Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:4](=[O:27])[C:5]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].[OH-].[Na+]>C1COCC1.O>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:5]2[C:4](=[O:27])[N:3]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:35])[F:37])[CH:29]=3)[C:2]([CH3:1])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=2)=[O:14])=[CH:22][CH:21]=1)(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-methyl-5-({[4-(methylsulfonyl)benzyl]amino}carbonyl)-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridine-3-carboxylate (0.70 g, 1.30 mmol) in THF (10 ml) and water (10 ml) was added NaOH (1M, 2 ml, 2 mmol), and the mixture was stirred for 1 h at room temperature, monitoring the progress of the reaction by LC-MS. 20% conversion was observed and another portion of NaOH (1M, 1 ml, 1 mmol) was added, and the reaction was allowed to run for another hour. This process was repeated until complete conversion of the ester was observed (normally 3-4 hours). The outcome of the reaction is two compounds with the same mass, in a 95:5 proportion. The main product is the subtitle compound, and the other is a regioisomer. The reaction mixture was evaporated in order to remove THF, and the residual water solution was acidified and then extracted into EtOAc. The organic phase was collected and dried over Na2SO4. Filtration and evaporation gave a crude product 0.60 g (90%) of a yellowish solid, which was used further without purification. A portion of the product was purified using preparative HPLC.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].[CH3:12]NC.C(N)CCC.N.S(=O)(=O)(O)O.[OH-:26].[Na+]>CO>[CH3:8][CH:7]([CH2:9][CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][C:2]([O:26][CH3:12])([CH3:3])[CH3:1]
Reactant: [OH-]
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CNC
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCN
Solvent: CO
Product: COC(C)(C)CCCC(C)CC=O

Procedure:
A process according to claim 1 which comprises the following steps (a) reacting citronellal with about 1-3 mols of dimethylamine, butylamine or ammonia per mol of citronellal at -5°C. to -25°C. (b) contacting the product of step (a) with methanol at -10°C. to +20°C. in the presence of 3.5-5 mols sulphuric acid per mol of citronellal used in step (a) and (c) neutralising the reaction mixture of step (b) with an aqueous solution of sodium hydroxide to produce methoxydihydrocitronellal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCCCC.[C:17]([N:24]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(OCC)C>[Cl:8][C:4]1[C:3]([F:9])=[C:2]([C:26]2([OH:29])[CH2:27][CH2:28][N:24]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:25]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1c(Cl)cccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Li]CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Yield: 66.6 %

Procedure:
Preparation according to Preparation 10: 1-Bromo-3-chloro-2-fluorobenzene (8 g, 38.3 mmol), dry diethyl ether (100 mL), n-hexyllithium (2.3 M in hexane, 16.64 ml, 38.3 mmol) and a solution of 1-N-boc-3-pyrrolidone (7.08 g, 38.3 mmol) in dry diethyl ether (50 mL). The crude product was purified by flash column chromatography (ethylacetate/isooctane, 1:9 to 1:1) to give the title compound (8.05 g, 66%). MS m/z (rel. intensity, 70 eV) 259 (20), 214 (42), 157 (26), 143 (23), 57 (bp).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17]1(=[O:23])CCCC[CH2:18]1>>[CH2:17]([O:23][C:6]1[CH:7]=[C:2]2[C:3]([C:8](=[O:10])[CH2:9][C:11]3([O:1]2)[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:5]=1)[CH3:18]
Reactant: O=C1CCCCC1
Reactant: O=C1CCCC1
Reactant: CC(=O)c1ccccc1O
Product: CCOc1ccc2c(c1)OC1(CCCC1)CC2=O

Procedure:
The title compound was prepared using the procedure as described in Example 1A, substituting 4′-ethoxy-2′-hydroxyacetophenone (Aldrich, CAS#37470-42-1) for 2′-hydroxyacetophenone and cyclopentanone for cyclohexanone. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.65 (d, J=8.6 Hz, 1H), 6.57 (dd; J=8.4, 2.3 Hz; 1H), 6.45 (d, J=2.4 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 2.79 (s, 2H), 1.94 (m, 2H), 1.60-1.80 (m, 6H), 1.32 (t, J=7.0 Hz, 3H). MS (DCI+) m/z 247 (M+H), 264 (M+NH4).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCO>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(N2CCN(CC(=O)OC(C)(C)C)CC2)cc1
Solvent: CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(N2CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
A solution of the product of Step E (0.05 g; 0.129 mmol) in 60% TFA in CH2Cl2 (5 ml) was refluxed for 2 h, cooled to room temperature then diluted to 7 ml with EtOH. The resulting mixture was evaporated to dryness under reduced pressure kept in vacuo for 1 h. The residue was treated dissolved in EtOH (2 ml) and 3 drops of concentrated NH4OH was added. The resulting mixture was partially concentrated under reduced pressure and the precipitate, formed was filtered off, washed with Et2O and dried to give the titled compound (0.02 g; 47%) as colourless solid. 1H-NMR (CD3OD+CDCl3) 7.07 (d, 2H, J=8.6 Hz); 6.86 (d, 2H, J=8.6 Hz); 4.63 (s, CD3OH); 3.58 (s, 2H); 3.38 (m, 8H); 2.49 (t, 2H, J=7.8 Hz); 1.53 (m, 2H); 1.24 (m, 10H); 0.83 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: Cc1cccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)c1C
Yield: 90.8 %

Procedure:
Compound 17 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH3:27][O:28][C:29]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([NH:38][CH2:39][C:40]3([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[NH:37][C:33]=2[CH:32]=1)=[O:30].CO>CN(C=O)C.C(O)(=O)C>[CH3:27][O:28][C:29]([C:31]1[CH:48]=[CH:47][C:34]2[N:35]=[C:36]([NH:38][CH2:39][C:40]3([F:46])[CH2:45][CH2:44][N:43]([CH2:5][C:4]4[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=4[OH:11])[CH2:42][CH2:41]3)[NH:37][C:33]=2[CH:32]=1)=[O:30]
Reactant: COC(=O)c1ccc2nc(NCC3(F)CCNCC3)[nH]c2c1
Reactant: O=Cc1cc(Cl)cc(Cl)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(NCC3(F)CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 3,5-dichloro-2-hydroxybenzaldehyde (57.3 mg, 0.3 mmol) and sodium triacetoxyborohydride (64 mg, 0.3 mmol) to a solution of 2-{[(4-fluoro-4-piperidyl)methyl]amino}benzimidazole-5-carboxylic acid methyl ester hydrochloride (30 mg, 0.1 mmol) in DMF-acetic acid (10:1) (1.0 ml), the mixture was stirred at room temperature overnight. Methanol (1.0 ml) was added to the reaction mixture to suspend the reaction, and after stirring for 1 hour, the solution was passed through SCX (Bond Elute SCX500MG: cationic ion-exchange resin, Varian). The SCX was washed with methanol and then with a mixed solution of chloroform/methanol (1/1), and elution was performed with a 0.5 N ammonia-dioxane solution to obtain 2-[({1-[(3,5-dichloro-2-hydroxyphenyl)methyl]4-fluoro-4-piperidyl}methyl)amino]benzimidazole-5-carboxylic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 52.6 %

Procedure:
To a solution of methyl 2-chloro-5-(cyclopropanecarboxamidomethyl)benzoate (10.0 g, 30 mmol) in THF:methanol (10:20 mL) was added aqueous solution of NaOH (6.0 g, 140 mmol). The reaction mixture was refluxed for 3-5 h. The reaction mixture was concentrated, diluted with water and acidified with dilute HCl. The reaction mixture was extracted with 10% MeOH:DCM and concentrated to afford 4.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.67 (m, 4H), 1.59 (m, 1H), 4.28 (d, J=6.0 Hz, 2H), 7.37-7.50 (m, 2H), 7.65 (s, 1H), 8.64 (m, 1H), 13.40 (br s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([NH:8][C:9]2[S:10][C:11](=[CH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[C:12](=[O:14])[N:13]=2)[CH:7]=1.Cl.[C:28](=[NH:31])(S)[CH3:29].CO>CN(C=O)C>[ClH:26].[Cl:26][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[NH:31])[CH3:29])=[CH:7][C:6]=1[NH:8][C:9]1[S:10][C:11](=[CH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[CH:19]3)[C:12](=[O:14])[N:13]=1
Reactant: CC(=N)S
Reactant: Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=N)Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled (0 deg.) solution of 2-(5-amino-2-chloro-phenylamino)-5-quinolin-6-ylmethylene-thiazol-4-one (39.7 mg, 0.1 mmol) in DMF (1 ml) was added thioacetimidate hydrochloride 9 (28 mg, 0.11 mmol). The mixture was warmed to room temperature and stirred for over night. DMF was removed by nitrogen gas blowing and resulting oil was dissolved with methanol. Insoluble solid was collected by filtration and washed with methanol, followed by desiccation in vacuo to afford the title (14 mg, 0.031 mmol).
Reaction SMILES: C(OC1C=CC(C(Cl)=O)=CC=1)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:36][CH3:37])=[CH:40][CH:41]=2)=[S:49])=[CH:30][C:29]=1[F:35]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: CCOc1ccc(C(=O)Cl)cc1
Agent: CCOc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-Ethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 92%). Mass spectrometry value (ESI-MS, m/z): 554 (M++1)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:11][C:4]1([CH3:12])[C:5]2[C:10](=[CH:9][C:8]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:7][CH:6]=2)[C:2]([CH3:14])([CH3:1])[CH:3]1[CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC1C(C)(C)c2ccc(C(=O)CCC(=O)O)cc2C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
To a solution of 11 g of 1,1,2,3,3-pentamethyl indane (0.058 mole) and 7 g of succinic anhydride (0.07 mole) in 100 cm3 of anhydrous 1,2-dichloroethane, stirred at 0° C, there are added, by small portions, 9.4 g of aluminum chloride in a manner such that the temperature remains lower than 30° C. The reaction mixture is stirred for 3 hours at ambient temperature and then poured into 250 cm3 of ice water. The organic phase is decanted and the aqueous phase is extracted twice with 1,2-dichloroethane. The organic phases are combined, washed with water and dried on magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting product is crystallized in isopropyl ether. 7 g of 4-(1,1,2,3,3-pentamethyl-5-indanyl)-4-oxo butyric acid in the form of white crystals whose melting point is 161° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O:5]CC)=[O:4].CO.[OH-].[Na+:19]>C1COCC1>[F:15][C:2]([F:1])([C:8]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O-:5])=[O:4].[Na+:19]
Reactant: CCOC(=O)C(F)(F)c1ncc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C(F)(F)c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To ethyl 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (470 mg, 2.13 mmol) were added MeOH (4 mL), THF (4 mL) and 1.2; N NaOH (2 mL, 2.4 mmol). The solution was stirred at rt for 30 min and then concentrated to dryness to afford sodium 2,2-difluoro-2-(5-fluoropyrimidin-2-yl)acetate (430 mg, 94%). 1H NMR (300 MHz, DMSO-d6) δ 8.94 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([N:24]2[C:28](B(O)O)=[CH:27][CH:26]=[N:25]2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[C:13]1([CH3:16])[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:28]4[N:24]([C:21]5[CH:22]=[CH:23][C:18]([CH3:32])=[CH:19][CH:20]=5)[N:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-n2nccc2B(O)O)cc1
Reactant: Cc1ccc(-n2cnc3ccc(Br)cc32)cc1
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: O
Solvent: COCCOC
Product: Cc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(C)cc4)c3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.4 %

Procedure:
To a mixture of 6-bromo-1-p-tolyl-1H-benzo[d]imidazole (intermediate F) (100 mg, 348 μmol) and 1-p-tolyl-1H-pyrazol-5-ylboronic acid (intermediate B) (91.5 mg, 453 μmol) in 1,2-dimethoxyethane (3 ml) was added 2M sodium carbonate solution (696 μl, 1.39 mmol) and the reaction mixture was purged with argon for 10 min in an ultrasonic bath. To the stirred mixture tetrakis(triphenylphosphine)palladium(0) (80.5 mg, 69.6 μmol) was added at room temperature and the reaction mixture was allowed to stir under reflux conditions for 15 h. The reaction mixture was cooled to room temperature, poured into water (20 ml) and extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude material (200 mg) was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1) and trituration from diethyl ether/heptane to yield the title compound as a off-white solid (55 mg, 43%), MS (ISP) m/z=365.2 [(M+H)+], mp 165° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:36])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[C:16]([Cl:36])=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(OC)cc2)c1OC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(4-methoxy-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 414 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=2)=[N:10][N:11]=1.[CH3:19][N:20](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)=[N:10][N:11]=1
Reactant: Ic1cccc(-c2nnc(-c3ccccn3)o2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2nnc(-c3ccccn3)o2)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
Under an argon atmosphere, a mixture of 2-(2-pyridyl)-5-(3-iodophenyl)-1,3,4-oxadiazole (0.03 g, 0.08 mmol), zinc cyanide (0.01 g, 0.12 mmol), and Pd(PPh3)4 (9.1 mg, 0.01 mmol) in N,N-dimethylformamide (2 ml) was heated at 80° C. for 2.5 hours. After cooling the reaction mixture was diluted with ethyl acetate and sequentially washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the crude product from 5% ethyl acetate in hexanes, afforded 5.8 mg (30%) of 2-(2-pyridyl)-5-(3-cyanophenyl)-1,3,4-oxadiazole.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl-:13].[Br:14][CH2:15][CH2:16][CH2:17][N+:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20]>>[Cl-:13].[Br-:14].[CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[CH2:15][CH2:16][CH2:17][N+:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: CC[N+](CC)(CC)CCCBr
Reactant: CC1=Nc2ccccc2C1(C)C
Agent: [Cl-]
Product: CC[N+](CC)(CC)CCC[N+]1=C(C)C(C)(C)c2ccccc21
Product: [Br-]
Temperature: 140 °C
Yield: 32.6 %

Procedure:
Freshly distilled 2,3,3-trimethylindolenine (0.53 g, 3.3 mmol) and N-(3-bromopropyl)triethylammonium chloride (1.01 g, 3.9 mmol) were mixed in the thick-wall tube and placed under an argon atmosphere. The mixture was then heated at 140° C. for 1.5 h, giving a deep red viscous product, which solidified to a glass on cooling. It was ground to a powder under acetone; product was collected by filtration, triturated 3 times with 10 mL portions of acetone and dried under vacuum to give 0.45 g (36%) of 2,3,3-trimethyl-1-(3-triethylammoniopropyl)-3H-indolium bromide chloride as a white powder. δH (200 MHz, DMSO-d6) 8.10 (1H, d, 6.7 Hz, arom.), 7.87 (1H, d, 5.8 Hz, arom.), 7.75-7.58 (2H, m, arom.), 4.56 (2H, t, 7.3 Hz, N+CH2), 3.27 (6H, q, 6.0 Hz, N+(CH2)3), 2.91 (3H, s, CH3), 2.34-2.10 (2H, m, N+CH2), 1.56 (6H, s, (CH3)2) 1.36-1.05 (11H, m, CH2, (CH3)3).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([OH:50])=O)=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12.[NH2:52][CH2:53][C:54]1[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=1>>[N:27]1[S:28][N:29]=[C:30]2[CH:35]=[C:34]([CH2:36][N:37]3[CH2:41][CH2:40][N:39]([C:42]4[S:43][C:44]([C:48]([NH:52][CH2:53][C:54]5[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=5)=[O:50])=[C:45]([CH3:47])[N:46]=4)[C:38]3=[O:51])[CH:33]=[CH:32][C:31]=12
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc4nsnc4c3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 44 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(benzo[c][1,2,5]thiadiazol-5-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a colorless solid in 44% yield: mp 105-107° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.50-8.48 (m, 1H), 7.96-7.93 (m, 1H), 7.71-7.68 (m, 1H), 7.57-7.55 (m, 2H), 7.29-7.24 (m, 1H), 6.18 (br s, 1H), 4.96 (s, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-4.04 (m, 2H), 3.68-3.62 (m, 2H), 2.58 (s, 3H); MS (ES+) m/z 466.2 (M+1).
Reaction SMILES: CC(S([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH:9]=[CH2:10])=O)(C)C.Cl.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CO>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34]([NH:7][CH:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:18])=[O:19])=[CH:15][CH:16]=1)[CH:9]=[CH2:10])=[O:35]
Reactant: C=CC(NS(=O)C(C)(C)C)c1ccc(S(=O)(=O)CCC)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CC(NC(=O)c1ccc(Cl)cc1Cl)c1ccc(S(=O)(=O)CCC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-N-{1-[4-(propylsulphonyl)phenyl]prop-2-en-1-yl}propane-2-sulphinamide (213 mg, 0.62 mmol) was dissolved in methanol. Methanolic hydrogen chloride was added and the reaction mixture was stirred at room temperature for 2 h. Following concentration in vacuo the residue was suspended in dichloromethane and stirred under nitrogen. Triethylamine (0.173 mL, 1.24 mmol) was added followed by 2,4-dichlorobenzoyl chloride (87 μL, 0.62 mmol) and the reaction mixture was stirred overnight. The reaction was quenched by addition of water and satd. NaHCO3(aq). The product was extracted into ethyl acetate (×2) and then the combined organic layers washed with brine, dried (MgSO4) and concentrated. 1H NMR 5 (400 MHz, CDCl3) δ 0.99 (3H, t, J=7.4 Hz), 1.66-1.76 (2H, m), 3.00-3.04 (2H, m), 5.30-5.37 (2H, m), 5.86 (1H, t, J=6.9 Hz), 6.02-6.10 (1H, m), 7.19 (1H, d, J=7.9 Hz), 7.29 (1H, dd, J=8.5, 2.1 Hz), 7.40 (1H, d, J=1.9 Hz), 7.56 (2H, dd, J=8.3, 2.5 Hz), 7.83 (2H, d, J=8.3 Hz).