Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]#N)=[CH:6][C:5]=1[O:20][CH3:21].[OH2:22]>C(O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][C:18]([OH:22])=[O:1])=[CH:6][C:5]=1[O:20][CH3:21]
Reactant: O
Reactant: COc1cc(Sc2ccccc2CC#N)ccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(Sc2ccccc2CC(=O)O)ccc1Cl
Yield: 90 %

Procedure:
A solution of potassium hydroxide (8.25 g) in water (20 ml) is added to a solution of the above-prepared nitrile (8.8 g) in ethanol (30 ml) and the mixture refluxed for 4 hours. The ethanol is evaporated under diminished pressure and the residue diluted with water. The solution is washed with ether, cooled and acidified with hydrochloric acid. The crude product is filtered and crystallized from a mixture of benzene (10 ml) and light petroleum (25 ml), yielding 8.5 g (90%) of 2-(4-chloro-3-methoxyphenylthio)phenylacetic acid. The pure product melts at 103°-105° C.
Reaction SMILES: [CH:1]([C@H:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([C@H:4]1[N:9]([C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]([C:21]([O:23][CH3:24])=[O:22])=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1nccc(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 150 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (0.9 g, 2.56 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (1.0 g, 5.1 mmol, 2 eq.) and DIEA (1.0 g, 7.7 mmol, 3 eq.) in i-PrOH (6 mL) was stirred in a microvave oven at 150° C. for 2 h. TLC showed the starting material was consumed completely (PE: EtOAc=3:1). The solvent was removed in vacuo at 40° C., and the residue was purified by column chromatography on silica gel eluting with PE/EtOAc=6/1 to give (R)-methyl 1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.0 g, 78% yield) as a white solid. LC-MS m/z 498.1 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 8.52 (d, J=4.8 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 6.83 (d, J=4.8 Hz, 1H), 6.06 (d, J=7.8 Hz, 1H), 5.39-5.28 (m, 1H), 4.33-4.24 (m, 1H), 4.20-4.12 (m, 1H), 3.93 (s, 3H), 3.77-3.65 (m, 1H), 3.39 (s, 3H), 2.52-2.38 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.6 Hz, 3H).
Reaction SMILES: N1C=CN=C1.C(=O)([O-])[O-].[Na+].[Na+].[CH:12]1[C:24]2[CH:23](CC3CC(=O)N(O)C3=O)C3C(=CC=CC=3)[C:16]=2C=[CH:14][CH:13]=1.[CH3:34][CH2:35][O:36][CH2:37][CH3:38]>O.CC(C)=O>[CH3:34][CH2:35][O:36][CH2:37][CH3:38].[CH3:14][CH2:13][CH2:12][CH:24]([CH3:23])[CH3:16]
Reactant: O=C1CC(CC2c3ccccc3-c3ccccc32)C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: CCCC(C)C
Reaction time: 0.33 h

Procedure:
The deprotected imidazole derivative (3.9 g, 14 mmole) was dissolved in water (50 ml), acetone (30 ml) and 1M sodium carbonate (30 ml) and the solution was cooled in an ice bath. 9-Fluorenylmethyl-N-hydroxysuccinimide (4.76 g) in acetone (30 ml) was added dropwise with stirring over a period of 20 minutes (pH maintained at 9 by the addition of 1M sodium carbonate solution) and the stirring was continued overnight. Acetone was removed by evaporation and the aqueous solution was acidified with 1M KHSO4 and the product was extracted into ethyl acetate. The organic phase was washed with water and saturated sodium chloride solution, dried over MgSO4, and evaporated to leave an oil. Trituration with ether and ether/isohexane gave a solid [3.66 g, 66%; (M+H)+ 392].
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[CH3:7])[CH:3]([OH:5])O.N1C=CC=CC=1.[F:17][C:18]([F:31])([F:30])[S:19]([O:22]S(C(F)(F)F)(=O)=O)(=[O:21])=[O:20]>ClCCl>[F:8][C:6]([F:9])([C:2]([F:10])([F:1])[CH2:3][O:5][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:21])=[O:20])[CH2:7][O:22][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:20])=[O:21]
Reactant: CC(F)(F)C(F)(F)C(O)O
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (about 0° C.) solution of 2,2,3,3-tetrafluorobutanediol (15 grams, 93 mmol) and pyridine (19 mL, 230 mmol) in dichloromethane (250 mL), was added dropwise trifluoromethanesulfonic anhydride (34 mL, 200 mmol). After the addition, the mixture was stirred at about 0° C. for about one hour, followed by stirring at room temperature for one additional hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to near dryness, leaving a dichloromethane-containing oil. 1H NMR (400 MHz, CDCl3) δ 4.82 (m). 19F NMR (376 MHz, CDCl3) δ−120.83 (m, 4H), −74.38 (s, 6H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([C@@H:11]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])=[CH:3][CH:2]=1.C([O-])(=O)[CH2:29][C:30]([O-:32])=[O:31].[CH2:35]([Mg+2])[CH3:36]>C1COCC1>[CH2:35]([O:32][C:30](=[O:31])[CH2:29][C:14](=[O:16])[CH2:13][CH2:12][C@H:11]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[CH3:36]
Reactant: CC[Mg+2]
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C([O-])CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Z-Glu-Obzl (a N-α-Cbz-L-glutamic acid α-benzyl ester) (5 g, 13.46 mmol) was dissolved in 50 ml of dry THF at room temperature. N,N′-carbonyl diimidazole (1.1 eq) was added slowly and the mixture was then stirred for 2 hrs at room temperature. Ethyl magnesium malonate (0.55 eq) was added, and the mixture was stirred at room temperature overnight. The product was extracted with ether, and washed with 10% NaHCO3, water, and brine. The residue containing 3 was purified by flash chromatography on silica gel (ethyl acetate:hexanes 50:50) and concentrated on a rotary evaporator to afford a white solid in 40% yield. 1H-NMR (400 MHz, CDCl3): δ 1.26 (t, J=7.2, 3H), 1.9-2.01 (m, 1H), 2.1-2.28 (m, 1H), 2.5-2.7 (m, 2H), 3.37 (s, 2H), 4.18 (q, J=7.2, 2H), 4.41 (s, 1H), 5.11 (s, 2H), 5.18 (s, 2H), 5.44 (d, J=8, 1H), 7.25-7.41 (m, 10H). LC-MS (ESI) calcd for C24H2NO7 (M+H+) 442.18, obsd. 442.0.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=3)[N:6]2[CH:30]=1)=O.[N+](=[C:33](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[CH:28][CH:29]=3)[N:6]2[CH:30]=1)#[CH:33]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cn2c(-c3ccc(C(=O)OC(C)(C)C)cc3)cnc(N3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of compound 81a (239 mg, 0.580 mmol) in anhydrous THF (8 mL) and anhydrous MeOH (3 mL), dimethyl (1-diazo-2-oxopropyl)phosphonate (164 mg, 0.850 mmol) in MeOH (2 mL) was added followed by potassium carbonate (252 mg, 1.82 mmol). The resulting yellow suspension was stirred at rt for 18 h. The mixture was filtered through a pad of diatomaceous earth. The filter cake was washed CH2Cl2. The combined filtrates were concentrated under reduced pressure. The residue was dissolved in DCM and washed with diluted NaHCO3, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on preparative TLC (EtOAc/CH2Cl2; 2:3, v/v) to afford compound 81b. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H25N4O3: 405.2 (M+H). found: 405.4.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]#[N:14])=[CH:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: N#Cc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 25 mmol) and 10% Pd—C (0.46 g) in EtOH (50 mL) was stirred under H2(1 atm) at room temperature overnight. After filtration, the filtrate was concentrated and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to give 6-amino-1H-indole-3-carbonitrile (1.0 g, 98%) as a pink solid, 1 H NMR (DMSO-d6) δ 11.51(s, 1 H), 7.84(d, J=2.4 Hz, 1 H), 7.22(d, J=8.4 Hz, 1 H), 6.62(s, 1H), 6.56(d, J=8.4 Hz, 1 H), 5.0(s, 2 H); MS (ESI) m/e (M+H+) 157.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N+:19]([O-])=O)[CH2:9][CH2:10]2)=[CH:5][CH:4]=1.Cl>O1CCCC1.CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])[CH2:9][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(c1ccccc1[N+](=O)[O-])=C2
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Temperature: 25 °C
Reaction time: 25 h
Yield: 70.3 %

Procedure:
To a solution of 7-methoxy-3-(2-nitrophenyl)-1,2-dihydronaphthalene (1.5 g) in tetrahydrofuran (10 ml) and methanol (10 ml) were sequentially added 10% palladium-activated charcoal (300 mg) and concentrated hydrochloric acid (0.8 ml), and the solution was stirred for 25 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solution was neutralized with ammonia solution, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, the resulting solid was washed with a hexane-diethyl ether system to provide the title compound (949 mg).
Reaction SMILES: N1C=CC=CN=1.C([O:14][C:15]1[N:16]=[N:17][C:18]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)=[CH:19][C:20]=1[O:21]CC1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([CH2:30][CH2:29][C:18]2[CH:19]=[C:20]([OH:21])[C:15](=[O:14])[NH:16][N:17]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Clc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: c1ccnnc1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(CCc2cccc(Cl)c2)cc1O
Yield: 32 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(3-chloromethyl)phenyl)ethynyl]pyridazine (Intermediate 24) except that the reaction was carried out in ethyl acetate. The crude material was purified by reverse phase chromatography (50 g C18) cartridge eluting with 5-100% acetonitrile/water with acidic modifier and the appropriate fractions combined to give an orange solid. This was recrystallised from ethyl acetate to give a white solid (yield=32%).
Reaction SMILES: [NH2:1][C:2]1[C:9](F)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[K+:12].C(O[C:16]([S-:18])=[S:17])C>CN(C=O)C>[K+:12].[C:6]([C:5]1[C:4]([F:11])=[CH:3][C:2]2[N:1]=[C:16]([S-:18])[S:17][C:9]=2[CH:8]=1)#[N:7]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc2sc([S-])nc2cc1F
Temperature: 25 °C
Yield: 120.2 %

Procedure:
A mixture of 4-amino-2,5-difluorobenzonitrile (1.0 g, 6.5 mmol) and O-ethylxanthic acid potassium salt (1.2 g, 7.8 mmol) in DMF (15 mL) was heated at reflux for 6 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 1 M aq Na2CO3 (100 mL). The organic layer was separated and the aqueous layer was extracted with additional EtOAc (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2% MeOH in DCM to afford 6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt (1.94 g) as an orange solid. LCMS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9]O)[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15].S(Cl)([Cl:18])=O.Cl>C1C=CC=CC=1>[CH3:1][C:2]12[CH2:12][CH2:11][CH:5]([CH2:6][CH:7]1[CH2:8][CH2:9][Cl:18])[C:4]([CH3:14])([CH3:13])[C:3]2=[O:15]
Reactant: CC1(C)C(=O)C2(C)CCC1CC2CCO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccccc1
Product: CC1(C)C(=O)C2(C)CCC1CC2CCCl
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To a 100 ml microflask equipped with thermometer, reflux condenser, dropping funnel and magnetic stirrer is charged 12.3 g of 1,3,3-trimethyl-6-(2-hydroxyethyl) bicyclo(2.2.2)-octan-2-one prepared according to the process of Example XVII, and 20 ml benzene. The dropping funnel is charged with 12 g thionyl chloride. The thionyl chloride is added to the reaction mass from the dropping funnel, slowly, over a period of five minutes as the temperature of the reaction mass rises to 35° C. The reaction mass is then refluxed for a period of 10 hours at 90° C. The flask is then vented to the atmosphere and heated on a steam bath in order to volatilize the unreacted thionyl chloride and any hydrogen chloride reaction product remaining. The reaction mass is then cooled and hydrolyzed with 50 g ice. The organic layer is separated, and the aqueous phase is extracted with four 20 ml portions of anhydrous diethyl ether. The organic layers are bulked and washed with (i) three 20 ml portions of saturated sodium bicarbonate solution and (ii) one 20 ml portion of water. The organic phase is then dried over anhydrous magnesium sulfate and stripped of the diethyl ether. The reaction product is then distilled at 105°-115° C. at a pressure of 0.2 mm Hg. Its structure, confirmed by NMR and mass spectral analyses is as follows: ##STR37##
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15])([CH3:8])[CH3:7])=[N+]=[N-].[ClH:19]>CCO.O=[Pt]=O>[ClH:19].[NH2:1][CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15])([CH3:8])[CH3:7]
Reactant: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(F)c(C#N)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Reaction time: 12 h
Yield: 65 %

Procedure:
To a stirred solution of 5-(4-azido-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (6.1 g, 24.7 mmol) in EtOH (100 mL) was added conc HCl (20 mL) and PtO2 (112 mg, 0.49 mmol, 0.02 eq). The mixture was stirred at 1 atm of H2 gas for 12 h, filtered through Celite™ and evaporated in vacuo. The residue was partitioned in DCM and water, and the aqueous layer was evaporated in vacuo. The resulting residue was triturated with Et2O-Hex to give 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride as a yellow solid (6 g, 65%). 1H NMR (400 MHz, CD3OD) δ 7.74-7.68 (m, 2H), 7.37 (t, J=8.8 Hz, 1H), 3.89 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12].C1COCC1>O>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: O
Product: ClCCCSc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 112.5 %

Procedure:
A mixture of benzenethiol (0.550 g, 5.00 mmol), 1-bromo-3-chloropropane (106 mg, 5.50 mmol), TEA (1.01 g, 10.0 mmol) and THF (10.0 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (40 mL), the aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using hexane:EtOAc (10:1) to give the desired product [(3-chloropropyl)sulfanyl]benzene (1.05 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:41][C:42](N1C=CN=C1)=[O:43]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:42]([NH:41][C:37]2[NH:36][CH:40]=[CH:39][N:38]=2)=[O:43])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(CCCCN)Cc2nccc3ccccc23)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cnc(CN(CCCCNC(=O)Nc2ncc[nH]2)Cc2nccc3ccccc23)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a warm (70° C.), stirred, solution of N-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-butane-1,4-diamine (0.130 g, 0.37 mmol) and DIPEA (0.39 mL, 2.24 mmol) in DMF (4 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equiv). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 75 mg (42%) of COMPOUND 154 as a white solid. 1H NMR (CDCl3) δ 1.32-1.36 (m, 2H), 1.56-1.72 (m, 2H), 2.18 (s, 3H), 2.29 (s, 3H), 2.68-2.77 (m, 4H), 3.80 (s, 2H), 4.—(s, 2H), 6.72 (s, 2H), 7.24-7.26 (m, 1H), 7.39-7.44 (m, 1H), 7.57-7.63 (m, 2H), 7.74-7.78 (m, 2H), 7.86 (d, 1H, J=8.4 Hz), 8.46 (s, 1H), 8.50 (d, 1H, J=5.7 Hz); 13C NMR (CDCl3) δ 18.33, 18.72, 23.45, 27.95, 38.86, 55.10, 58.91, 59.22, 121.06, 126.47, 127.09, 127.31, 128.06, 130.36, 132.61, 133.16, 136.57, 139.42, 141.66, 144.62, 147.15, 153.65, 156.21, 158.75; ES-MS m/z 480 (M+23). Anal. Calcd. For C26H31N7O.0.8CH3OH: C, 66.62; H, 7.13; N, 20.29. Found: C, 66.84; H, 6.93; N, 20.23.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CO.O1CCOCC1.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc(OCc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)Cc1ccc(OCc2ccc([N+](=O)[O-])cc2)cc1
Yield: 91.9 %

Procedure:
After 3.15 g (10.0 mmol) of ethyl 4-(4-nitrobenzyloxy)phenylacetate were dissolved in a mixed solvent of 50 ml of methanol and 50 ml of 1,4-dioxane, 70 ml of a 1 N aqueous solution of sodium hydroxide were added, and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was acidified with diluted hydrochloric acid and extracted with chloroform. The resultant extract was then dried over anhydrous sodium sulfate. After distilling off chloroform under reduced pressure, deposited crystals were ground with ether, thereby obtaining 2.64 g (yield: 92.0%) of the intended compound as crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])=[C:7]([Cl:21])[C:6]=1[Cl:22])=O.[C:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]1)(=[S:25])[NH2:24]>CN(C=O)C>[Cl:22][C:6]1[C:7]([Cl:21])=[C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]([CH3:20])[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]1[N:24]=[C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:34])[CH3:33])[CH2:28][CH2:27]2)[S:25][CH:2]=1
Reactant: CC(=O)N1CCN(C(N)=S)CC1
Reactant: CC(C)c1ccccc1Sc1ccc(C(=O)CBr)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(-c3ccc(Sc4ccccc4C(C)C)c(Cl)c3Cl)cs2)CC1

Procedure:
A solution of compound 41 (30 mg, 0.07 mmole) and 1-thiocarbamyl-4-acetyl piperazine (20.5 mg, 0.11 mmole) in DMF (1.0 ml) was stirred at ambient temperature for two hours. The solvent was evaporated and the residue was purified on a 5-g silica gel cartridge, giving the desired product 39 as a white solid. 23 mg, 65.7%. 1H-NMR (CDCl3, 500 MHz) δ 1.19 (d, J=8.5 Hz, 6H), 2.14 (s, 3H), 3.46-3.60 (m, 7H),), 3.75-3.78 (m, 2H), 6.48 (d, J=8.4 Hz, 1H), 7.09 (s, 1H), 7.21 (m, 1H), 7.44-7.51 (m, 3H), 7.57 (d, J=8.4 Hz, 1H). MS (DCI/NH3) m/z 506 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36](=[O:38])[CH3:37])[N:34]=2)[N:31]=1>CN(C)C(=O)C.O1CCCC1>[C:36]([NH:35][C:33]1[N:34]=[C:29]2[CH:28]=[CH:27][C:26]([O:25][C:24]3[CH:23]=[C:22]([NH:21][C:7]([C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)=[O:9])[CH:41]=[CH:40][CH:39]=3)=[N:31][N:30]2[CH:32]=1)(=[O:38])[CH3:37]
Reactant: Cn1cncc1C(=O)O
Reactant: CC(=O)Nc1cn2nc(Oc3cccc(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cncn4C)c3)ccc2n1
Yield: 47.2 %

Procedure:
Using 1-methyl-1H-imidazole-5-carboxylic acid (80 mg, 0.64 mol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (111 μL, 1.27=mol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (150 mg, 0.53 mmol) and N,N-dimethylacetamide (3.0 mL) as starting materials and in the same manner as in Example 119, the title compound (98 mg, 47%) was obtained as a white powder.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)#[N:10]>CC(C)=O>[C:9]([C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:1])=[O:18])=[CH:13][CH:12]=1)#[N:10]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1ccc(C#N)nc1
Yield: 80.2 %

Procedure:
Potassium carbonate (6.1 g, 43.9 mmol) and methyl iodide (21 mL, 338 mmol) were added sequentially to a solution comprising 6-cyanopyridine-3-carboxylic acid (5 g, 33.8 mmol) in acetone (300 mL). The mixture was heated at reflux for 15 hours and concentrated under reduced pressure. The residue was partioned between ether and saturated sodium bicarbonate. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure to provide methyl 6-cyanopyridine-3-carboxylate (4.4 g, 27.1 mmol) as a tan solid. 1H-NMR (300 Mhz, DMSO-d6): 3.9 (s, 3H), 8.2 (d, 1H, J=7.5 Hz), 8.5 (d, 1H, J=7.5 Hz), 9.2 (s, 1H).