Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[F:44]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:45])=[O:4])=[C:8]([F:44])[CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:33])([F:34])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.145 mL, 0.145 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 72-(1); 29.6 mg, 0.049 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (27.5 mg, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:5][NH:6][C:7]([C:9]1[N:21]=[C:20]2[N:12]([O:13][C:14]3[C:19]2=[C:18]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=3)[C:11](=[O:28])[C:10]=1[O:29]CC1C=CC=CC=1)=[O:8].Cl>ClCCl.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[Cl:40])[CH2:5][NH:6][C:7]([C:9]1[N:21]=[C:20]2[N:12]([O:13][C:14]3[C:19]2=[C:18]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:17]=[CH:16][CH:15]=3)[C:11](=[O:28])[C:10]=1[OH:29])=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2c3c(N4CCOCC4)cccc3on2c(=O)c1OCc1ccccc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1nc2c3c(N4CCOCC4)cccc3on2c(=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
Iron(III) chloride (10 mg, 0.062 mmol) was added to a stirred solution of the product from Example 19.7 (12 mg, 0.021 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 1.5 h then aqueous hydrochloric acid (1.0 M) was added dropwise until the solution became clear. Products were extracted with ethyl acetate and the organic phase dried and concentrated in vacuo. The residue was recrystallized from a mixed solvent (hexane/ethyl acetate 10/1) to afford the desired compound (8 mg, 80%) as a gray solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])[N:3]=[CH:2]1.[CH:12]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH:22](O)[C:16]=2[CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:9]([O:8][C:6]([C:4]1[N:3]([CH:18]2[C:17]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:2]=[N:1][CH:5]=1)=[O:7])([CH3:11])[CH3:10]
Reactant: CC(C)OC(=O)c1c[nH]cn1
Reactant: OC1CCCCc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cncn1C1CCCCc2ccccc21
Temperature: 0 °C

Procedure:
To a solution of isopropyl 4-imidazolecarboxylate (601 mg, 3.9 mmol) in THF (30 mL) is added 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (CAS#35550-94-8, 487 mg, 3.0 mmol), which can be prepared as described in Ollivier, R.; et al. Journal of Medicinal Chemistry, 1997, 40, 952-960, followed by triphenylphosphine (1.02 g, 3.9 mmol). The reaction is cooled to 0° C. and diisopropyl azodicarboxylate (755 μL, 3.9 mmol) is added. The reaction is permitted to warm to room temperature and stirred until LC-MS analysis indicates complete consumption of 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol. The reaction mixture is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:1) to provide 3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; HRMS: (ESI) m/z 299.1775 [(M+H)+; calcd for C18H23N2O2: 299.1760]; 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (d, J=6.3 Hz, 3 H), 1.23 (d, J=6.3 Hz, 3 H), 1.36-1.50 (m, 1 H), 1.87-2.24 (m, 4 H), 2.37-2.49 (m, 1 H), 2.85-2.95 (m, 1 H), 2.97-3.09 (m, 1 H), 4.99-5.14 (m, 1 H), 5.94 (d, J=7.8 Hz, 1 H), 6.44 (d, J=10.6 Hz, 1 H), 6.97-7.08 (m, 1 H), 7.08-7.21 (m, 2 H), 7.82-7.93 (m, 2 H). The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 3-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-3H-imidazole-4-carboxylic acid isopropyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.ClCCl.[CH:19]1([OH:25])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh].O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:25][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: OC1C=CCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
In a dry 25 mL round bottom flask under argon was placed diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (from Example 1, 552 mg, 2.25 mmol), dichloromethane (10 mL) and rac-2-cyclohexen-1-ol (0.45 mL, 4.51 mmol). The solution was stirred at 25° C. and then the rhodium (II) acetate dimer (20 mg, 0.045 mmol) was added. Gas evolution began immediately and the color changed from bright yellow to an aquagreen color. After the solution was stirred at 25° C. for a period of 1 h, it was poured into water and the layers were separated. The aqueous layer was washed with dichloromethane (3×15 mL), then the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate to afford rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid methyl ester (552 mg, 78% yield) as a light yellow oil: EI-HRMS m/e calcd for C15H16Cl2O3 (M+) 314.0468, found 314.0476.
Reaction SMILES: C(C1C(=O)OC(O)C=1)CCCCCCCCCCCC.OC1OC(=O)C=C1.C(CC[CH2:33][C:34]([O:36][CH:37]([C:50]1[CH:54]([OH:55])[O:53][C:52](=[O:56])[CH:51]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=O)(O)=O.COCCOCOC(C1C(O)OC(=O)C=1)CCCCCCCCCCCC.C[S:85](NC(C1C(O)OC(=O)C=1)CCCCCCCCCCCC)(=O)=O.COC(NC(C1C(O)OC(=O)C=1)CCCCCCCCCCCC)=O.BrCCCC(OC(C1C(O)OC(=O)C=1)CCCCCCCCCCCC)=O>>[C:34]([O:36][CH:37]([C:50]1[CH:54]([OH:55])[O:53][C:52](=[O:56])[CH:51]=1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=[S:85])[CH3:33]
Reactant: CCCCCCCCCCCCC(NS(C)(=O)=O)C1=CC(=O)OC1O
Reactant: CCCCCCCCCCCCC(OC(=O)CCCC(=O)O)C1=CC(=O)OC1O
Agent: CCCCCCCCCCCCC(NC(=O)OC)C1=CC(=O)OC1O
Agent: CCCCCCCCCCCCC(OC(=O)CCCBr)C1=CC(=O)OC1O
Agent: CCCCCCCCCCCCC(OCOCCOC)C1=CC(=O)OC1O
Product: CCCCCCCCCCCCC(OC(C)=S)C1=CC(=O)OC1O

Procedure:
4-[1-(glutarylamido)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound 101); 4-[1-(N-methylcarbamoyl)-N-methyl)carbamoyl]tridecyl-5-hydroxy-2(5H)furanone (Compound 102); 4-[(1-phenylcarbamoyl)tridecyl]-5-hydroxy-2(5H)-furanone (Compound 103); 4-[1-ethoxycarbonyloxy)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound 104); 4-[1-(4-carboxybutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone (Compound 105); 4-[1-4-carbomethoxybutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone (Compound 106); 4-[1-(2-methoxyethoxy)methoxytridecyl]-5-hydroxy-2(5H)-furanone; 4-[1-(methylsulfonamido)-tridecyl]-5-hydroxy-2(5H)-furanone (Compound 107); 4-(1-(methoxycarbonylamino)tridecyl]-5-hydroxy-2(5H)-furanone (Compound 108); 4-[1-(4-bromobutanoyloxy)tridecyl]-5-hydroxy-2(5H)-furanone (Compound 109), and 4-[1-PO(OCH3)CH3O-tridecyl]5-hydroxy-2(5H)-furanone (Compound 110).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]([NH:10]C(=O)OC(C)(C)C)([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4]>Cl.C(OCC)(=O)C>[NH2:10][C:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3]([NH:2][CH3:1])=[O:4]
Reactant: CCC(CC)(NC(=O)OC(C)(C)C)C(=O)NC
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC(N)(CC)C(=O)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of tert-butyl 3-(methylcarbamoyl)pentan-3-ylcarbamate (0.18 g, 0.74 mmol) in 10 ml saturated hydrochloride in ethyl acetate was stirred for 60 min at room temperature. Then the solution was evaporated to dryness to obtain the product (80 mg, 75%) as a light yellow solid; MS (LC/MS): 145.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5](C(O)=O)[N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>[Cu]=O.CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(O)c1cc(Cl)nn1-c1cccnc1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2cccnc2)n1

Procedure:
In step d of Scheme 2, 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (6e) is decarboxylated in the presence of copper (II) oxide in polar solvents such as N,N-dimethylformamide at temperatures from about 80° C. to about 140° C. to yield 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b). It was surprisingly discovered that this decarboxylation only occurs in the presence of copper (II) oxide. Several known decarboxylation agents from the literature such as, for example, hydrochloric acid (See alternate synthetic route, Example 14), sulfuric acid, and palladium (II) trifluoroacetate/trifluoroacetic acid (Pd(TFA)2/TFA) (See “CE-5”) did not yield the desired product.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCc3ccccc3)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (2.00 g, 9.02 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added benzylamine (4.88 mL, 90.20 mmol) and the reaction mixture was stirred for 1.5 h at 160° C. then 45 min at 180° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up in a mixture of THF:1 N aq. HCl=1:1 (50 mL) and stirred for 1 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) provided a mixture of the desired product and its benzyl imine derivative. This mixture was taken up in a mixture of THF:1 N aq. HCl=1:1 (20 mL) and stirred for 2 h at RT. The volatiles were then removed at 40° C. under vacuum and the residue was then neutralised with a saturated NaHCO3 aqueous solution before extraction with CH2Cl2 (100 mL). The organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 75:25) gave, after evaporation and drying, 2-(benzylamino)-6-methoxyquinoline-3-carbaldehyde SLA 41002 as a yellow solid (0.431 g, 16% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:3]=1.[NH2:18][C:19]1[CH:33]=[CH:32][C:22]2[N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:24]=[N:25][C:21]=2[CH:20]=1>CC(O)C>[C:26]1([N:23]2[C:22]3[CH:32]=[CH:33][C:19]([NH:18][C:2]4[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:4][N:3]=4)=[CH:20][C:21]=3[N:25]=[CH:24]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccc2c(c1)ncn2-c1ccccc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CC(C)O
Product: c1ccc(-c2nnc(Nc3ccc4c(c3)ncn4-c3ccccc3)c3ccccc23)cc1
Yield: 99.6 %

Procedure:
A solution of 1-chloro-4-phenylphthalazine (156 mg, 0.65 mmol) and 5-amino-1-phenylbenzimidazole (4) (105 mg, 0.5 mmol) in i-PrOH (10 mL) is stirred at 95° C. under argon for 2 h. The reaction mixture is concentrated, diluted with sat. NaHCO3 (15 mL), and extracted with CHCl3 (100 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (1% to 9% methanol/ethyl acetate) to give 206 mg (99%) of 5 as an orange solid, mp 265° C. IR 3285, 2842, 1615, 1476 cm−1; 1H NMR (CDCl3) δ 7.45-7.61 (m, 5H, 1-PhH), 7.62-7.77 (m, 6H, 4′-C6H5, 7-BenzimidH), 7.82 (dd, J=8.7, 2.1 Hz, 1H, 6-BenzimidH), 7.86-7.90 (m, 1H, 5′-PhthH), 7.91-7.98 (m, 1H, 6′-PhthH), 8.00-8.08 (m, 1H, 7′-PhthH), 8.50 (d, J=2.1 Hz, 1H, 4-BenzimidH), 8.56 (s, 1H, 2-BenzimidH), 8.72 (d, J=8.7 Hz, 1H, 8′-PhthH), 9.37 ppm (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[Cl:18][C:19]1[C:28](B(O)O)=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>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>[Cl:18][C:19]1[C:28]([C:2]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: OB(O)c1cc2ccccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cc3ccccc3nc2Cl)c2ncn(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.55 g, 2.18 mmol), 2-chloroquinolin-3-ylboronic acid (0.90 g, 4.35 mmol, Aldrich, St. Louis, Mo.) and tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.11 mmol, Strem Chemicals, Inc., Newburyport, Mass.) in dioxane (3 mL) and water (1 mL) was sealed and purged with argon for several minutes. The reaction mixture was stirred at 90° C. for 6 h and then allowed to cool to room temperature. The organic phase was taken and the solvents removed under vacuum. Purification of the crude reaction mixture by silica gel chromatography (0 to 3% MeOH/CH2Cl2) provided the title compound as an orange solid. m/z (ESI, +ve ion) 380 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)([CH2:11]2)[CH:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][NH2:15])([CH2:11]2)[CH:9]1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(CN2C(=O)c3ccccc3C2=O)C1c1ccccc1
Agent: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC2(CN)C1c1ccccc1
Yield: 69.4 %

Procedure:
To the starting material, 1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.560 g, 1.34 mmol) (Intermediate 20) was added ethanol (10 mL) and hydrazine (35% in H2O, 0.483 mL, 5.36 mmol). The reaction was heated to reflux, and although within a few minutes a solid precipitated that impeded stirring, the reaction was heated for a total of 80 minutes. The solvent was removed at reduced pressure and the residue partitioned between 1N NaOH solution and methylene chloride. The organics were washed with a saturated solution of citric acid two times and the methylene chloride discarded. The aqueous layer was basified with sodium bicarbonate and extracted with methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1-aminomethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester as an oil (0.268 g, 69% yield).
Reaction SMILES: [C:1]([OH:6])(=O)/[CH:2]=[CH:3]/[CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>C1COCC1>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])/[CH:2]=[CH:3]/[CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: C/C=C/C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C/C=C/C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
A solution of 0.637 g (7.40 mmol) of E-but-2-enoic acid in 25 mL of THF under N2 was chilled in ice. Isobutyl chloroformate (1.01 g, 7.40 mmol) and N-methylmorpholine (0.747 g, 7.40 mmol) were added and the solution was stirred cold for 10 min. A slurry of 1.00 g (2.96 mmol) of 6-amino-4-(3-bromophenylamino)-quinoline-3-carbonitrile in 15 mL of THF was added and the mixture was stirred at 25° C. overnight. The mixture was evaporated and the residue was slurried in water, collected and dried. The residue was boiled twice with EtOAc and dried in vacuo (50° C.) to give 0.965 g of (E)-but-2-enoic acid [4-(3-bromophenylamino)-3-cyano-quinolin-6-yl]amide as a yellow solid: mass spectrum (electrospray, m/e): M+H 406.9, 408.9.
Reaction SMILES: Cl[CH:2]([N:7]=[C:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[C:17](#[N:20])[CH:18]=[CH2:19].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[NH:7][C:2]([C:3]([F:6])([F:5])[F:4])=[CH:19][C:18]=2[C:17]#[N:20])=[CH:10][CH:11]=1
Reactant: FC(F)(F)C(Cl)N=C(Cl)c1ccc(Cl)cc1
Reactant: C=CC#N
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A solution of N-[1-chloro-(2,2,2-trifluoroethyl)]-4-chlorobenzimidoyl chloride (5.80 g, 0.02 mol) and acrylonitrile (1.33 g, 0.025 mol) in N,N-dimethyl-formamide (15 mL) is treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 8.53 g, 0.056 mol) over 1 hour while maintaining the temperature at 45°-50° C. The reaction mixture is then stirred at 50° C. for 4 hours, quenched with dilute HCl, and extracted with ethyl acetate. The organic extract is concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel, packed and eluted with 20% ethyl acetate in heptane, and crystallization from heptane and small amount of ethyl acetate gives the title product as a white crystalline solid (2.1 g, 38.9% yield): mp 239-240° C. (dec).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:11][C:10]=12)=[O:5])C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+].[OH-].[K+]>C(O)C.CCOC(C)=O.CN(C=O)C>[CH2:23]([N:11]1[CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][C:14]([CH3:16])([CH3:15])[N:9]2[N:8]=[CH:7][C:6]([C:4]([OH:3])=[O:5])=[C:10]12)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cnn2c1NC(c1ccccc1)CC2(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC(c2ccccc2)N(Cc2ccccc2)c2c(C(=O)O)cnn21
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir bar was added 1.80 g (6.01 mmol) of 7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester, 30 mL of DMF and 0.786 mL (6.61 mmol) of benzyl bromide, followed by 0.265 g (6.6 mmol) of sodium hydride (60% dispersion in mineral oil) which was added in several portions. After 2 h, the reaction was quenched with water and the product was extracted with AcOEt. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude N-benzylated ester as a golden colored oil. The crude ester was dissolved in 15 mL of ethanol and 2.5 mL of 6N potassium hydroxide was added. The solution was then heated to 70° C. for 18 h at which time no starting material could be detected by HPLC analysis. The crude reaction mixture was concentrated in vacuo and diluted with water. The aqueous solution was acidified with 6N HCl and the resulting cream-colored precipitate was collected by filtration. The crude acid thus isolated was dissolved in AcOEt, dried over sodium sulfate, filtered and concentrated to a cream colored powder. The resulting acid was washed with several portions of hexanes and dried in vacuo to give 1.95 g (90%) of the title compound as an off white powder. 1H NMR (DMSO-d6) δ 1.10 (s, 3H), 1.40 (s, 3H), 1.98-2.16 (m, 2H), 3.71 (d, J=15.4 Hz, 1H), 4.36 (dd, J=4.5, 11.5 Hz, 1H), 5.81 (d, J=15.6 Hz), 6.97 (dd, J=1.4, 7.2 Hz, 2H), 7.26-7.45 (m, 7H), 7.67 (s, 1H), 11.81 (s, 1H). MS Calcd.: 361. Found: 344 (M−OH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([Cl:15])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
According to the synthesis scheme shown above, a mixture of indole-2-carboxylic acid (98 mg, 0.61 mmol, purchased from ACROS Co.), 10 ml benzene and thionyl chloride (SOCl2) (224 ml, 3.1 mmol) was placed in a 50 ml round-bottom flask purged with nitrogen gas and refluxed for 2 h while stirring, followed by cooling to room temperature. The mixture was concentrated to dry within a concentrator under a reduced pressure, and after the addition of 10 ml benzene, the mixture was concentrated again. Excess thionyl chloride (SOCl2) was removed from the mixture by three repeats of adding 10 ml benzene and concentrating the mixture, thus obtaining the title compound in the form of a yellow solid.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])/[C:9]1=[O:37])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:54])=[C:43]([CH:45]=[N:46][C:47]([O:49][Si](C)(C)C)=[CH2:48])[CH:44]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:37])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:48][C:47](=[O:49])[NH:46][CH:45]3[C:43]3[CH:44]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=3[CH3:54])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCCNC(=O)OC(C)(C)C)C12C(=O)Nc1cc(Cl)ccc12
Yield: 9 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-3-[2-(2-tert-butoxycarbonylamino-ethoxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (8 g, 14.6 mmol) prepared in Example 32d was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (43.8 mmol) in toluene (22 mL) to give the title compound as a white solid (830 mg).