Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=2[C:3]1=O.[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[S:18])[NH2:17]>C(O)C.CN1C(=O)CCC1>[CH2:22]([O:21][C:19]([C:16]1[S:18][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[C:10]([F:14])[C:11]([Br:13])=[CH:12][C:4]=3[C:3]=2[N:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C1c2cc(Br)c(F)cc2OCCC1Br
Solvent: CN1CCCC1=O
Solvent: CCO
Product: CCOC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.3 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed 4,7-Dibromo-8-fluoro-3,4-dihydro-2H-benzo[b]oxepin-5-one (1400 g, 4.14 mol, 1.00 equiv), NMP (0 mg), and ethyl carbamothioylformate (554 g, 4.16 mol, 1.00 equiv). The resulting solution was stirred at 80° C. for 3 h, cooled to 25° C. and diluted with 6 L of ethanol. The solids were collected by filtration, washed with 3×1 L of ethanol and dried to afford 390 g (25%) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](/[C:14](/[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2F)=[N:15]/[OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(/C(=N/O)c2cc(F)ccc2F)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2noc3ccc(F)cc23)CC1
Yield: 85.2 %

Procedure:
4-{(2,5-Difluoro-phenyl)-[(E)-hydroxyimino]-methyl}-piperazine-1-carboxylic acid tert-butyl ester (28.3 g, 82.9 mmol) was suspended in 200 ml dioxane and stirred together with 300 ml 30% KOH in water for 16 hours at reflux. The reaction mixture was cooled and extracted two times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with hexane:ethyl acetate (95:5 to 40:60) to give 22.7 g (85%) of the product as a white solid. MS (m/e): 322.2 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[O:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:30]3[CH2:29][CH2:28][N:27]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:32][CH2:31]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(CCN2CCN(C3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 34.3 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (72 mg, 0.24 mmol) in DCE (15 mL) was added 1-(tetrahydropyran-4-yl)piperazine (60 mg, 0.35 mmol), powdered 4 Å molecular sieves and sodium triacetoxyborohydride (103 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a yellow solid (37 mg, 34%). LCMS (Method H): RT=2.46 min, [M+H]+ 450.5
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33](O)=[O:34])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2].Cl.Cl.[CH3:38][N:39]([CH2:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1)[CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([NH:4][CH2:5][C:6]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:33]([NH:51][C:50]2[CH:49]=[CH:48][C:47]([CH2:46][N:39]([CH3:38])[CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:53][CH:52]=2)=[O:34])[CH2:10][CH2:9]1)=[O:7])(=[O:3])[CH3:2]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)CNC(C)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C(=O)CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
In DMF (20 ml) were suspended 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.85 g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.52 g) and 1-hydroxybenzotriazole (0.3 g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 g), triethylamine (1.7 ml) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight. The solvent was evaporated and, to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified with basic silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give 1-(N-acetylglycyl)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.1 g) as pale yellow amorphous.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])[CH2:10][CH2:11]1
Reactant: CN1CCC(Nc2ccccc2I)CC1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccccc1NC1CCN(C)CC1
Temperature: 100 °C

Procedure:
A solution of N-(2-iodophenyl)-1-methylpiperidin-4-amine (550 mg, 1.74 mmol), methyl acrylate (157 μL, 1.74 mmol), palladium acetate (39 mg, 0.17 mmol), tri-o-tolylphosphine (106 mg, 0.35) and diisopropylethylamine (608 μL, 3.48 mmol) in 7 mL DMF was deoxygenated with argon then heated at 100° C. for 5 hours. The mixture was cooled to room temperature then partitioned between EtOAc (150 mL) and H2O (20 mL). After extraction, the organic layer was separated and rinsed with brine. The organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue, which was subjected to flash chromatography on silica gel using 5%, 2M NH3 in MeOH/CH2Cl2. A viscous yellow oil was obtained (350 mg, 73.4%). 1H-NMR (CDCl3) δ 7.85 (d, J=15.9 Hz, 1H), 7.37-7.35 (m, 1H), 7.24-7.21 (m, 1H), 6.72-6.67 (m, 2H), 6.33 (d, J=15.9 Hz, 1H), 3.88-3.85 (m, 1H), 3.81 (s, 3H), 3.36 (brs, 1H), 2.84-2.81 (m, 2H), 2.31 (s, 3H), 2.18-2.05 (m, 4H), 1.63-1.51 (m, 2H). MS (ESI): 275.2 (M+1, 100%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:10][C:5]1[CH:4]=[C:3]([CH2:2][NH:1][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: NCc1cc(N)nc(N)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Nc1cc(CNC(=O)C2CCCC2)cc(N)n1
Yield: 26.6 %

Procedure:
A solution of 205.6 mg (1.49 mmol) 4-aminomethyl-pyridine-2,6-diamine in 5 ml pyridine was treated with 198 mg (1.49 mmol) cyclopentane carboxylic acid chloride and a catalytic amount 4-dimethylaminopyridine and stirred for 2.5 h at room temperature. The mixture was evaporated to dryness and the residue was purified by column chromatography on silica eluting with dichloromethane/methanol 9/1 to yield 93 mg (26%) of the title compound.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C@H:15]1[CH2:20][NH:19][CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1.CCN(C(C)C)C(C)C>CCO>[CH3:14][C@H:15]1[CH2:20][N:19]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:18][C@@H:17]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:16]1
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Temperature: 100 °C
Yield: 74.9 %

Procedure:
To a microwave vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (from Example 9, step 3) (47.8 mg, 0.164 mmol) and tert-butyl [(3S,5R)-5-methylpiperidin-3-yl]carbamate (33.7 mg, 0.157 mmol), EtOH (1.00 mL) was added, followed by DIPEA (41.5 mg, 0.321 mmol). The mixture was heated under microwave irradiation at 100° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a yellow solid (44.5 mg, 75%). LCMS calc. for C18H27N4O5 (M+H)+: m/z=379.2. found 379.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1OS(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:2].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[NH:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1sc(C)nc1OS(=O)(=O)c1ccc(C)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(C)nc1NCc1ccccc1
Temperature: 120 °C
Yield: 49.4 %

Procedure:
To a solution of 2-methyl-4-(toluene-4-sulfonyloxy)-thiazole-5-carboxylic acid ethyl ester (2.0 g, 5.865 mmol) in 1,4-dioxane (50 mL) was added benzylamine (1.92 mL, 17.6 mmol) and the mixture was heated at 120° C. for 6 h. The reaction mixture was cooled to RT and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.80 g, 49%).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH:7]=O)[CH:4]=[C:3]([CH:9]=O)[CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH2:7][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:4]=[C:3]([CH2:9][NH:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:2]=1
Reactant: O=Cc1cc(C=O)cc(-c2ccccc2)c1
Reactant: CCCCNCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCNCCCNCCCNCc1cc(CNCCCNCCCNCCCC)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[1,1′-Biphenyl]-3,5-dicarbaldehyde (0.66 g, 3.15 mmol) and MeOH (50 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-butylpropane-1,3-diamine (1.18 g, 6.31 mmol) and the reaction mixture was stirred at rt for 24 h. Sodium borohydride (0.48 g, 12.62 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aq. NaOH (10%, 100 mL) and EtOAc (100 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a clear oil which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)([OH:3])=[O:2].Cl.[CH3:16]O>>[CH3:16][O:2][C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:14])[NH:9]2)=[O:3]
Reactant: CO
Reactant: O=C(O)c1cccc2[nH]c(=O)ccc12
Agent: Cl
Product: COC(=O)c1cccc2[nH]c(=O)ccc12

Procedure:
2 Grams of 5-carboxycarbostyril was suspended in 100 ml of methanol, and hydrogen chloride gas was saturated by bubbling into this suspension, then the reaction mixture was refluxed for 3 hours. The reaction mixture was concentrated to be reduced one-half volume of its initial value, and the precipitated crystals were collected by filtration. The crystals were purified by a silica gel column chromatography, and recrystallized from methanol-chloroform to obtain 230 mg of 5-methoxycarbonylcarbostyril in the form of colorless powdery product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=1.S(Cl)([Cl:22])=O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:22])=[O:16])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2cccnc2)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(NS(=O)(=O)c2cccnc2)cc1

Procedure:
Into a 500 ml-flask fitted with a mechanical stirrer and a condenser were introduced 26 g (0.093 mol) of 4-(3-pyridylsulfonamido)-benzoic acid and 180 ml of thionyl chloride, after which a few drops of dimethylformamide were added as catalyst. The mixture was progressively heated to boiling, which was maintained for three hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[C:41]([F:43])[C:40]([F:44])=[C:39]([F:45])[CH:38]=2)[O:33][C:32]1=[O:46].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:38]=[C:39]([F:45])[C:40]([F:44])=[C:41]([F:43])[CH:42]=2)[O:33][C:32]1=[O:46]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(F)c(F)c(F)c4)[C@@H]3C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(F)c(F)c(F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-(3,4,5-trifluorophenyl)-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (23 mg, 0.0358 mmol) in MeOH (1 mL) was added 4 M KOH solution (0.5 mL). The reaction was stirred at room temperature for 3 hours, then quenched with 1 N HCl (5 mL) and diluted with EtOAc (15 mL). The aqueous layer was extracted with EtOAc (10 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) to afford 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-(3,4,5-trifluorophenyl)-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS=629.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 8.01-7.93 (m, 2H), 7.70-7.62 (m, 2H), 7.43-7.38 (m, 2H), 7.33-7.30 (m, 1H), 7.14-7.12 (m, 1H), 7.09-7.06 (m, 1H), 6.88-6.80 (m, 2H), 5.39 (d, J=8.0 Hz), 5.15 (d, J=8.0 Hz), 4.92 (d, J=15.6 Hz), 4.86 (d, J=15.6 Hz), 4.16 (d, J=15.8 Hz), 3.95 (d, J=15.8 Hz), 3.86 (m, 3H), 3.72-3.69 (m, 1H), 2.38 (s), 2.34 (s), 0.57 (d, J=6.6 Hz), 0.46 (d, J=6.6 Hz).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[CH2:21]([SH:26])[CH2:22][CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C(C)=CC=CC=1>[CH2:21]([S:26][C:2]1[N:6]=[CH:5][N:4]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C[Si](C)(C)CCOCn1cnc(Br)c1-c1cccnc1
Reactant: CCCCCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCCSc1ncn(COCC[Si](C)(C)C)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a degassed solution of xylene (100 ml) containing 73 (1.82 g, 5.16 mmol), were added 1.25 eq (0.80 ml) of pentane-1-thiol and 1.25 eq of K2CO3 (0.8 g). The resulting mixture was stirred for another 2 hours under N2. Successively were added 10 mol % of Pd2(dba)3 (470 mg) and 20 mol % mmol Xantphos (600 mg). After the addition, the resulting solution was stirred for 18 hours at 130° C. under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether followed by ethyl acetate) to afford 3-[5-pentylsulfanyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-pyridine (74A) as an oil (530 mg, 30%) and starting material (73, 380 mg, 21%), 1H-NMR (400 MHz, CDCl3): δ 9.38 (d, J=2 Hz, 1H), 8.53 (dd, J=5 Hz, 2 Hz, 1H), 8.42 (dt, J=8 Hz, 2 Hz, 1H), 7.82 (s, 1H), 7.35-7.30 (m, 1H), 5.43 (s, 2H), 3.59-3.54 (m, 2H), 2.66 (t, J=7 Hz, 2H), 1.47-1.38 (m, 2H), 1.28-1.10 (m, 4H), 0.96-0.89 (m, 2H), 0.80 (t, J=7 Hz, 3H), 0.0 (s, 9H).
Reaction SMILES: ClC1C=CC(C(Cl)=O)=CC=1[N+]([O-])=O.N1C=CN=N1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][C:27]=1[C:35]1[O:36][CH:37]=[CH:38][N:39]=1.NC1C=CC=CC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>S1(CCCC1)(=O)=O.C1COCC1.O>[O:36]1[CH:37]=[CH:38][N:39]=[C:35]1[C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:26]=1[Cl:25])[NH2:32]
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2ncco2)c1
Agent: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: Nc1ccc(Cl)c(-c2ncco2)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[[-((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-(2-oxazolyl)-4-chloroaniline to generate the title compound. The 3-(2-oxazolyl)-4-chloroaniline was prepared by treating commercial 4-chloro-3-nitrobenzoyl chloride sequentially with 1,2,3-triazole at 140° C. in sulfolane containing K2CO3 to generate 4-chloro-3-(2-oxazolyl)nitrobenzene which was reduced to the desired aniline with Na2S2O4 in THF/H2O at 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=O.[OH-].[Na+].Cl.[NH2:24][CH2:25][C:26]1[C:31](=[O:32])[CH:30]=[C:29]([CH3:33])[NH:28][C:27]=1[CH3:34].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:24][CH2:25][C:26]1[C:31](=[O:32])[CH:30]=[C:29]([CH3:33])[NH:28][C:27]=1[CH3:34])=[O:9]
Reactant: Cc1cc(=O)c(CN)c(C)[nH]1
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C)CC2)c1C
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CO
Product: Cc1cc(=O)c(CNC(=O)c2cc(Cl)cc(OC3CCN(C)CC3)c2C)c(C)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of methyl 5-chloro-2-methyl-3-((1-methylpiperidin-4-yl)oxy)benzoate (120 mg, 0.403 mmol) in MeOH (2 mL) was treated with 6 N NaOH (2 mL). The reaction was stirred for 2 h at RT, at which time it was concentrated in vacuo. The residue was suspended in water, acidified with 6 N HCl, filtered and dried. The resultant product was dissolved in DMF (4.0 mL) and treated with 3-(aminomethyl)-2,6-dimethylpyridin-4(1H)-one, hydrochloride (76 mg, 0.403 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (82 mg, 0.604 mmol), EDC (116 mg, 0.604 mmol) and N-methylmorpholine (177 μl, 1.612 mmol). The reaction was stirred for 3 h at RT, at which time it was poured into saturated sodium bicarbonate solution and extracted with DCM (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-chloro -N-((2,6-dimethyl-4-oxo-1,4-dihydropyridin-3-yl)methyl)-2-methyl-3-((1-methylpiperidin -4-yl)oxy)benzamide (0.050 g, 0.120 mmol, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.54-1.74 (m, 2 H) 1.80-1.94 (m, 2 H) 2.06 (s, 3 H) 2.12-2.22 (m, 6 H) 2.25 (d, J=9.60 Hz, 2 H) 2.31 (s, 3 H) 4.19 (d, J=5.05 Hz, 2 H) 4.48 (br. s., 1 H) 5.87 (s, 1 H) 6.79 (d, J=2.02 Hz, 1 H) 7.10 (d, J=2.02 Hz, 1 H) 8.21 (t, J=4.93 Hz, 1 H) 11.00 (s, 1 H). MS(ES) [M+H]+ 418.3.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4](=O)[CH2:5][CH2:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH3:2].CC1C=C(C(=O)C)C=CC=1NS(C)(=O)=O.CSC.B.C(Cl)Cl.Cl>C1COCC1.CCO.CO>[CH2:1]([N:3]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCCCCCCN(CC)C(=O)CCC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: B
Agent: CC(=O)c1ccc(NS(C)(=O)=O)c(C)c1
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: CCO
Product: CCCCCCCN(CC)CCCCc1ccc(NS(C)(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of N-ethyl-N-heptyl-γ-oxo-4-[(methylsulfonyl)amino]benzenebutanamide as prepared in Preparation 3 (2.0 g, 0.005 mol) in THF (20 ml), under N2, is treated during 1 hour with a 1M solution of borane dimethylsulfide in CH2Cl2 (15.8 ml, 0.0158 mol). The mixture is kept at ambient temperature for 30 minutes and at reflux for 4 hours. It is then cooled in an ice bath and treated slowly with MeOH (2 ml). This mixture is kept at ambient temperature for 18 hours, acidified with a solution of HCl in EtOH and refluxed for 1 hour. The cooled solution is concentrated and the residue is mixed with saturated NaHCO3 and extracted with CH2Cl2. The extracts are washed with brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (350 g) with 5% MeOH-0.5% NH4OH--CH2Cl2. The N-[4-[4 -(ethylheptylamino)butyl]phenyl]methanesulfonamide thus obtained is mixed with saturated NaHCO3 and extracted with Et2O. The extracts are washed with brine, dried (MgSO4) and concentrated. A solution of the residue in pentane is filtered through Magnisol and concentrated. MS: theory for C20H36N2O2S(M+): 368.2497. Found: 368.2498.