Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([NH:9][C:10]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(NC2(Cc3ccccc3)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(NC3(Cc4ccccc4)CC3)nc(N)n2)cc1F
Temperature: 110 °C
Yield: 51.5 %

Procedure:
A mixture of 6-chloro-N4-[1-(phenylmethyl)cyclopropyl]-2,4-pyrimidinediamine (185 mg, 0.67 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (247 mg, 1 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and Na2CO3 (178 mg, 1.68 mmol) in 1,4-dioxane (30 mL) and water (10 mL) was stirred and heated at 110° C. for 3.5 hours under nitrogen. Then the mixture was cooled to room temperature and concentrated. The resulting residue was portioned between EtOAc and water. The aqueous was extracted with EtOAc (2×50 mL), and the organics were dried (MgSO4), filtered, concentrated to dryness, and purified by SGC using a petroleum ether to 4:1 petroleum ether/EtOAc to 1:1 petroleum ether/EtOAc as eluent to afford the title compound (124 mg) as a brown oil solid. LC-MS (ES) m/z=360 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[N:11]([O-])=O.[Na+].[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([N:11]=[N:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])[CH3:17]
Reactant: COC(=O)c1sccc1N
Reactant: CNC
Reactant: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1sccc1N=NN(C)C

Procedure:
Diazotization of methyl 3-aminothiophene-2-carboxylate or its precursors with sodium nitrite followed by treatment with dimethylamine provides methyl 3-[(dimethylamino)diazenyl]thiophene-2-carboxylate or its derivatives in good yield. Treatment of the above esters with ammonia gave the triazene analogs of formula (I) (3-[(dimethylamino)diazenyl]thiophene-2-carboxamide (compd No. 1), compd. No. 2, compd. No. 3, compd. No. 4, compd. No. 5).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)#N.C(O)(=[O:20])C>N1C=CC=CC=1.O.[Ni]>[CH:1]([C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2)=[O:20]
Reactant: CC(=O)O
Reactant: COC(=O)C[C@H]1CCc2c1ccc(C#N)c2C
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C[C@H]1CCc2c1ccc(C=O)c2C
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of methyl (R)-(5-cyano-4-methyl-indan-1-yl)acetate (1.00 g, 4.36 mmol, from EXAMPLE 110, Step J) in pyridine (28 mL), acetic acid (15 mL), H2O (15 mL) and NaH2PO2 (3.07 g, 34.9 mmol) Rainey nickel was added (1.0 g) and the mixture was heated to 50° C. After 5 hr, the reaction was concentrated in vacuo and filtered through Celite®. The filtrate was concentrated in vacuo and partitioned between EtOAc (150 mL) and H2O (50 mL). The organic layer was washed with 5.0 N HCl (7×50 mL), sat. NaHCO3 (2×50 mL), brine (1×50 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10% EtOAc/hexanes) to give 882 mg of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 1.76-1.84 (m, 1H), 2.41-2.51 (m, 2H), 2.57 (s, 3H), 2.78 (dd, 1H, J=5.5, 15.6 Hz), 2.81-2.87 (m 1H), 2.93-2.99 (m, 1H), 3.61-3.67 (m, 1H), 3.72 (s, 3H), 7.16 (d, 1H, J=7.8 Hz), 7.63 (d, 1H, 7.8 Hz), 10.2 (s, 1H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[N:17]2[CH:12]([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[CH2:11]1.CN(C)[CH:22]=[O:23].[C:25](Cl)(=[O:27])[CH3:26].P([O-])([O-])([O-])=O>O1CCCC1>[O:9]=[C:10]1[N:17]2[CH:12]([CH2:13][CH2:14][O:15][C:16]2([CH3:19])[CH3:18])[C:11]1=[CH:22][O:23][C:25](=[O:27])[CH3:26]
Reactant: CN(C)C=O
Reactant: CC1(C)OCCC2CC(=O)N21
Reactant: CC(=O)Cl
Agent: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)OC=C1C(=O)N2C1CCOC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of 2.0 equivalents of freshly prepared lithium diisopropylamide in 5 ml anhydrous tetrahydrofuran under nitrogen atmosphere at -78° C. is added a solution of 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (98 mg., 0.629 mmmole) in 2 ml anhydrous tetrahydrofuran which has been cooled to -78° C. After two minutes excess anhydrous N,N-dimethylformamide (460 mg, 6.29 mmole) is added followed immediately by distilled and degassed acetyl chloride (148 mg, 1.89 mmole) which has been cooled to -78° C. After stirring at -78° for a period of 5 minutes, the reaction mixture is poured into 0.2M pH 7 phosphate buffer. The product is extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give 64 mg of a colorless oil. Purification by preparative thick-layer chromatography on silica gel developing twice with ether gives 8 -oxo-7-acetoxy-methylene-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane (25 mg).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>ClC(Cl)C.ClCCl>[OH:27][C:25]1[CH:26]=[C:21]([OH:20])[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:23][C:24]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COC(=O)CCCCc1ccc(O)cc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCc1cc(C(=O)c2ccccc2C(=O)O)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2-liter round-bottomed flask was charged with 12.83 g (86.6 mmoles) of phthalic anhydride and a stir bar. Anhydrous 1,2-dichloroethane (190 ml) was added. The flask was flushed with argon, and a reflux condenser was added to the flask. A drying tube was added to the top of the condenser. The mixture was stirred for 30 minutes. (The solid did not dissolve completely.) Then 28.6 g (214.5 mmoles) of aluminum chloride was added (by momentarily removing the condenser). Most solids were dissolved; a greenish-yellow solution results. Stirring was continued for another 30 minutes while a solution of 18.5 g (82.5 mmoles) of methyl-5-(2,4-dihydroxyphenyl)-pentanoate (5a) in 130 ml of dichloroethane was made. This solution was poured into the flask, the headspace was flushed with argon, and the condenser was replaced. With good stirring, the solution in the flask was heated to a light reflux for 30 to 60 minutes. The solution in the flask became slightly warm and turned dark. HCl gas was evolved for about 10-20 minutes. Then the solution was cooled to room temperature. A tarry precipitate formed. The reaction was concentrated to a gum. To this material a mixture of ice (400 g) and concentrated HCl (200 ml) was added followed by 500 ml of ethyl acetate. The flask was capped with a septum and placed on an orbital shaker until all solid dissolved. The mixture was transferred to a 2-liter separatory funnel. The organic layer was separated, washed with 400 ml of 1 N HCl, 2×200 ml of saturated NaCl and dried over sodium sulfate. Concentration afforded an oil. To this material, 200 ml of dichloromethane was added. The resulting solution was sonicated for 30 minutes, and then cooled to −20° C. for 2 hours. The crystalline precipitate was filtered off, washed with 2:1 hexanes/dichloromethane, followed by 4:1 hexanes/dichloromethane and dried. Yield was 20.0 g (65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)cc1
Temperature: 0 °C
Yield: 89.8 %

Procedure:
Dissolve 4-bromo-benzenethiol (1.0 g, 5.3 mmol) in dry dimethylformamide (50 mL) and cool to 0° C. under nitrogen. Add dry sodium hydride (153 mg, 6.4 mmol) in portions. After the vigorous gas evolution stops, add 2-bromo-propane (0.60 mL, 6.4 mmol) and stir the reaction overnight at room temperature. Slowly pour the reaction into water (300 mL) and extract with ethyl acetate (2×150 mL). Wash the combined organic layers with water (100 mL) and brine (100 mL). Dry the organic layer with sodium sulfate, filter and concentrate in vacuo. Chromatograph the resultant residue on a SiO2 column with 5% ethyl acetate in hexanes to yield 1.1 g of 1-bromo-4-isopropylsulfanyl-benzene (92%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([CH:13]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O>[ClH:14].[CH2:1]([C:5]1[CH:6]=[C:7]2[N:12]([C:13]=1[C:22]([C:21]1[CH:25]=[CH:26][C:18]([CH2:17][CH2:16][CH2:15][N:12]([CH2:7][CH2:6][CH3:5])[CH2:11][CH2:10][CH3:9])=[CH:19][CH:20]=1)=[O:23])[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccc(CCCCl)cc1
Reactant: CCCCc1cc2ccccn2c1
Solvent: O
Product: CCCCc1cc2ccccn2c1C(=O)c1ccc(CCCN(CCC)CCC)cc1
Product: Cl
Temperature: 50 °C
Yield: 109.9 %

Procedure:
A mixture of 9 g (56 mmoles) of 2-butyl-indolizine and 12.4 g (57 mmoles) of 4-(3-chloropropyl)benzoyl chloride was heated to 50° C. for 18 hours. It was taken up in water, extracted with dichloromethane, washed with sodium carbonate solution, the organic phase was dried over sodium sulphate and concentrated to dryness. Next, it was purified by flash chromatography over silica (eluent: methylene chloride-heptane, 80/20). In this manner, 14 g of the desired compound was obtained in the form of an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2].[CH2:21]([NH2:23])[CH3:22]>>[C:1]([C:3]1[CH:4]=[C:5]([N:11]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][C:13]([NH:23][CH2:21][CH3:22])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]#[N:10])#[N:2]
Reactant: CCN
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C#N
Product: CCNC(=O)CN(CC(F)(F)F)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3,4-dicyanophenyl)-N-(2,2,2-trifluoroethyl)glycine and ethylamine: MS (ES) m/z 311 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O.[NH2:21][NH2:22]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: O
Product: Cc1nccn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, the reaction of 4-(2-methyl-1H-imidazol-1yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone (3b).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:8][N:7]=1.C(Cl)(Cl)Cl>C(OC(C)C)(C)C>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:8]1)=[O:4]
Reactant: CN=C=O
Reactant: Oc1nsc(Cc2ccccc2)n1
Solvent: CC(C)OC(C)C
Solvent: ClC(Cl)Cl
Product: CNC(=O)n1sc(Cc2ccccc2)nc1=O
Temperature: 20 °C
Reaction time: 72 h

Procedure:
50 ml of methyl isocyanate were added to a solution of 15 g of 3-hydroxy-5-benzyl-1,2,4-thiadiazole in 400 ml of isopropyl ether and the mixture was stirred at 20° C for 72 hours. 50 ml of chloroform were added thereto and the mixture was vacuum filtered. The recovered crystals were dried to obtain 10 g of 2-(methylcarbamoyl)-5-benzyl-1,2,4-thiadiazole-3-one melting at 146° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][CH2:30][O:20][C:19](=[O:21])[CH2:18][NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)O
Reactant: OCCCc1ccccc1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NCC(=O)OCCCc1ccccc1

Procedure:
Following General Procedure X and using N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine (prepared from N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester (from Example 73 below) using General Procedure O) and and 3-phenyl-1-propanol (Aldrich), the title compound was prepared as a solid (mp=137° C.). The reaction was monitored by tlc (Rf=0.15 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[O:9]1[C:5]2[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)OCC2
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)OCC2
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 73 mmol) in DMSO (100 mL) was added KCN (7.1 g, 109.5 mmol). The reaction mixture was stirred at 100 □ for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried, concentrated in vacuo and purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford 2-(2,3-dihydrobenzofuran-6-yl)acetonitrile (8.4 g, 70.4% yield). 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J=7.6, 1H), 6.79 (d, J=7.2, 1H), 6.72 (s, 1H), 4.58 (t, J=8.4, 2H), 3.67 (s, 2H), 3.19 (t, J=8.4, 2H).
Reaction SMILES: [SH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:30][O:29][C:27]([C:26]1[CH:25]=[CH:24][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][S:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[N:18]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CSC3CCN(C(=O)OC(C)(C)C)CC3)c(C)o2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
A mixture of the crude tert-butyl 4-mercaptopiperidine-1-carboxylate (2.34 g, 10.78 mmol, 1.20 equiv), methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.33 g, 8.79 mmol, 1.00 equiv) and potassium carbonate (1.74 g, 12.39 mmol, 1.50 equiv) in N,N-dimethylformamide (23.4 mL) was stirred overnight in a 100-mL round-bottom flask at 50° C. The reaction mixture was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The organic layer was washed with 2×40 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted with ethyl acetate/petroleum ether (1:30-1:5) on a silica gel column to give 920 mg (23%) of tert-butyl 4-((2-(4-(methoxycarbonyl)phenyl)-5-methyloxazol-4-yl)methylthio)piperidine-1-carboxylate as a yellow solid. LC-MS: (ES, m/z): 447 [M+H]+, 347, 271, 146, 105.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][NH:10][C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]4([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=2)=[N:16]3)=O)[N:4]=[CH:3]1.C(O)(=O)C.O1CCOCC1>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:20]3[C:11]([C:12]4[CH:13]=[C:14]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:15]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:28][CH2:29][CH2:30]6)=[CH:25][CH:26]=5)=[N:16][C:17]=4[CH:18]=[CH:19]3)=[N:10][N:9]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(C(=O)NNc2nccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)cc23)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)nc4ccn23)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a round bottom flask was added tert-butyl {1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) (2.73 g, 4.63 mmol), acetic acid (5.30 mL, 93 mmol), and 1,4-dioxane (20 mL). The reaction mixture was heated to 80° C. while stirring open to the atmosphere (capped) in a hot oil bath. After 3 hours the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 1-15% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo. The resulting residue was repurified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (1-8) as an off-white solid. MS (M+H)+: observed=572.3, calculated=572.7.
Reaction SMILES: [NH2:1][C:2]1[C:11](/[CH:12]=[CH:13]/[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[C:21]([O:23][CH3:24])=[O:22].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:17]([O:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:11]1[C:2]([NH:1][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])=[C:3]([C:21]([O:23][CH3:24])=[O:22])[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COC(=O)c1c(N)c(/C=C/C(=O)OC(C)(C)C)cc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1c2c(cc(/C=C/C(=O)OC(C)(C)C)c1NS(=O)(=O)c1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
A solution of Example 476B (0.12 g, 0.36 mmol) in pyridine (1 mL) was treated with benzenesulfonyl chloride (0.071 g, 0.40 mmol), and stirred for 16 hours at ambient temperature. The mixture was concentrated, diluted with 1M NaHSO4 and extracted with dichloromethane. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography eluting with 30% ethyl acetate/hexanes gave the desired product (0.12 g). MS (DCI) m/e 472 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH3:21]>CN(C=O)C.C(OCC)C.[I-].[K+]>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH2:20][CH3:21]
Reactant: CCCBr
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCOc1cc(C=O)ccc1OC
Temperature: 65 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
To a suspension of 3-hydroxy-4-methoxybenzaldehyde (2.00 g, 13.2 mmol), potassium carbonate (2.74 g, 19.8 mmol) and potassium iodide (60.0 mg, 0.361 mmol) in DMF (15 mL) was slowly added 1-bromopropane (1.56 mL, 17.2 mmol) via syringe. The reaction mixture was stirred at 65° C. for 5 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 mL), and the organic phase was washed with water (2×50 mL). After drying over anhydrous MgSO4, filtration and evaporation of the filtrate in vacuo gave crude 3-(propyloxy)-4-methoxybenzaldehyde (2.60 g) which was used in the next step without further purification.
Reaction SMILES: C(I)I.[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[CH2:10])[CH3:5].[CH3:13]COC(C)=O>C(OCC)C>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]1([CH3:13])[CH2:11][CH2:10]1)[CH3:5]
Reactant: C=C(C)CC(=O)OCC
Reactant: CCOC(C)=O
Solvent: ICI
Solvent: CCOCC
Product: CCOC(=O)CC1(C)CC1
Temperature: 60 °C

Procedure:
Zn—Cu couple (10.726 g) suspended in diethyl ether (20 ml) was treated at RT under an argon atmosphere with CH2I2 (14.86 g) and 3-methyl-but-3-enoic acid ethyl ester (3.9 g) and heated in a closed reaction vial at 60° C. for 20 h. The mixture was then cooled to RT, AcOEt (50 ml) were added and reaction mixture was filtered. The filter cake was washed with AcOEt, the combined filtrates washed with water (125 ml), dried over MgSO4 and then evaporated (applying a 40 mbar vacuum). This gave the desired (1-methyl-cyclopropyl)-acetic acid ethyl ester (4.4 g) as a brown liquid that was essentially pure (according to NMR) and used directly in the next reaction step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]3[CH:18]=[CH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:21][C:10]=3[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)cc1)n2C1CCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(NC(=O)c3ccccc3)cc1)n2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.5 %

Procedure:
Ethyl 1-cyclopentyl-2-(4-aminophenyl)benzimidazole-5-carboxylate (300 mg) obtained in Example 22 was dissolved in pyridine (3 ml) and chloroform (3 ml), and benzoyl chloride (127 mg) was added. The mixture was stirred for 30 min at room temperature. The reaction mixture was concentrated under reduced pressure and water was added to the residue to allow crystallization. The crystals were collected by filtration to give the title compound (403 mg, yield 100%).