Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][CH:13]=[N:14][NH:15][CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[C:28]([N+]([O-])=O)[CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[CH:23][CH:22]=1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH2:11][CH2:12][C:13]1[C:28]([CH2:29][CH:30]2[O:34][CH2:33][CH2:32][O:31]2)=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[N:15]([CH:16]([CH3:17])[CH3:18])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NN=CCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of [3-(isopropyl-hydrazono)-propyl]-carbamic acid benzyl ester (1.0 mg, 3.8 mmol), 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (0.96 mg, 3.8 mmol), and Et3N (1.53 g, 15.2 mmol) in THF (40 mL) was stirred at 60° C. for 3 days. The mixture was cooled to rt, concentrated, and the residue purified by FCC to give the title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24](SC)[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1.[CH3:43][NH2:44].C1COCC1>C(Cl)Cl>[Br:12][C:13]1[C:18]([C:19]2[C:30]([CH3:31])=[N:29][C:22]3[N:23]=[C:24]([NH:44][CH3:43])[N:25]=[CH:26][C:21]=3[CH:20]=2)=[CH:17][C:16]([NH:32][C:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])=[C:15]([F:42])[CH:14]=1
Reactant: CN
Reactant: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3Br)c(C)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
Add mCPBA (0.152 g, 0.616 mmol) portion wise to a solution of 1-(4-bromo-2-fluoro-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3,3-dimethylbutyl)urea (0.26 g, 0.513 mmol) in DCM (10 mL) and stir at RT for 2 h. Add methylamine in THF (2.0M, 1.027 mL, 2.054 mmol) and stir at RT overnight. Add water, extract with DCM (3×), wash the combined organics with saturated. NaHCO3, then brine, dry over MgSO4, concentrate to dryness and purify via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). Combine fractions, remove the organics under reduced pressure and neutralize the resulting aqueous residue with NaHCO3. Extract the mixture with EtOAc (2×), wash the combined organics with saturated. NaHCO3, then brine, dry over Na2SO4, concentrate to dryness, treat with 1:1 MeCN/H2O, freeze and lyophilize to afford the title compound as a pale yellow solid (34 mg, 13% yield). MS (m/z): 489.1 (M+1)/491.1 (M+3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C@@H:10]12[C:19](=O)[O:18][C:16](=[O:17])[C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:18][CH2:19][CH:10]1[CH:11]([C:16]([NH:1][CH2:2][CH2:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:17])[CH2:12][CH:13]=[CH:14][CH2:15]1
Reactant: NCCN1CCCCC1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 6 h

Procedure:
N-(2-Aminoethyl)piperidine (2.11 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 6 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.12 g) was added thereto at room temperature. After being stirred for 68 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was adjusted to pH 9 with saturated sodium hydrogencarbonate aqueous solution and 1N sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate anhydride, and concentrated, thereby yielding a crude (3.34 g) containing the entitled compound as brown syrup.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:28]3[CH2:29][CH2:30][C:25]([OH:33])([C:16]4[CH:17]=[CH:18][C:19]5[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:15]=4)[CH2:26][CH2:27]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: OC1(c2ccc3ccccc3c2)CCN(CCCOc2cccc3[nH]ccc23)CC1

Procedure:
The title compound was prepared in similar fashion from 1-chloro-3-(1H-indole-4-oxy)propane and 4-(2-naphthyl)-piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 24% overall yield as a foam. FDMS m/e=400 (M+ of free base).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C[O:23]C(=O)CCCCOC1C=CC=C(C2C=CC=CC=2)C=1.[K+].[Br-].[NH3:45]>O>[C:15]1([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([NH:45][OH:23])=[O:2])=[CH:10][CH:11]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCOc1ccc(-c2ccccc2)cc1
Reactant: N
Reactant: COC(=O)CCCCOc1cccc(-c2ccccc2)c1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: O=C(CCCCOc1ccc(-c2ccccc2)cc1)NO

Procedure:
The desired compound was prepared according to the method of Example 18, steps 2 and 3, except substituting 5-(4-phenylphenoxy)pentanoic acid methyl ester, prepared as in step 1, for 5-(3-phenylphenoxy)pentanoic acid methyl ester. mp 151.5°-153.5° C. 1H NMR(DMSO-d6) δ 10.36 (S, 1H), 8.66 (d, 1H, J=1.5 Hz), 7.65-7.55 (c, 4H), 7.46-7.39 (c, 2H), 7.34-7.26 (c, 2H), 4.00 (t, 2H, J=6 Hz), 2.03 (t, 2H, J=6 Hz), 1.80-1.58 (c, 4H). IR (KBr) 3200, 3040, 2920, 2860, 1660, 1640, 1620, 1610, 1520, 1490, 1470, 1290, 1270, 1250, 1200, 1180, 1030, 840, 780, 690 cm-1. MS (DCI/NH3) 269 (M-16), 286 (M+H)+, 303 (M+NH4)+. Anal. Calcd for: C17H19NO3.0.25 H2O: C, 70.44; H, 6.78; N, 4.83. Found: C, 70.71; H, 6.82; N, 4.98.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[C:32]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([S:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:39]3[CH:40]=[CH:41][C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:37][CH:38]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)s1
Product: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Sc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)s1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-4,4,4-trifluoro-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester chiral Isomer 1 and 4-t-butyl-phenyl boronic acid as the starting materials. MS(ES): 592.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([OH:14])=O)[CH:4]=1.[NH:17]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:18]2)=[O:14])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)COCc1cc(C(F)(F)F)ccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a solution of {[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetic acid (450 mg, 1.9 mmol) and tert-butyl (3S)-pyrrolidin-3-ylcarbamate (360 mg, 1.9 mmol) in DMF (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (880 mg, 2.0 mmol) followed by triethylamine (0.80 mL, 5.7 mmol). After being stirred at room temperature overnight, ethyl acetate was added. The solution was washed with 1 N NaOH and water. Purification on silica gel column eluting with EtOAc provided the title compound (300 mg) as a clear oil. MS (M+H) 404.3.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1Br.[C:32]([C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1)#[CH:33].O>C1COCC1.[Cu]I.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>[NH2:8][C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:13][C:14]=1[C:33]#[C:32][C:34]1[N:38]([CH3:39])[CH:37]=[N:36][CH:35]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C#Cc1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(-c2nc(C#Cc3cncn3C)c(N)nc2-c2ccccc2)ccc1=O
Yield: 84.5 %

Procedure:
In the presence of copper(I) iodide (3.7 mg) and dichlorobis(triphenylphosphine)palladium(II) (13.7 mg), triethylamine (0.0596 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and 5-ethynyl-1-methyl-1H-imidazole (45.4 mg) in THF (1.5 ml) at 50° C. The mixture was refluxed for 2 hours. Water was added to the reaction mixture to give a solid. The solid was purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (2:98 v/v) to give 6-{5-amino-6-[(1-methyl-1H-imidazol-5-yl)ethynyl]-3-phenyl-2-pyrazinyl}-2-isopropyl-3(2H)-pyridazinone as a solid (135 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([Br:23])[CH:17]=1.[H-].[Na+]>CO>[Br:23][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=1.[Br:23][C:18]1[CH:19]=[CH:20][C:21]([O:22][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][N:5]3[CH:10]=2)=[CH:16][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)c1c(Cl)nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(Oc2cn3ccccc3n2)cc1
Product: CCOC(=O)c1c(Oc2ccc(Br)cc2)nc2ccccn12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 2-chloroimidazo[1,2-a]pyridine-3-carboxylate (2.00 g) was added to a solution of p-bromophenol (1.617 g) and NaH (0.427 g) in DMF(dry) (10 ml) at 100° C. The mixture was stirred at 100° C. under a dry atmosphere overnight. The reaction mixture was diluted with MeOH, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give ethyl 2-(4-bromophenoxy)imidazo[1,2-a]pyridine-3-carboxylate (1.5 g) as a colorless solid and 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (530 mg) as a colorless solid. The mixture of 2-(4-bromophenoxy)imidazo[1,2-a]pyridine (410 mg), 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one (164 mg), trans-N,N′-dimethylcyclohexane-1,2-diamine (174 mg), copper(I) iodide (116 mg), K2CO3 (338 mg) and THF(dry) (5 mL) was heated at 180° C. for 3 h under microwave irradiation. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound (72 mg) as an orange solid (mixture with 1,3-dihydro-2H-pyrrolo[2,3-b]pyridine-2-one, ca. 20% purity).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH3:14]>CO>[CH3:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[N:3][C:4]=2[N:5]=1
Reactant: CC(=O)c1cccs1
Reactant: Cc1ncc(C=O)c(N)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2ccc(-c3cccs3)nc2n1
Reaction time: 20 h
Yield: 17 %

Procedure:
1 ml of 40% strength by weight aqueous potassium hydroxide solution was added to a suspension of 2.0 g (14.6 mmol) of 4-amino-5-formyl-2-methylpyrimidine and 1.93 g. (15.3 mmol) of 2-acetylthiophene in 25 ml of methanol. The reaction mixture was then stirred for 20 hours at 20°-25° C. after which the solvent was removed After the residue had been taken up in dichloromethane, the organic phase was washed with water, dried and evaporated down. Yield: 17%; mp.: 175°-180° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:46])([CH3:45])[C:15](=[O:44])[CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH3:27])[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:31][CH:30]=2)[C:18]1=[O:43]>C(Cl)(Cl)Cl>[CH3:46][C:14]([CH3:45])([CH3:13])[C:15](=[O:44])[CH2:16][N:17]1[C:22](=[O:23])[CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH3:27])[N:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[NH:3][C:4](=[O:7])[O:5][N:42]=3)=[CH:31][CH:30]=2)[C:18]1=[O:43]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCOc1cc(=O)n(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCCOc1cc(=O)n(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogencarbonate (2.18 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[3-(3,3-dimethyl-2-oxobutyl)-2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (30 mL), N,N′-carbonyldiimidazole (0.33 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as a colorless amorphous solid (0.17 g, 19%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:34]=[CH:33][C:15]([C:16]([NH:18][C:19]3[C:20](=[O:32])[N:21]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH:22]=[CH:23][CH:24]=3)=[O:17])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH2:42])[CH2:38][CH2:37]1>O>[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:34]=[CH:33][C:15]([C:16]([NH:18][C:19]4[C:20](=[O:32])[N:21]([C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH:22]=[CH:23][CH:24]=4)=[O:17])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:37]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1cccn(-c2ccc(F)cc2)c1=O)c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc(C(=O)Nc4cccn(-c5ccc(F)cc5)c4=O)cc3)c3nccn3n2)CC1
Reaction time: 12 h

Procedure:
To 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide (0.011 g, 0.023 mmol) from 1a was added trans-1,4-diaminocyclohexane (0.5 g, 57.0 mmol). The mixture was allowed to melt at 160° C. for 12 hours. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was then concentrated in vacuo to give 0.020 g of crude product. Purification was done via preparative HPLC providing 0.006 g of the title compound as a TFA salt. 1H NMR (400 MHz, MeOD) δ ppm 8.56 (1H, dd, J=7.38, 1.78 Hz), 7.92-8.10 (3H, m), 7.88 (1H, d, J=2.03 Hz), 7.42-7.61 (3H, m), 7.39 (1H, dd, J=7.12, 1.53 Hz), 7.30 (2H, t, J=8.65 Hz), 6.77 (1H, s), 6.54 (1H, t, J=7.12 Hz), 3.97 (1H, s), 3.66-3.84 (1H, m), 3.03-3.24 (1H, m), 2.26 (2H, m), 2.00-2.20 (2H, m), 1.44-1.68 (2H, m), 1.22-1.46 (2H, m). LC/MS, m/e 533 (M+1). HPLC Rt, 2.14 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:44]([NH:46][C@H:47]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:51][CH:50]=1)=[O:45])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:80][C:81]([O:84][C:85]([NH:87][C@H:88]([C:93]([OH:95])=O)[CH2:89][C:90]([NH2:92])=[O:91])=[O:86])([CH3:83])[CH3:82].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:87]([C:85]([O:84][C:81]([CH3:80])([CH3:82])[CH3:83])=[O:86])[C@H:88]([C:93]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:23]([NH:25][C@@H:26]([C:44]([NH:46][C@H:47]([C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:54]=1)=[O:45])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:34])=[O:35])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:95])[CH2:89][C:90](=[O:91])[NH2:92]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COCc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 2.20 g Boc-Ser(Bzl)-Phe-D-Arg(Tos)-Tyr(Bzl)-OBzl, 0.61 g Boc- Asn-OH, 0.51 g HONB and 0.58 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(IV).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.I[CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28].C1C=CC=CC=1.[BrH:40]>C(O)(=O)C.O>[Br-:40].[O:17]([C:15]([C:13]1[C:12]2[C:7]([N+:6]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12
Reactant: CC(C)(C)OC(=O)CCI
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)CC[n+]1c2ccccc2c(C(=O)Oc2ccccc2)c2ccccc21
Product: [Br-]
Temperature: 130 °C

Procedure:
A mixture of phenyl acridine-9-carboxylate (100 mg) and t-butyl 3-iodopropionate (5 g) is stirred and heated at 130° C. for sixteen hours. The resulting solution is poured into benzene (25 ml) and the resulting precipitate isolated by filtration. Part of this precipitate (10 mg) is stirred with 33% hydrobromic acid in acetic acid (1 ml), and heated at 50° C. for two hours. The reaction mixture is poured into water, and the resulting precipitate (ca. 6 mg) isolated.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1.[CH2:12]([CH:15]([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:15]([CH2:2][N:3]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4]1)([C:18]#[N:19])[C:16]#[N:17])[CH:13]=[CH2:14]
Reactant: COC(=O)c1cnn(CCl)c1
Reactant: C=CCC(C#N)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cn1cc(C(=O)OC)cn1
Yield: 45.2 %

Procedure:
0.79 g of 1-(chloromethyl)-4-methoxycarbonyl-1H-pyrazole and 0.49 g of allyl malononitrile were dissolved in 15 ml of N,N-dimethylformamide. 1.26 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-chloroform to obtain 0.50 g of allyl [{4-(methoxycarbonyl)-1H-pyrazole-1-yl}methyl]malononitrile (referred to as the compound of the present invention (24), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:8]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OCC)(=O)C>C(Cl)Cl>[C:39]1([S:45]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12]([C:14]4[C:15]([C:20]5[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=5)=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH:8]=3)[CH2:3]2)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a solution of the title F compound (4′-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide, 0.100 g, 0.250 mmol) in methylene chloride (10 mL) is added diisopropylethyl amine (0.036 g, 0.280 mmol) followed by benzenesulfonyl chloride (0.046 g, 0.260 mmol). After 1 h, the reaction mixture is poured into ethyl acetate and washed with 1 N HCl, 8% NaHCO3 solution, water, and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give an oil which is purified by silica gel chromatography. Drying under vacuum at 60° C. gives 4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)-amide as a non-crystalline solid; mp 96° C. sinters. MS (ES+), m/z 537 (M+1), 554 (M+NH4+).