Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH2:21]Br)=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:21]([C:19](=[O:20])[C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.6 %

Procedure:
To 150 ml of acetone were suspended 20 g of 5-bromosalicylaldehyde, 22.9 g of 2-bromo-4-methoxyacetophenone and 27.6 g of anhydrous potassium carbonate. After stirring at room temperature for 4 hours, the resulting reaction solution was concentrated to dryness, and then mixed with water to collect precipitated crystals by filtration. After washing with water and subsequent recrystallization from ethanol, 14.02 g of 5-bromo-2-(4-methoxybenzoyl)benzofuran was obtained in the form of colorless prism crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:19]1([C:22]([NH2:30])([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH3:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:30][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:24]2[N:28]=[C:27]([CH3:29])[O:26][N:25]=2)[CH3:23])[CH2:21][CH2:20]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (190 mg, 27%) as alight yellow oil; MS (ESI, m/z): 411.0 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([P:10]([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9].Cl[C:23]1[N:31]=[C:30]([I:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C1COCC1>[CH2:7]([P:10]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:23]2[N:31]=[C:30]([I:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:19][CH:20]=1)([CH2:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH3:9]
Reactant: Clc1nc(I)nc2c1ncn2C1CCCCO1
Reactant: CCCP(=O)(CCC)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCP(=O)(CCC)c1ccc(Nc2nc(I)nc3c2ncn3C2CCCCO2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Potassium tert-Butoxide (0.19 g, 1.65 mmol) was suspended in 4.5 mL anhydrous THF under nitrogen and cooled to −10° C. in an ice-salt bath. 4-(Dipropylphosphoryl)benzenamine (0.12 g, 0.55 mmol) was added to the suspension and the mixture was stirred at −10° C. for 30 min. 6-Chloro-2-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Tetrahedron 2002, 58, 7911-7923, 0.18 mg, 0.5 mmol) was then added to the reaction mixture and the content was warmed to room temperature and stirred over night. The reaction mixture was cooled to 0° C., and quenched by the addition of 0.1 N HCl (˜500 mL). The mixture was concentrated on a rotavapor. The residue was partitioned between ethyl acetate (10 mL)/water (4 mL), organic layer was separated and washed with 0.1 N HCl (4×4 mL), saturated NaHCO3 (4 mL), brine (4 mL), and dried over Na2SO4. The final product was obtained by flash column chromatography on silica gel (7.5% MeOH/DCM).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([NH:11]C(OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[OH:27])=[CH:22][CH:21]=1>>[NH2:11][CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][CH2:2][N:31]1[CH2:32][CH2:33][CH:28]([CH:26]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=2)[OH:27])[CH2:29][CH2:30]1
Reactant: OC(c1ccc(F)cc1)C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC(CCBr)c1ccccc1
Product: NC(CCN1CCC(C(O)c2ccc(F)cc2)CC1)c1ccccc1

Procedure:
The procedure given in Example 2 was followed using 3-bromo-1-(tert-butoxycarbonyl)amino-1-phenyl propane and (4-fluorophenyl)-piperidin-4-yl-methanol as reactants, instead of d-1-bromo-2-(tert-butoxycarbonyl)amino-3-phenyl propane and hexamethyleneimine to give [1-(3-Amino-3-phenyl-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanol.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[CH:15]1([N:21]([CH3:25])[CH2:22][CH2:23][NH2:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([N:21]([CH3:25])[CH2:22][CH2:23][NH:24][C:12](=[O:14])[CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CN(CCN)C1CCCCC1
Product: CN(CCNC(=O)CCc1c[nH]c2ccccc12)C1CCCCC1

Procedure:
Compound 12a was prepared using the amino acid coupling procedure described in Example 10 using 3-(1H-Indol-3-yl)-propionic acid and N1-Cyclohexyl-N1-methyl-ethane-1,2-diamine as the starting materials: LC-MS (Method B, retention time=0.427 min. MS calc'd for C20H30N3O (MH+): 328.2. Found 328.2.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[OH-].[K+]>CO>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C:21]2[CH:20]=[C:19]([CH2:18][O:17][CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[CH:24]=[CH:23][N:22]=2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COc1cc(-c2cc(COC3CCN(C(=O)OCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc(COC3CCNCC3)ccn2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyloxy]piperidine (213 mg) in methanol (10 mL) was added 40% aqueous potassium hydroxide (10 mL). The mixture was stirred at 100° C. for 3 hours and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to column chromatography of silica gel using chloroform-ammonia saturated methanol (20:1) to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([F:25])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([F:25])=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=2[F:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)cc([N+](=O)[O-])cc2F)CC1
Temperature: 25 °C
Reaction time: 9 h
Yield: 76 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (1.73 g), 2,6-difluoro-4-nitrophenol (1.37 g) and triphenylphosphine (2.67 g) in dichloromethane (30 ml) was added dropwise diethyl azodicarboxylate (1.57 ml) in an ice bath and the mixture was stirred at room temperature for 9 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=6/1 as an eluant to give the desired compound (2.13 g, yield 76%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1.[CH2:26](Br)[CH3:27].[H-].[Na+]>CN(C)C=O.O1CCCC1>[CH2:26]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[CH:2]1)[CH3:27]
Reactant: CCBr
Reactant: COc1cc(C(=O)/C=C/c2c[nH]c3ccccc23)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCn1cc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
Compound 1 (1.69 g) obtained in Example 1 was dissolved in a mixed solvent of N,N-dimethylformamide (12.5 ml) and tetrahydrofuran (12.5 ml), and ethyl bromide (817.3 mg) and sodium hydride (300 mg, 60% mineral oil dispersion) were added thereto, followed by stirring at room temperature for 3 hours. Ice was added to the reaction solution, and the mixture was subjected to partitioning between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from 2-propanol to give Compound 3 (1.54 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](SC)=[N:19][C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[NH2:30][C@H:31]([CH2:34][CH3:35])[CH2:32][OH:33]>CS(C)=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20]([NH:30][CH:31]([CH2:32][OH:33])[CH2:34][CH3:35])=[N:19][C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2
Reactant: CC[C@@H](N)CO
Reactant: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Solvent: CS(C)=O
Product: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
3-[4-(6-Methylsulfanyl-2-oxo-3-propyl-3,7-dihydro-2H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (105 mg) was dissolved in 2 mL of DMSO along with an appropriate amino alcohol (e.g., 160 uL of (R)-2-amino-1-butanol for compound 3). The reaction mixture was stirred at 150° C. for 3 h. It was then cooled to rt and purified by preparative HPLC to afford 50 mg of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:11][Br:19])=[N:4][C:5]([O:9][CH3:10])=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(C)c(Br)c(C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)c(CBr)n1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-6-methoxy-2,4-dimethylpyridine obtained in Preparation Example 22 (200 mg), NBS (165 mg) and benzoyl peroxide (6.73 mg) was heated under reflux in a carbon tetrachloride solvent (4 mL) for two hours. The reaction mixture was cooled to room temperature and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 5%) to give the title compound (126 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH:68]([CH3:70])[CH3:69])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:65][C@@H:66]([CH2:67][CH:68]([CH3:70])[CH3:69])[C:71]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH2:29][CH3:30])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:72]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2OC(=O)[C@@H](N)CC(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.1 %

Procedure:
To a solution of propyl 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoate (19, 180 mg, 0.42 mmol), DCC (105 mg, 0.50 mmol) and DMAP (6 mg, 0.042 mmol) in ethyl acetate (10 mL), was added Fmoc leucine (148 mg, 0.42 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (210 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 30% ethyl acetate in petroleum ether as an eluent to yield 120 mg (53%) of the title compound as a colorless semi solid.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1>O>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]=1[N+:6]([O-:9])=[O:7]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of sulfuric acid (5.79 g, 59.03 mmol, 2.25 equiv) and nitric acid (2.48 g, 39.37 mmol, 1.50 equiv) was added into 1-bromo-4-tert-butylbenzene (5.6 g, 26.28 mmol, 1.00 equiv) while maintaining the temperature below 10° C. The resulting solution was stirred for 20 h at 25° C., poured into water and extracted with ether. The organic phase was dried over anhydrous sodium sulfate. After filtered and concentrated under reduced pressure, the residue was purified through a silica gel column with ethyl acetate/petroleum ether (1:200-1:50) to afford the title compound as a yellow liquid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 1.361(s, 9H), 7.454(dd, J=2.4 Hz, J=8.4 Hz, 1H), 7.65(d, J=8.4 Hz, 1H), 7.848(d, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][NH:19][C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:16][C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:11]2[S:15][CH:14]=[N:13][CH:12]=2)=[O:9])[C@@H:18]1[CH2:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-c2cncs2)c(C(=O)O)c1
Product: Cc1ccc(-c2cncs2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(thiazol-5-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 475 [M+1]+.
Reaction SMILES: Br[C:2]1[S:10][C:5]2[S:6][C:7](Br)=[CH:8][C:4]=2[C:3]=1[CH2:11][N:12]1[CH2:15][CH:14]([CH2:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13]1.[H][H]>[Pd].CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([CH2:16][CH:14]2[CH2:15][N:12]([CH2:11][C:3]3[C:4]4[CH:8]=[CH:7][S:6][C:5]=4[S:10][CH:2]=3)[CH2:13]2)(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: O=S(=O)(CC1CN(Cc2c(Br)sc3sc(Br)cc23)C1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=S(=O)(CC1CN(Cc2csc3sccc23)C1)c1ccc(F)cc1
Yield: 9.4 %

Procedure:
A mixture of 1-[(2,5-dibromothieno[2.3-b]thien-3-yl)methyl]-3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine (Step 4, 39 mg, 0.07 mmol) and 10% palladium on carbon (50 mg) in methanol (7 mL) was stirred under a balloon of hydrogen for 3.5 hours. The catalyst was removed by filtration through Celite®, washing with methanol after the addition of triethylamine (30 μL) to quench any HBr formed. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC (50% ethyl acetate/isohexane) to give the title compound (2.5 mg). 1H NMR (500 MHz, CDCl3) δ 7.91–7.89 (2H, m), 7.34 (1H, dd, J=1.0, 5.2 Hz), 7.23 (3H, t, J=7.3 Hz), 7.10 (1H, s), 3.70 (2H, s), 3.47 (2H, t, J=7.3 Hz), 3.38 (2H, d, J=7.3 Hz), 2.96 (2H, br s), 2.88–2.82 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:28]([C:35]([NH:37][OH:38])=O)C1C=CC=CC=1>C1COCC1>[OH:38][NH:37][C:35]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:28]
Reactant: Cc1cc(Cl)cnc1CN(Cc1nccc2ccccc12)C1CCNCC1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1nccc2ccccc12)C1CCN(C(=O)NO)CC1
Yield: 50.4 %

Procedure:
A solution of (5-Chloro-3-methyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidine-4-yl-amine (140 mg, 0.37 mmol) and N-(phenoxycarbonyl)hydroxylamine (112 mg, 0.74 mmol) in anhydrous THF (4 mL) was stirred for 16 hours at 70° C. The solution was then cooled and concentrated under reduced pressure and dried in vacuo. The crude material was purified by column chromatography with silica gel (50:1:0.1 CH2Cl2/MeOH/NH4OH) to give COMPOUND 308 as a white solid (82 mg, 51%). 1H NMR (CDCl3): δ 1.73 (q, 2H, J=11.1 Hz), 1.96 (s, 3H), 1.99 (br, 2H), 2.70 (br, 3H), 3.85 (s, 2H), 4.05 (d, 2H, J=13.2 Hz), 4.26 (s, 2H), 6.65 (br, 1H (Oh)), 6.81 (br s, 1H (NH)), 7.33 (s, 1H), 7.42 (t, 1H, J=7.2 Hz), 7.54 (d, 1H, J=4.8 Hz), 7.62 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.95 (d, 1H, J=7.2 Hz), 8.26 (s, 1H), 8.39 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 18.75, 28.62 (2C), 45.17 (2C), 56.17, 56.61, 61.23, 122.76, 127.88, 128.44, 128.59, 129.29, 132.10, 132.65, 137.35, 138.33, 139.35, 141.74, 145.51, 156.93, 160.35, 162.80. ES-MS m/z 441 (M+H). Anal. Calcd. for C23H26N5O2Cl.0.2H2O: C, 62.28; H, 6.00; N, 15.79; Cl, 7.99. Found: C, 62.31; H, 5.83; N, 15.50; Cl, 8.06.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][CH:46]1[CH:51]([CH3:52])[CH2:50][CH2:49][CH2:48][CH:47]1[NH2:53]>CN(C=O)C>[CH3:45][CH:46]1[CH:51]([CH3:52])[CH2:50][CH2:49][CH2:48][CH:47]1[NH:53][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:3]2[CH:4]=[C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:15][CH:16]=1)=[O:21]
Reactant: CC1CCCC(N)C1C
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CCCC(C)C4C)cc3)c2)o1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2,3-dimethylcyclohexylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-(2,3-dimethylcyclohexyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[N:9]2)=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:28]([Cl:30])=[O:29])[C:10]([C:20]3[S:21][CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Product: CCOc1ccsc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride. The enantiomers of cis-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride were separated by chiral chromatography using a Modcol spring column (50 mm×70 cm) packed with R,R-Whelk-O1 spherical Kromasil silica gel (Regis Technologies, eluent: 30% methylene chloride in hexane, flowrate: 85 mL/min) to give the desired 2-{4-[(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(3-ethoxy-thiophen-2-yl)-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=3)[C:10]([CH2:22][CH3:23])=[C:9]([CH3:24])[N:8]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[O:27][C:28]1[CH2:31][CH2:30][C:29]=1[O:32][Si](C)(C)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]4[C:28](=[O:27])[CH2:31][CH2:30][C:29]=4[OH:32])=[CH:16][CH:15]=3)[C:10]([CH2:22][CH3:23])=[C:9]([CH3:24])[N:8]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=C(O[Si](C)(C)C)CC1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C=O)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(C2=C(O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
A 18-mL vial was charged with 4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzaldehyde (139 mg, 0.39 mmol, 1 eq.), trimethyl-(2-trimethylsilyloxycyclobuten-1-yl)oxy-silane (140 mg, 0.6 mmol, 1.53 eq.), and dichloromethane (2 ml). To the mixture was added BF3/Et2O (80 μL, 0.63 mmol, 1.6 eq.). The mixture was stirred at room temperature overnight and then added to sodium bicarbonate solution (10 ml). The mixture was extracted with ethyl acetate (3×5 ml). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using 2˜3% of methanol in dichloromethane as eluent to give the title compound as a solid (22 mg, 13% yield). MW=425.93. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (brs, 1H), 8.52 (brs, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.56 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 3.34 (m, 4H), 2.73 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).