Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[S:37])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)N4CCCCC4)cc3c2c1C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=S)N4CCCCC4)cc3c2c1C
Yield: 127.2 %

Procedure:
400 mg of 6-piperidinocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated in 16 ml of toluene with 200 mg of Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithiaphosphetane-2,4-disulfide] for one hour to 100° C. Thereafter the mixture is combined with water and extracted twice with ethyl acetate. The ethyl acetate phase is dried, filtered, concentrated, and chromatographed over silica gel with methylene chloride/ethanol=10:1. Recrystallization of the corresponding fractions from ethanol/water yields 240 mg of 6-piperidinothiocarbonyl-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 225°-230° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:12](Cl)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[CH3:16][OH:17]>>[Cl:2][C:3]1[C:12]([O:17][CH3:16])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: COc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: CO
Agent: [Na]
Product: COc1ccc2nc(Cl)c(OC)nc2c1
Temperature: 50 °C

Procedure:
In a flame-dried reaction flask under a dry nitrogen atmosphere, there was slowly added a solution consisting of 850 mg. of sodium dissolved in 80 ml. of methanol to a slurry of 7.1 g. of 2,3-dichloro-6-methoxyquinoxaline in 60 ml. of methanol at 50° C. over a period of seven hours. The resulting mixture was then heated at 50° C. overnight and finally cooled to room temperature. Upon completion of this step, the spent reaction mixture was concentrated in vacuo and the residue subsequently dissolved in chloroform, followed by washing with water and drying over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, the resulting residue was subsequently chromatographed on a column of 400 ml. of silica gel, followed by elution with toluene. The good fractions were combined and concentrated in vacuo to ultimately afford a white solid consisting of 6.1 g. (88%) of pure 2-chloro-3,6-methoxyquinoxaline. m.p. 79°-81° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:32]([O:34]CCC#N)=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1.[OH-].[Na+]>COCCOC.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:39])=[C:5]([C:32]([OH:34])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CN(C)Cc3ccccc3)no2)=C(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC1=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(c2nc(CN(C)Cc3ccccc3)no2)=C(C)N1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
To a stirred solution of 1.06 g of 2-cyanoethyl 1,4-dihydro-2,6-dimetyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate in 5 ml of ethylene glycol dimethyl ether was added a solution of 240 mg of sodium hydroxide in 10 ml of water. The reaction mixture was stirred at room temperature for 7 hours and then diluted by adding 5 ml of water. The mixture was washed with three 20 ml portions of methylene chloride and then acidified with dilute hydrochloric acid until the pH of the solution was about 1. The solution was decanted and the oily precipitate was dissolved in isopropyl alcohol. After the organic phase was concentrated in vacuo, the residue was chromatographed on silica gel using chloroform-isopropyl alcohol (10:1) as eluent to give 0.715 g of 1,4-dihydro-2,6-dimethyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylic acid as an amorphous solid. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals, m.p. 171° C. (decomp.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:19]O>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:17][N:19]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc(F)c2)on1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of ethyl 4-(3-fluorophenyl)-2,4-dioxobutanoate (30.0 g, 126 mmol) in EtOH (300 mL) was added hydroxylamine hydrogen chloride (17 g, 252 mmol). The mixture was stirred at 80° C. for 1 h. The mixture was concentrated to 80 mL and diluted with H2O (100 mL). The precipitate was filtered and washed with H2O to give ethyl 5-(3-fluorophenyl)isoxazole-3-carboxylate (25.8 g, 87%). LRMS (M+H+) m/z 236.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)O)=[CH:5][CH:4]=1.[C:21]1([OH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCC.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[CH:25]=[CH:26][C:21]([OH:27])=[CH:22][CH:23]=2)[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(O)c2cccc3ccccc23)cc1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(c2ccc(O)cc2)c2cccc3ccccc23)cc1
Reaction time: 3 h

Procedure:
A solution of compound (4-methoxyphenyl)-naphth-1-yl-carbinol of formula II (3.0 gm, 0.011 mol) and phenol (5.4 gm, 0.057 mol) in a mixture of anhydrous benzene and anhydrous hexane (40.0 ml), 1:1) was gradually added to a mixture of phenol (1.5 gm, 0.061 mol) and anhydrous aluminum chloride (1.5 gm, 0.011 mol) at 0° C. under stirring. After the addition was over, the stirring was continued at room temperature for 3 hrs, the reaction was decomposed by adding crushed ice with conc. HCl (0.5 ml) and extracted with ethyl acetate. The organic layer was washed with water, 5% NaOH, dried over sodium sulphate and concentrated to give an oil which was chromatographed over silica gel to yield the title compound of formula I. Yield 2.3 gm (59.3%).
Reaction SMILES: [Mg].[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19]Cl)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:21][O:22][Si:23](OC)([O:26][CH3:27])[O:24][CH3:25]>C1COCC1>[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][Si:23]([O:26][CH3:27])([O:24][CH3:25])[O:22][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CO[Si](OC)(OC)OC
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCl)CC2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C[Si](OC)(OC)OC)CC2)CC1
Reaction time: 2 h

Procedure:
A Grignard reagent was prepared from 100 ml of THF, magnesium (120 mmole) and trans-1-pentyl-4-(trans-4-chloromethylcyclohexyl)cyclohexane (100 mmole) under nitrogen atmosphere. A THF 100 ml solution of tetramethoxysilane (150 mmole) was heated to 65° C., and the Grignard reagent was added dropwise thereto. Further, the solution was stirred at the same temperature for 2 hours, and after left standing for cooling, the reaction mixture was filtered. The solvent was distilled off, and then trans-1-pentyl-4-(trans-4-trimethoxysilylmethyl-cyclohexyl)cyclohexane (65 mmole) was obtained by distillation under reduced pressure.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10])=[C:2]=[O:3].[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH2:18].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][C:17](=[O:19])[NH:18][C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[C:2]=[O:3]
Reactant: O=C=NCCCCCC(=O)Cl
Reactant: COCCOC(N)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCOC(=O)NC(=O)CCCCCN=C=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
8.8 g (50 mmol) of 6-isocyanato-caproyl chloride were introduced into 25 ml of toluene. A mixture of 5.95 g (50 mmol) of carbamic acid-β-methoxyethyl ester, 3.96 g (50 mmol) of pyridine and 15 ml of toluene was added dropwise at 0° C. The mixture was stirred for 6 hours at 25° C. and then heated to 60° C. for 10 hours. It was diluted with 100 ml of toluene and extracted once with 50 ml of 0.1N HCl. The organic phase (MgSO4) was dried and filtered and the solvent was evaporated off. 5.1 g of a product similar in its properties to the product from Example 2 were obtained. Yield: 5.1 g=40%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[CH:9])[CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][C:17](I)=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([NH2:15])=[O:14])[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cncc(Cl)c1
Reactant: NC(=O)c1cc(I)ccc1F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Add bis(triphenylphosphine)palladium (II) dichloride (51 mg, 0.07 mmol), copper (I) iodide (28 mg, 0.15 mmol), and 3-chloro-5-ethynylpyridine, (prepared as described in PREPARATION 27), (250 mg, 1.82 mmol) to a solution of 2-fluoro-5-iodobenzamide, (prepared as described in PREPARATION 44), (0.482 g, 1.82 mmol) in triethylamine (7 mL, 53 mmol) and heat at 70° C. After 10 minutes, add toluene (10 mL) to the solidified reaction mixture, heat at 70° C. for 1 h, cool to room temperature and stir overnight. Concentrate and purify the residue by silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes, to give the title compound as a white solid (260 mg, 32%).
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:3].[NH2:12][CH:13]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(N(CC)CC)C>ClCCl>[N:15]1([CH2:14][CH:13]([NH:12][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CCOC(=O)CCCC(=O)Cl
Reactant: COc1ccc(COCC(N)Cn2ccnc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCC(=O)NC(COCc1ccc(OC)cc1)Cn1ccnc1
Reaction time: 12 h

Procedure:
A solution of ethyl 4-(chloroformyl)butyrate (0.714 g, 0.004 mol) in dichloromethane (5 ml) was added dropwise to a stirred solution of 1-[2-amino-3-[(4-methoxyphenyl)methoxy]propyl]-1H-imidazole (Example 32c; 1.0 g, 0.0038 mol) and triethylamine (0.4 g, 0.004 mol) in dichloromethane (20 ml) at room temperature. The solution was stirred for 12 hours, washed with an aqueous saturated solution of ammonium chloride and dried (Na2SO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, 2% ethanol in chloroform) to give ethyl 5-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethyl]amino]-5-oxopentanoate as a pale-yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][N:37](COCC[Si](C)(C)C)[C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH:23]([F:25])[F:24])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][CH:4]([N:26]1[CH:30]=[C:29]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:28]=[N:27]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH:23]([F:24])[F:25])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4C(F)F)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cc2F)CC1C(F)F)n1cc(-c2ncnc3[nH]ccc23)cn1

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(difluoromethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (27 mg, 0.041 mmol; Peak 3 from Step 8) was stirred in a 1:1 mixture of TFA:DCM (4 mL) for 1 h. Solvent was removed in vacuo. The residue was dissolved in methanol (1.9 mL), and 0.2 mL of ammonium hydroxide aqueous solution was added. Preparative HPLC-MS (C18, eluting with a gradient of H2O/MeCN containing 0.15% NH4OH) afforded purified product (7.7 mg, 35%). 1H NMR (400 MHz, DMSO-d6, rotamers): δ 12.13 (br s, 1H), 8.82 (s, 0.55H), 8.81 (s, 0.45H), 8.68 (s, 0.45H), 8.68 (s, 0.55H), 8.38 (s, 0.45H), 8.37 (s, 0.55H), 8.01 (dd, 0.45H), 7.96 (dd, 0.55H), 7.81 (dd, 0.45H), 7.76 (br d, 0.55H), 7.65-7.57 (m, 2H), 6.97 (d, 1H), 6.24 (br t, 1H), 4.91 (ddd, 1H), 4.25 (d, 0.55H), 4.05 (br m, 0.45H), 3.53-2.33 (m, 10H); 19F NMR (400 MHz, DMSO-d6): −114.10 to −115.21 (m, 1F), −123.22 to −125.01 (m, 2F); LCMS (M+H)+: 534.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][C@@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:5][C:6]([OH:8])=[O:7].[CH2:33](O)[CH3:34].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:33]([O:7][C:6](=[O:8])[CH2:5][C@H:4]([C:9](=[O:31])[NH:10][C@H:11]1[CH2:28][C:27]2=[CH:29][N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=32)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:30])[CH2:3][CH:2]([CH3:32])[CH3:1])[CH3:34]
Reactant: CC(C)C[C@H](CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](CC(C)C)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCNC1=O
Reaction time: 8 h
Yield: 55 %

Procedure:
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (183 mg) was taken up in 40 mL of dry CH2Cl2 and at 0° C. ethanol (0.5 mL, 5 eq) was added followed by N,N-dimethylaminopyridine (0.1 eq, 5 mg) and finally EDCI (209 mg, 5 eq). The resulting solution was stirred from 0° C. to room temperature overnight. Additional CH2Cl2 (100 mL) was added and the mixture was washed with 0.5N HCl (2×50 mL), saturated NaHCO3 (2×50 mL) and finally with brine (1×50 mL). The organic layer was dried over Na2 SO4, filtered and evaporated to dryness. Recrystallization from ethyl acetate and petroleum ether gave (3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl ester as a white solid (Yield: 108 mg, 55%), MS: 470 (M+H)+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1.[Cl:36]C1C=CC(C2NC3C=C(CN4CCN(C)CC4)C=CC=3N=2)=CC=1I>>[Cl:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([CH2:17][N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH:15]=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[C:25]#[C:26][C:27]1[N:31]2[N:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][CH:28]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5cnc6cccnn56)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine (as prepared in Example 3) and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzoimidazole in a manner similar to that described for in Example 1. The intermediate compound 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole was made as for Example 1 (Step 4 to 7) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 8.52 (1 H, s), 7.95-7.98 (1 H, d, J=9.0 Hz), 7.45-7.48 (1 H, d, J=9.0 Hz), 7.43-7.46 (1 H, d, J=9.0 Hz), 7.23 (1 H, s), 7.21-7.24 (1 H, d, J=9.0 Hz), 3.59 (2 H, s), 2.51 (8H, brs), 2.29 (3 H, s).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=2)[C:17]([O:19]C)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2].Cl>CO.C1COCC1.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][N:23]=2)[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(-n3cccc3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(-c2cc(C(=O)O)ccn2)ccc1-n1cccc1
Yield: 99.6 %

Procedure:
131 mg of methyl 2-(4-amino-3-cyanophenyl)isonicotinate and 67 μl of 2,5-dimethoxytetrahydrofuran were dissolved in 1.3 ml of acetic acid solution, followed by heating and stirring at 100° C. for 4 hours. The solution was poured into water, followed by extraction with ethyl acetate. The solvent of the organic layer was evaporated under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1 to 1:1) to obtain 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate. (2) 100 mg of methyl 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinate was dissolved in a mixture of 2 ml of methanol and 3 ml of THF, and 66 μl of aqueous 1 M sodium hydroxide solution was added, followed by heating under reflux for 3 hours. The reaction mixture was cooled, then neutralized with 66 μl of 1 M hydrochloric acid, followed by extraction with a mixture of 2-propanol and chloroform (1:4). The organic layer was washed with brine. The solvent of the organic layer was evaporated under reduced pressure, and the resulting residue was recrystallized from a mixture of 2-propanol and chloroform (1:4) to obtain 95 mg of 2-[3-cyano-4-(1H-pyrrol-1-yl)phenyl]isonicotinic acid.
Reaction SMILES: C(O[C:5]1[C:6](=[O:20])[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)C.[C:21]([NH2:26])([CH2:24][CH3:25])([CH3:23])[CH3:22]>>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:19])[C:6](=[O:20])[C:5]=2[NH:26][C:21]([CH3:23])([CH3:22])[CH2:24][CH3:25])=[CH:14][CH:13]=1
Reactant: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Reactant: CCC(C)(C)N
Product: CCC(C)(C)Nc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O

Procedure:
In a manner similar to Example 1, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.30 g, 1.056 mmol) and tert-amylamine (0.86 mL, 7.39 mmol) were converted to the title compound. Recrystallization from hot ethyl acetate afforded 0.250 g (76%) of compound as a tan solkd: m.p. 115.4-119° C. (dec); 1H NMR (DMSO-d6) δ8.60(br s,1H), 8.15(ABq, 2H), 7.86(ABq,2H), 1.81(q,2H), 1.43(s,6H), 0.88(s,3H); IR (KBr) 3170, 2980, 1770, 1720, 1580, 1310, 1170, 1125, 1060, 1010, 850 cm−1; MS (m/z) 311 [M+].
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:17]1[S:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:5]([C:17]1[S:21][C:20]([C:22]([Cl:3])=[O:24])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)s1
Product: CCCCCCCCCCCCc1ccc(C(=O)Cl)s1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4 ml of thionyl chloride was added to 0.57 g (1.93×10-3 ml) of 5-dodecylthiophene-2-carboxylic acid, followed by heat-stirring for 4 hours at 70° C. and removal of excessive thionyl chloride by reduced-pressure distillation to obtain 5-dodecylthiophene-2-carboxylic chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:18][C:11]3[NH:12][C:13](=[S:17])[NH:14][C:15](=[O:16])[C:10]=3[CH2:9][C:8]=2[CH:19]=1)([OH:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:18][C:11]3[NH:12][C:13](=[S:17])[NH:14][C:15](=[O:16])[C:10]=3[CH2:9][C:8]=2[CH:19]=1)=[O:3])[CH3:21]
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2
Agent: Cl
Product: CCOC(=O)c1ccc2c(c1)Cc1c([nH]c(=S)[nH]c1=O)O2

Procedure:
Suspend 7-carboxy-(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione (5 g.) in ethanol and pass in HCl gas until saturated. Reflux the mixture for 24 hours then cool, filter and wash with ethanol and ether to yield 7-ethoxycarbonyl(1H,3H,5H)-(1)-benzopyrano-(2,3-d)-pyrimidine-4-one-2-thione.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[N:36]=[C:35]([O:37]C)[C:34]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:33][CH:32]=2)=[CH:13]\[C@H:14]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:31]2[NH:36][C:35](=[O:37])[C:34]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:33][CH:32]=2)=[CH:13]\[C@H:14]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(OC)n2)c(OC)c1
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCC(=O)O)c(=O)[nH]2)c(OC)c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
48% hydrobromic acid (1.7 mL) was added to a solution of 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)propanoic acid (172 mg) in 1,4-dioxane (1.7 mL), and the mixture was stirred at 65° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 3-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-oxo-1,2-dihydropyridin-3-yl)propanoic acid as a yellow oil (153 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[N+:8]([O-:10])=[O:9])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2[N+](=O)[O-])CC1
Yield: 94.7 %

Procedure:
The specific operation referred to the step (1) described in Example 1 for details. 2,4-dichloro-3-nitropyridine (772 mg, 4.0 mmol), and piperazine-1-carboxylic acid tert-butyl ester (744 mg, 4.0 mmol) were charged to afford 1.299 g crude product with a yield of 94.7%, which was directly used in the subsequent reaction.