Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(Cc1ccccc1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(Cc2ccccc2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1

Procedure:
Using the method described in Example 17 from 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid (Intermediate 30) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-phenyl-propionamide was obtained as a white solid (0.26 g, 34%); ES+-HRMS m/e calcd for C26H25N5O4F2 [M+H+] 510.1948 found 510.1949. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.06 (s, 3H) 1.07 (s, 3H) 3.35-3.56 (m, 2H) 3.91 (s, 2H) 4.67 (s, 1H) 5.81 (dd, J=10.7, 4.9 Hz, 1H) 5.92 (d, J=3.0 Hz, 1H) 6.44 (d, J=2.3 Hz, 1H) 7.10-7.20 (m, 1H) 7.24 (t, J=7.1 Hz, 2H) 7.29 (d, J=7.1 Hz, 2H) 7.32-7.40 (m, 2H) 7.40-7.50 (m, 1H) 7.55 (d, J=2.3 Hz, 1H) 8.24 (d, J=3.0 Hz, 1H) 11.00 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:23][C:24]([F:33])([F:32])[C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(N(CC)CC)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([C:24]([F:23])([F:32])[F:33])=[CH:26][CH:27]=3)=[O:14])=[CH:15][CH:16]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a suspension of 4-(3-chloro-pyridin-2-yl)-benzoic acid (5.0 g, 21.4 mmol) in methylene chloride (100 mL) at ambient temperature was added oxalyl chloride (5.43 g, 42.79 mmol) followed by two drops of DMF and the mixture was heated to reflux for 30 minutes. The clear solution was then concentrated to dryness, dissolved in methylene chloride (100 mL) and was treated with 4-trifluoromethyl aniline (4.14 g, 25.68 mmol) followed by triethylamine (2.6 g, 25.68 mmol) and the mixture was gently heated to reflux for 30 minutes and agitated overnight at ambient temperature. After treating the mixture with sat. Na2CO3, the organic layer was separated, washed with water, dried and concentrated to give the crude product which was chromatographed on silicagel to obtain 4.0 g (49.6%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[CH2:16][CH2:15][NH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:8]=3[NH:9][C:10]=2[CH:11]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([N:14]1[CH2:15][CH2:16][C:7]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=3[NH:9][C:8]=2[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1cc(OC)ccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccccc2)CCc2c1[nH]c1cc(OC)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 8-methoxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and benzoyl chloride; 1H-NMR (CDCl3): δ 10.41 (1H, br s), 7.98 (1H, s), 7.56 (2H, m), 7.52 (1H, m), 7.46 (2H, m), 7.39 (1H, d), 6.86 (1H, d), 6.79 (1H, dd), 4.22 (2H, q), 4.19 (2H, t), 3.86 (3H, s), 3.23 (2H, t), 1.20 (3H, t); MS (ES): 391 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]1[C:26]([C:27]([O:29]C)=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:2].O.[OH-].[Li+].O>O1CCOCC1>[CH2:32]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]1[C:26]([C:27]([OH:29])=[O:28])=[C:25]2[C:20]([CH:21]3[CH2:31][CH:22]3[CH2:23][O:24]2)=[CH:19][CH:18]=1)(=[O:15])=[O:14])[CH3:33]
Reactant: CCN(CC)C/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 80 °C
Yield: 30.6 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 153, 0.495 g) and lithium hydroxide monohydrate (0.442 g) was suspended in dioxane (20 mL) and water (5 mL) and the mixture was stirred and heated at 80° C. for 12.5 hours. After cooling, the volatiles were removed in vacuo and the residue was acidified by addition of aqueous citric acid solution (10%) and extracted with DCM. The organic layer was dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 35-70% to give (1aRS,7bSR)-5-[2-((Z)-3-diethylaminoprop-1-enyl)benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.147 g) as a white solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:14]2[N:13]=[CH:12][N:11]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[C:10]=2[CH:9]=[C:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2[CH:41]=[CH:42][CH:43]=[N:44]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH:43]1([NH:44][C:19](=[O:21])[C:18]2[CH:17]=[CH:16][C:15]([N:11]3[C:10]4[CH:9]=[C:8]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:7]=[C:6]([NH:5][CH2:1][CH:2]([CH3:3])[CH3:4])[C:14]=4[N:13]=[CH:12]3)=[CH:23][CH:22]=2)[CH2:41][CH2:42]1
Reactant: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)O)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CNc1cc(-c2ccccc2)cc2c1ncn2-c1ccc(C(=O)NC2CC2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 84.7 %

Procedure:
To a solution of 44 mg (114 μmol) 4-[4-(isobutylamino)-6-phenyl-1H-benzimidazol-1-yl]benzoic acid which was prepared according to intermediate example 4-2 in 2.8 mL THF were added 47.7 mg HATU, 22 μL N,N-diisopropylethylamine and the mixture was stirred at 23° C. for 20 hours. The solvent was removed and the residue purified by chromatography to give 41.0 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.N[C:19]([NH2:21])=S.[CH3:22]S(C)=O>>[CH:22]1[C:15]2[C:6]3[C:5]([CH:4]=[CH:3][C:2]=2[N:1]=[CH:19][N:21]=1)=[CH:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=3
Reactant: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reactant: NC(N)=S
Reactant: CS(C)=O
Product: c1ccc2cc3c(ccc4ncncc43)cc2c1
Temperature: 140 °C
Yield: 33 %

Procedure:
To a 20 mL microwave reaction vial with a micro magnetic stir bar, were added 0.300 g of 1-aminoanthraquinone, 0.207 g of thiourea and 3 mL of DMSO. Then the vial was sealed and heated with microwave at 140° C. for 20 hours. A dark brown gel like mixture was obtained which was purified in a similar fashion with hexane/EtOAc (5:1 to 1:1) as the eluent, and 0.103 g of anthrapyrimidine was obtained, in a yield of 33.0%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[C:25](F)[CH:24]=[CH:23][C:22]=3[N+:28]([O-])=O)[CH:18]=2)=[O:12])[CH2:9][CH2:8]1.[C:33]([O-])(O)=O.[Na+]>CS(C)=O>[CH:7]1([NH:10][C:11](=[O:12])[C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([N:19]3[C:20](=[O:31])[C:21]4[C:22](=[CH:23][CH:24]=[C:25]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)[CH:26]=4)[N:28]=[CH:33]3)[CH:18]=2)[CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(N3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Morpholine (0.21 ml) was added to a stirred solution of N-(5-[(cyclopropylamino)carbonyl]-2-methylphenyl)-5-fluoro-2-nitrobenzamide (0.71 g) in DMSO (1.0 ml). The mixture was stirred at room temperature for 18 hours. The mixture was poured into a saturated NaHCO3 solution (100 ml) and the resultant solid was filtered and dried under vacuum at 40° C. There was thus obtained N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholin-4-yl-2-nitrobenzamide (0.722 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.83 (m, 1H), 3.45 (m, 4H), 3.74 (m, 4H), 7.07 (m, 2H), 7.28 (m, 1H), 7.56 (m, 1H), 7.95 (s, 1H), 8.06 (d, 1H), 8.36 (s, 1H), 9.92 (s, 1H); Mass Spectrum: M+Na+ 447. B) 10% Palladium-on-carbon (0.050 g) was added to a stirred suspension of N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholinyl-2-nitrobenzamide (0.722 g) in ethanol (10 ml) and the mixture was stirred under an atmosphere of hydrogen gas at a pressure of 10 bar. After cessation of hydrogen uptake, the catalyst was removed by filtration through diatomaceous earth (Celite®). The filtrate was concentrated under reduced pressure, which provided the crude 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-morpholin-4-ylbenzamide which was used without further purification; Mass Spectrum: M+H+ 395.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(O)cc2N)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2N)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.1 %

Procedure:
A mixture of the product from Example 232b (56 mg, 0.17 mmol), benzyl bromide (21 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hr. The next day, the reaction mixture was poured onto ice and the solid collected by filtration providing the title compound (62 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[C:3]=1[F:10].Cl[C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:14])=[C:4]([F:9])[C:3]=1[F:10]
Reactant: Nc1ccc(Br)c(F)c1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C[C@@H]1CCN(C(=O)C2CC2)C1)NNC(=O)Nc1ccc(Br)c(F)c1F
Temperature: -78 °C

Procedure:
To a round bottom flask, 4-bromo-2,3-difluoroaniline (2 g, 9.62 mmol) and triphosgene (0.999 g, 3.37 mmol) were added under nitrogen and cooled to −78° C. Dichloromethane (40 mL) was added followed by the slow addition of Hunig's base (3.36 mL, 19.23 mmol). The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired intermediate formation. The solution was re-cooled to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (1.051 g, 4.97 mmol) in dichloromethane (10 mL) was added. The solution was allowed to warm to room temperature, and analysis by LCMS indicated desired product formation. After 2 h of stirring at room temperature and blowing nitrogen gently over the solution, the desired product began to precipitate and was collected by filtration and dried via vacuum filtration to afford the title product (1400 mg, 63%). MS(ES)+ m/e 445.1, 447.1 M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[O:6][C:5]=1[C:22]([NH2:24])=O)[CH3:2]>O>[CH2:1]([O:3][C:4]1[C:8]2[N:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=2[O:6][C:5]=1[C:22]#[N:24])[CH3:2]
Reactant: CCOc1c(C(N)=O)oc2c3ccccc3n(-c3ccccc3)c12
Solvent: O
Product: CCOc1c(C#N)oc2c3ccccc3n(-c3ccccc3)c12
Yield: 91 %

Procedure:
Prepared by the procedure described in Example 21 from 6.5 g (0.020 mole) of 3-ethoxy-4-phenyl-4H-furo-[3,2-b]indole-2-carboxamide. The crude product (5.5 g, 90% yield), after being washed with water and dried, was converted to the corresponding tetrazole without additional purification. A portion of the crude nitrile recrystallized from methanol yielded an analytically pure sample, mp 121°-122° C.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:32])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:6]1=[O:31].C1COCC1.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[OH:1][NH:2][C:3](=[O:32])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:6]1=[O:31]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CCCC2Sc3ccc(C(=O)O)cc3N(CC(=O)NO)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To the compound of Example 1 (0.51 g) were added THF (10 ml) and water (10 ml). After the resulting mixture was ice-cooled, a 0.5N aqueous lithium hydroxide solution (4.4 ml) was slowly added dropwise thereto. The resulting mixture was slowly warmed up to room temperature and stirred overnight. Ice-cooled 1N aqueous hydrochloric acid solution and ethyl acetate were added thereto to effect extraction. The oil layer was washed twice with a 1N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Chloroform was added to the residue, and after standing for 4 days, the solid precipitated was collected by filtration and dried under reduced pressure. 4-[2-(Hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (325 mg) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[ClH:8].[ClH:8].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl
Product: Clc1ncc(OC[C@H]2CCCN2)cc1-c1cccs1
Yield: 60 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (310 mg, 0.87 mmol), 2-thienylboronic acid (167 mg, 1.3 mmol), 2 M Na2CO3 (3 mL) and Pd(0) (32 mg) were mixed together in toluene (6 mL), and the mixture was heated at reflux for 4 hours. The mixture was cooled and extracted with CHCl3. The CHCl3 was removed under reduced pressure, and the residue was chromatographed on a silica gel column, eluting with hexane/EtOAc 1:1 to afford the title compound (64 mg, 20% yield). MS (CI/NH3) m/z 287 (M+H)+. 1H NMR (CDCl3, 300 MHz) 1.47 (s, 9H), 1.84-2.11 (m, 3H), 3.31-3.48 (m, 2H), 3.82-4.30 (m, 3H), 7.12 (dd, J=4.5, 6, 1H), 7.34-7.42 (m, 3H), 7.46-7.57 (m, 1H), 8.23 (d, J=3, 1H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH:10]([OH:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1C(O)c1ccc(O)cc1
Temperature: -10 °C

Procedure:
A solution containing commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (0.500 g, 17.0 mmol) and lithium aluminum hydride (34.0 mmol) in THF (84 mL) was refluxed for 3 h. The reaction was cooled to −10° C., and carefully quenched with 0.1N NaOH and H2O. The aqueous solution was extracted with ether and concentrated. Purification on silica gel gave the title compound as a white solid, mp 94-96° C. (DMSO-d6) δ 0.90 (t, 3H), 1.35 (sextet, 2H), 1.64 (quintet, 2H), 2.84 (t, 2H), 5.67 (d, 1H), 5.87 (d, 1H), 6.69 (d, 2H), 7.07 (t, 1H), 7.15 (dt, 1H), 7.22 (d, 2H), 7.40-7.43 (m, 2H), 9.24 (s, 1H). IR (KBr) 3350, 2950, 1610, 1510 and 1450 cm−1. mass spectrum (EI) m/z 296 (M+). Anal. Calcd. for C19H20O3: C, 77.00; H, 6.80; N, 0.00. Found: C, 75.63; H, 6.86; N, 0.04.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: Cc1cccc(B(O)O)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2cc(F)ccc2OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 56.6 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2,3-dimethylphenylboronic acid (27 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (30 mg, 57%). MS m/e 435.30 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6](OC(CC)C(O)=O)[C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][CH:3]=1.[C:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)(N1C=CN=C1)=[O:27]>O1CCCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:12][CH2:8][CH2:7][CH2:6][C:26]([N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)=[O:27]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(OC1c2ccc(Cl)c(Cl)c2C(=O)C1(C)C1CCCC1)C(=O)O
Solvent: C1CCOC1
Product: CC1(C2CCCC2)Cc2cc(OCCCC(=O)n3ccnc3)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
(+) [(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-yl)oxy]butanoic acid (Example 8, Step B) (0.77 g, 0.002 mole) is suspended in dry tetrahydrofuran (20 ml) and cooled to 0° C. A solution of 1,1'-carbonyldiimidazole (0.32 g, 0.002 mole) in teterahydrofuran (5 ml) is added. The solution of 1-{(+)-4-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]butanoyl}imidazole that is formed is used in the next step without isolation.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[I-:10].[NH4+].OO.ClCCl>C(O)(=O)C.CCCCCC>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [I-]
Reactant: N#Cc1ccccc1N
Agent: OO
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cc(I)ccc1N
Reaction time: 12 h
Yield: 48.2 %

Procedure:
2-Amino-benzonitrile (10 g, 0.085 mol) and ammonium iodide (13.5 g, 0.094 mol) were dissolved in acetic acid (200 mL). 30% aqueous hydrogen peroxide solution (5.3 mL, 0.094 mL) was slowly added at room temperature and stirred for 12 h. After completion of the reaction, the reaction solution was filtered through celite. The filtrate was treated with aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The solid obtained using dichloromethane (10 mL) and hexane (200 mL) was filtered and dried under nitrogen gas to give the title compound (10 g, Yield 48%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH3:5])=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Thionyl chloride (1.85 ml) was added to a solution of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (5.00 g) in toluene (40 ml) and the mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried over MgSO4 and concentrated to give crystals (5.23 g; yield: 99%) of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole. Recrystallization from ethyl acetate-hexane gave colorless crystals. Melting point: 108-109° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C@H:44]3[CH2:49][CH2:48][C@H:47]([CH:50]=O)[CH2:46][CH2:45]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:20][C:21]([Br:24])=[CH:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([CH2:43][CH2:42][C:39]2[CH:38]=[CH:37][C:36]([C:33]3[CH:34]=[CH:35][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=3)=[CH:41][CH:40]=2)[CH2:45][CH2:46]1
Reactant: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=O)CC3)cc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1ccc(-c2ccc(CC[C@H]3CC[C@H](C=C(Br)Br)CC3)cc2)cc1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
A solution of 6.7 g of triphenylphosphine in 60 ml of methylene chloride was placed at -20° C. under argon gasification in a sulphonation flask equipped with a thermometer, dropping funnel and solid substance addition tube and treated within 5 minutes with 4.3 g of tetrabromomethane. The clear orange solution was stirred at -15° C. for a further 10 minutes and then a solution of 2.33 g of trans-4-[2-(4'-pentyl-4-biphenylyl)ethyl]cyclohexanecarboxaldehyde in 40 ml of methylene chloride was added dropwise at -5° C. within 10 minutes. The mixture was stirred at -5° C. for a further 10 minutes, then poured into 700 ml of hexane and freed from precipitated triphenylphosphine oxide by filtration. The concentrated filtrate was digested with 300 ml of hexane, filtered and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.5 g) on silica gel with 1% ethyl acetate/petroleum ether gave 2.87 g (87%) of 4-[2-[trans-4-(2,2-dibromovinyl)cyclohexyl]ethyl]-4'-pentylbiphenyl as colourless crystals.