 150 °C

Procedure:
A mixture of N-(6-bromo-1H-indazol-4-yl)-2-pyridinecarboxamide (38 mg, 0.12 mmol), 1H-indol-4-ylboronic acid (23 mg, 0.14 mmol, available from Apollo), Pd(dppf)Cl2 (10 mol %, 12 mg, 0.015 mmol), aqueous sodium carbonate solution (2M, 0.18 ml, 0.36 mmol) in dioxane/water 1:1 (2 ml) was heated at 150° C. for 30 mins under microwave irradiation. The reaction mixture was filtered through a silica cartridge eluting with MeOH, then the solvent was removed in vacuo. Purification by mass directed preparative HPLC (Method B) give after evaporation of solvents the title compound as a light brown solid (21 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH3:23])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1ccc2c(-c3ccc(F)cc3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3ccc(F)cc3)cn(C)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 119.9 %

Procedure:
To a solution of compound 53d (300 mg, 0.78 mmol) in DMF (3 mL) was added NaH (60% in mineral oil, 68.9 mg, 1.72 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, then CH3I (0.053 mL, 0.86 mmol) was added and stirring continued at 0° C. for another 1 h. The resulting mixture was diluted with EtOAc and water. The organic layer was washed with brine and concentrated. The residue was recrystallized from heptane, filtered and dried the solid to give compound 53f (265 mg) as a light yellow solid. MS m/z (M+H+) 284.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:24](Cl)(=[O:26])[CH3:25].[OH-].[Na+]>[N+](C)([O-])=O>[C:24]([C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:19])([CH3:1])[CH2:7][CH:6]([C:8]3[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=3)[C:5]=2[CH:15]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1cccnc1C1CC(C)(C)Oc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(c1ncccc1C)CC(C)(C)O2
Yield: 19.9 %

Procedure:
712 mg of 3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl)-2H-1-benzopyran were suSsended in 10 ml of nitromethane at room temperature. 750 mg of aluminum chloride and then 500 mg of acetyl chloride were added. After 1 hour at room temperature dilute sodium hydroxide solution was added and the mixture was extracted with ethyl acetate. The organic extract was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:3) and then ethyl acetate/ petroleum ether (1:1) for the elution. The resulting oil was triturated with n-hexane to give a solid which, after recrystallization from cyclohexane, yielded 165 mg of 6-acetyl-3,4-dihydro-2,2-dimethyl-4-(3-methyl-2-pyridyl) -2H-1-benzopyran of melting point 87-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[CH2:32]([NH2:35])[CH2:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH2:32][CH2:33][CH3:34])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.2 g, 2.71 mmol) in CH2Cl2 (60 mL) was added propylamine (0.7 mL, 8.51 mmol), HATU (1.08 g, 2.84 mmol) and diisopropyl ethyl amine (1.2 mL, 6.9 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaken. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.10 g (84%). LC-MS m/z 484 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(OCC)(=O)C>CN(C=O)C.O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:12][C:11]1[CH:13]=[CH:14][C:8]([Br:7])=[CH:9][CH:10]=1
Reactant: COC(=O)CBr
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1ccc(Br)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
Potassium carbonate (2.41 g, 17.4 mmol) is added to a stirred solution of 4-bromo-aniline (2.00 g, 11.6 mmol) and methyl bromoacetate (1.78 g, 11.6 mmol) in dry DMF (20 mL) at ambient temperature. The mixture is heated at 100° C. for 1 hour. At ambient temperature ethyl acetate (60 mL) and water (60 mL) are added to the mixture. The organic layer is separated, washed with half-saturated brine, dried, filtered and concentrated. After MPLC separation on silica (gradient 0-15% ethyl acetate in hexane), 0.94 g (33% yield) of the title compound is obtained. 1H NMR (DMSO-d6): δ3.62 (s, 3H), 3.87 (d, J=6.4 Hz, 2H), 6.22 (t, J=6.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=2)=CC=1)([O-])=O>C(N(CC)CC)C>[NH2:37][C:36](=[N:38][C:56](=[O:55])[C:57]1[CH:62]=[CH:61][C:60]([CH3:63])=[CH:59][CH:58]=1)[C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetic acid salt (1.6 g) and DMF (120 mL), 4-methylbenzoic acid 4-nitrophenyl ester [CAS No. 15023-67-3] (815 mg) and triethylamine (1.21 mL) were added, and the resulting mixture was stirred overnight at room temperature. The solvent in the reaction solution was distilled off under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (1.01 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH2:21]([N:23]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37])[C:24](=[O:30])[CH2:25][CH:26]([CH3:29])[CH2:27]Cl)C.[Na+].[Cl-]>CN(C=O)C>[CH3:21][N:23]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH3:37])[C:24]([CH2:25][CH:26]([CH3:29])[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)=[O:30]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: CCN(C(=O)CC(C)CCl)C1CCCCC1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(COc1ccc2[nH]c(=O)ccc2c1)CC(=O)N(C)C1CCCCC1C
Reaction time: 4.5 h

Procedure:
1.6 Grams of 6-hydroxycarbostyril, 1.4 g of K2CO3, 1.6 g of sodium iodide and 3.3 g of N-ethyl-N-(4-chloro-3-methylbutyryl)-2-methylcyclohexylamine are added to 30 ml of DMF and agitated at 70° to 80° C. for 4.5 hours. After the reaction, the reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The resultant crude crystals are recrystallized from benzene-ligroin to produce 1.4 g of 6-{3-[N-methyl-N-(2-methylcyclohexyl)aminocarbonyl]-2-methylpropoxy}carbostyril with melting point of 146°-149° C.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[C:8]([F:27])[CH:7]=1>CS(C)=O.CN(C=O)C.CCOC(C)=O>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=2[F:27])=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
Potassium cyanide (0.473 g) was added to a stirred solution of the product from step (vi) (0.85 g) in DMSO (10 mL) and DMF (10 mL). The mixture was stirred at rt for 15 h, diluted with EtOAc, washed with saturated NaHCO3 solution, saturated brine dried, filtered and evaporated. The crude product was purified by chromatography eluting with 0 to 5% MeOH in DCM to afford the subtitle compound as a yellow solid 0.530 g.