Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]2[C:10]=1[C:11]([CH3:21])=[C:12]([CH3:20])[NH:13]2)C1C=CC=CC=1.C(O)C>[Pd].C1CCCCC1>[CH3:20][C:12]1[NH:13][C:14]2[C:10]([C:11]=1[CH3:21])=[C:9]([OH:8])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19]
Reactant: COc1ccc(OCc2ccccc2)c2c(C)c(C)[nH]c12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCCCC1
Product: COc1ccc(O)c2c(C)c(C)[nH]c12

Procedure:
0.14 mole (39.5 g) of 4-benzyloxy-2,3-dimethyl-7-methoxyindole and 4 g of 10% palladium-on-charcoal in 120 ml of 96° ethanol to which have been added 80 ml of cyclohexane is heated under reflux. After 1 hour 30 minutes the catalyst is removed by hot filtration. The desired product is obtained by concentrating the filtrate to dryness. It is purified by dissolving it hot in isopropyl ether, filtering in the presence of charcoal and evaporating the filtrate to dryness. It melts at 164° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH:27]([NH2:29])[CH3:28])=[CH:22][CH:23]=2)[CH2:18]1)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:14][C:15]([N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH:27]([NH:29][C:8](=[O:10])[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=3)[CH3:28])=[CH:22][CH:23]=2)[CH2:18]1)=[O:16]
Reactant: COC(=O)N1CCc2ccc(C(C)N)cc2C1
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2ccc(C(C)NC(=O)C=Cc3ccc(F)cc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-fluorocinnamic acid (1 mmol), (±)-7-(1-aminoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester, Preparation 10 (280 mg, 1.2 mmol), EDC hydrochloride (387 mg, 2 mmol), DMAP (122 mg, 1 mmol), and triethylamine (404 mg, 4 mmol) in CH2Cl2 (8 mL) was stirred at room temperature for 16 hours. The reaction mixture was directly subjected to purification by flash column chromatography on silica gel eluted with EtOAc/hexane (50%) to provide the title compound (295 mg).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:27])=[C:14]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=3[Cl:26])[CH:15]=2)=[CH:6][CH:5]=1.O.[Li+].[OH-]>C(O)(C)C.CCOC(C)=O.[Cl-].[Na+].O>[NH2:27][C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=2)=[CH:15][C:14]=1[O:16][CH2:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[Cl:26]
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OCc3c(F)ccc(F)c3Cl)c2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: Nc1ncc(-c2ccc(C(=O)O)cc2)cc1OCc1c(F)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a stirred solution of 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid methyl ester (2.5 g, 6 mmol) in warm isopropanol (300 mL) was added H2O (100 mL) containing LiOH (0.74 g, 31 mol). The reaction immediately turned orange and was left to stir at room temperature for 18 hr. The reaction was diluted with EtOAc (200 mL) and brine (50 mL). The organic was separated off and the aqueous was extracted with EtOAc (2×50 mL). The organic layers were combined and washed with brine (2×25 mL), dried with Na2SO4 and concentrated to dryness under vacuum to yield 4-[6-amino-5-(2-chloro-3,6-difluoro-benzyloxy)-pyridin-3-yl]-benzoic acid (2.4 g, 6 mmol, 99%) as an off-white solid.
Reaction SMILES: [CH2:1](O)[CH3:2].[CH:4]([CH:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH:4]([CH:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:30])[CH2:24][O:25][CH2:26][C:27]([O:29][CH2:1][CH3:2])=[O:28])[CH2:21][CH2:22]1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: O=C(O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCOC(=O)COCC(=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To about 50 milliliters of ethanol is added 3.63 grams (10 millimoles) of [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetic acid (prepared as described in Example V) and 200 milligrams of p-toluenesulfonic acid and the mixture refluxed for about four hours whereupon a reaction takes place with the formation in the reaction mixture of the desired ester product as confirmed by chromatographic analysis. The reaction mixture is subjected to reduced pressure to evaporate the ethanol and to obtain a product residue which is then dissolved in dichloromethane. The dichloromethane solution is first washed with aqueous bicarbonate solution, then dried over potassium carbonate and finally evaporated under reduced pressure to recover an ethyl [2-(4-benzhydrylpiperidino)-2-oxoethoxy]acetate product as residue. The ester product which may be further purified by distillation under reduced pressure has a molecular weight of 391.5.
Reaction SMILES: OO.[NH2:3][C:4]([CH:11]([CH3:13])[CH3:12])=[C:5]([C:9]#[N:10])[C:6](=[S:8])[NH2:7]>C(O)C>[NH2:7][C:6]1[S:8][N:3]=[C:4]([CH:11]([CH3:13])[CH3:12])[C:5]=1[C:9]#[N:10]
Reactant: CC(C)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Product: CC(C)c1nsc(N)c1C#N
Temperature: 25 °C
Reaction time: 19 h
Yield: 97 %

Procedure:
While maintaining the temperature below 50°, 86.1 g of 30% hydrogen peroxide was added dropwise to a solution of 128.3 g of 3-amino-2-cyano-4-methyl- 2-pentenethioamide in 600 ml of absolute ethanol. The mixture was stirred at room temperature for 19 hours, filtered and concentrated to about half volume. Water was added to cloud point and the solid allowed to separate. The solid was collected and dried to give 123.0 g of 5-amino-4-cyano-3-isopropylisothiazole, mp 133°-135°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23]Cl)[CH:17]=[CH:18][C:19]=1[Cl:20].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:25])[CH2:23][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(CCl)Nc1ccc(Cl)c(Cl)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3,4-dichlorophenyl)-2-chloroacetamide (48 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 58 mg (41%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.65 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.65 (t, J=5 Hz, 1H), 6.85 (d, J=6 Hz, 1H), 7.41 (m, 2H), 7.55 (t, J=6 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.25 (d, J=6 Hz, 1H), 10.08 (s, 1H); MS (ESI/APCI+) m/e 365 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[N:3]=1.[CH3:18][O-:19].[Na+].C(Cl)(Cl)Cl.O>CO>[Cl:12][C:11]1[C:2]([O:19][CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:6]([CH3:17])[CH:5]=2
Reactant: C[O-]
Reactant: COC(=O)c1cc2nc(Cl)c(Cl)nc2cc1C
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2nc(Cl)c(OC)nc2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under cooling in an ice-acetone bath, to a mixed liquid of 10.0 g of methyl 2,3-dichloro-7-methylquinoxaline-6-carboxylate in methanol was added dropwise a mixed liquid of 8.54 g of a 28% sodium methoxide solution in methanol and 80.0 mL of methanol over 6 hours. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature, followed by stirring for 1 hour. To the reaction mixture were added chloroform and water, followed by extraction with chloroform, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 10.1 g of methyl 3-chloro-2-methoxy-7-methylquinoxaline-6-carboxylate as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH:15]=1)[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 50 °C

Procedure:
To a solution of a mixture of 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid ethyl ester and methyl ester (56 mg, 0.09 mmol) in MeOH (1 mL) was added 3N NaOH (0.060 mL) and heated to 50° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 4-methyl-2-{4′-trifluoromethyl-5-[1-(4-trifluoromethyl-benzyl)-piperidin-4-yl]-biphenyl-3-yl}-pentanoic acid.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[C@H:51]12[CH2:57][C@H:54]([NH:55][CH2:56]1)[CH2:53][N:52]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:52]3[CH2:53][C@@H:54]4[CH2:57][C@H:51]3[CH2:56][NH:55]4)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (46 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (227.5 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient on a C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky, white solid [71.5 mg (59%)]. LC-MS m/z 752.3 (M+H)+.
Reaction SMILES: N[C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.N([O-])=O.[Na+].[C:23]([Cu])#[N:24]>Cl>[CH3:18][N:15]1[CH2:16][CH2:17][C:3]2[C:2]([C:23]#[N:24])=[CH:11][C:10]3[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6][C:5]=3[C:4]=2[CH2:14]1
Reactant: CN1CCc2c(N)cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: N#C[Cu]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CN1CCc2c(C#N)cc3[nH]c(=O)c(=O)[nH]c3c2C1

Procedure:
The product from Example 79 is treated with sodium nitrite in 37% HCl solution at 0° C. The reaction mixture is poured into a solution of CuCN and the title compound is isolated by filtration.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Reactant: C1CCNC1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCN2CCCC2)cc1

Procedure:
In a manner similar to that described in Example 217, 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and pyrrolidine are converted to the named compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14](=[O:16])[CH3:15])=[C:9]([CH3:17])[CH:8]=1)(=O)=O.[F-].[K+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:17][C:9]1[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:11]([CH3:13])[C:10]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)c1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1C
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(=O)c1c(C)cc(-c2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a solution of 4-acetyl-3,5-dimethylphenyl trifluoromethanesulfonate (1.00 g, 3.38 mmol), KF (0.65 g, 11 mmol), and phenylboronic acid (0.49 g, 4.0 mmol) in THF (4.0 mL) was added tricyclohexylphosphine (11.4 mg, 0.04 mmol) and Pd(OAc)2 (7.6 mg, 0.03 mmol). The reaction mixture was stirred at room temperature for 5.0 h under N2. The reaction mixture was filtered through a small pad of Celite, and the cake was washed with ethyl acetate (40 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give 1-(3,5-dimethyl-[1,1′-biphenyl]-4-yl)ethanone (0.68 g) in 90% yield: 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.0 Hz, 2H), 7.44 (t, J=7.0 Hz, 2H), 7.35 (m, 1H), 7.25 (s, 2H), 2.52 (s, 3H), 2.33 (s, 6H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([CH2:11][CH2:12][CH:13]([OH:26])[C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:14]1([OH:17])[CH:13]([OH:26])[CH2:12][CH2:11][CH:10]2[CH:15]1[CH2:16][NH:8][CH2:9]2
Reactant: COc1ccccc1C1(O)C(O)CCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)C(O)CCC2CNCC21
Temperature: 60 °C
Yield: 91.3 %

Procedure:
A mixture of 1.5 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol and 120 cm3 of anhydrous ethanol is heated to 60° C. with stirring; 0.49 g of 20% palladium hydroxide on charcoal is added and the reaction mixture is then hydrogenated, with stirring, at a temperature of 60° C. and at atmospheric pressure. After reaction for 2 hours, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 50 cm3 of isopropyl ether. 1.02 g of (3aRS,4RS,5RS,7aSR)-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained, melting at 168° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:5][CH:6]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:16]([O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[N:3]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:5][CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1nc(I)c[nH]1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1c[nH]c(C(C)(C)C)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
A mixture of 4-iodo-2-tert-butylimidazole (200 mg, 0.80 mmol) obtained in Step 3 of Example 81, tert-butyl acrylate (240 μL, 1.63 mmol), palladium acetate (18 mg, 0.080 mmol), triphenylphosphine (42 mg, 0.016 mmol), potassium carbonate (133 mg, 0.962 mmol), and DMF (10 mL) was stirred at 100° C. for 3 hours. The mixture was left to cool to room temperature and filtered through Celite. To the filtrate, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 3-(2-tert-butyl-1H-imidazol-4-yl)acrylic acid tert-butyl ester (51 mg, 0.22 mmol, yield: 26%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Br:8])[Br:7])[CH:3]1[C:9]([O:11]CC)=[O:10].[OH-].[K+]>C(O)C>[CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=[C:6]([Br:8])[Br:7])[CH:3]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1C(C=C(Br)Br)C1(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)C(C=C(Br)Br)C1C(=O)O

Procedure:
2.02 Parts of ethyl 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropane-carboxylate obtained in Example 11 was agitated with 7.06 parts of a 10% aqueous solution of potassium hydroxide in the presence of ethyl alcohol at 40° to 50° C. for 2 hours to effect hydrolysis of the ester and obtain 1.08 parts of 2,2-dimethyl-3-(2',2'-dibromovinyl)-cyclopropane-carboxylic acid having a melting point of 116° - 117° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.[Cl-].[NH4+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Into a 50 ml round bottom flask were added 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.86 g, 5.78 mmol) and dry tetrahydrofuran (20 ml). The solution was cooled in an ice bath at 0° C. and sodium hydride (305 mg, 60% dispersion in mineral oil, 6.36 mmol) was added in small portions. After 20 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (1.12 mL, 6.35 mmol) was added, and the reaction mixture was allowed to warm to room temperature over 30 minutes. The reaction mixture was allowed stirred at this temperature for an additional 30 minutes. Methanol (1.0 mL) was then added to quench the reaction, followed by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was then extracted with dichloromethane (2×20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (20% ethyl acetate in hexanes) to give 2.36 g (90%) 5-bromo-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine as a yellowish oil. 1H-NMR (250 MHz, CDCl3) δ 8.49 (d, J=2 Hz, 1H), 7.84 (d, J=2.25 Hz, 1H), 7.44 (s, 1H), 3.50 (t, J=8.25 Hz, 2H), 0.88 (t, J=8.25 Hz, 2H), −0.08 (s, 9H); MS: m/z 452.9+454.9 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=O)=[O:9])[NH2:7])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:8](=[O:9])[NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)CN(N)C(=O)Nc1ccccc1C(=O)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2NC1=O
Reaction time: 0.25 h

Procedure:
[1-[[[2-(Cyclohexylcarbonyl)phenyl]amino]carbonyl]hydrazino]-acetic acid ethyl ester (20 mg) was dissolved in TFA (0.2 mL) and aged for about 15 min. HPLC analysis at this point revealed the disappearance of the signal @ 10.5 min corresponding to starting material, and the appearance of a signal @ 11.01 min corresponding to product. This material was characterized by comparison of the HPLC traces with that of an authentic sample.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:33])([F:32])C1C=C(B(O)O)C=CC=1>>[F:21][C:22]([F:33])([F:32])[C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C1NCCc2c(-c3cccc(C(F)(F)F)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-trifluoromethylphenylboronic acid (322 mg, 1.70 mmol) were coupled to yield 2-(3-trifluoromethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 300 mg (80%), as a pale-yellow solid. mp 212.5-213.5° C.; 1H NMR (300 MHz, d6-DMSO) δ3.08 (m, 2H), 3.40 (m, 2H), 7.27 (app t, 1H, J=7.8 Hz), 7.60 (d, 1H, J=7.8 Hz), 7.71 (d, 1H, J=7.5 Hz), 7.77 (m, 2H), 7.96 (m, 2H), 8.13 (br t, 1H), 11.78 (br s, 1H); MS (FAB, MH+) 331; Anal. (C18H13F3N2O.0.5 H2O) N.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:26]#[C:27][NH2:28]>O1CCOCC1>[ClH:1].[NH:2]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)[C:27]([NH2:28])=[NH:26]
Reactant: COC(=O)CCc1ccc(-c2nc(-c3cccc(N)c3)c[nH]2)cc1
Reactant: N#CN
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(-c2nc(-c3cccc(NC(=N)N)c3)c[nH]2)cc1

Procedure:
Prepared from 4-(3-amino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazole-hydrochloride by refluxing for three hours with cyanamide in dioxane.