Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[C:14]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])([CH3:16])[CH3:15]>CCCCC>[C:25]([C:20]1[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:19]=1[O:29][Al:5]([O:29][C:19]1[C:20]([C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: CCCCC
Product: Cc1cc(C(C)(C)C)c(O[Al](CC(C)C)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1

Procedure:
Using a 250 ml balloon flask in an argon atmosphere and provided with a magnetic stirrer rod, a solution of 2 ml of triisobutylaluminium in 30 ml of pentane is introduced, then a solution of 3.49 g of 2,6-di-t-butyl-4-methylphenol in 40 ml of pentane is injected drop by drop with agitation and at ambient temperature. After about 30 hours of reaction the pentane is evaporated under vacuum and analysis of the remaining white solid indicates that it is essentially formed by bis-(2,6-di-t-butyl-4-methylphenoxy)-isobutylaluminium.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[Cl:11][CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1.ClCCl>C(N(CC)CC)C>[Cl:11][CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:9])[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]3[N:23]=[N:24][N:25]=[C:17]3[C:16]=2[N:26]=1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCN)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)NC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Cyclohexyl isocyanate (0.285 mL, 2.20 mmol) was added to a flask containing 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butan-1-amine hydrochloride (680 mg, 1.98 mmol), triethylamine (0.311 mL, 2.2 mmol), and dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 2 hours and additional triethylamine and cyclohexyl isocyanate (1.1 equivalents each) were added. The reaction mixture was stirred overnight at room temperature, then was partitioned between dichloromethane (50 mL) and 2:1 water/saturated aqueous sodium carbonate (30 mL). The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layers were combined, washed with 0.5 M aqueous sodium hydroxide (2×30 mL), and concentrated under reduced pressure. The resulting white solid was triturated with ethyl acetate, isolated by filtration, and washed with ethyl acetate and water to provide 777 mg of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-N′-cyclohexylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]C)=[O:34].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:22]([O:23][CH3:24])=[C:19]([O:20][CH3:21])[CH:18]=2)[CH2:9][CH2:10][CH2:11][C:12]([NH:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCN(CCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1OC
Reactant: COC(=O)CCCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCN(CCCC(=O)NCCCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-homoveratrylaminobutyric acid and methyl 4-aminobutyrate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-(homoveratrylamino)butyryl]-4-aminobutyric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]2[C:6]([CH:7]([NH2:18])[CH2:8][C:9]3([O:15]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:5][CH:4]=1.COC([N:23]1[C:31]2[C:26](=[C:27]([NH:32][C:33](ON3C(=O)CCC3=O)=[O:34])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1)=O.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C)C=O.O.O1CCCC1>[NH:23]1[C:31]2[C:26](=[C:27]([NH:32][C:33]([NH:18][CH:7]3[C:6]4[C:16](=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[O:15][C:9]4([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8]3)=[O:34])[CH:28]=[CH:29][CH:30]=2)[CH:25]=[N:24]1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: COc1ccc2c(c1)OC1(CCCCC1)CC2N
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC1(CCCCC1)CC2NC(=O)Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
The product of Example 16C (0.195 g) was stirred with the product of Example 1H (0.215 g, 0.647 mmol) and diisopropylethylamine (0.15 mL, 0.86 mmol) in 2 mL N,N-dimethylformamide at room temperature for 1 h. After this time, the mixture was diluted with H2O. The precipitate thus formed was collected by filtration, dissolved in methanol (2 mL) and tetrahydrofuran (0.5 mL), and treated with 1N aq NaOH (0.75 mL, 0.75 mmol). The mixture was stirred at room temperature for 3 h, and precipitated with H2O. The precipitate was dissolved in ethyl acetate, and washed with water, and brine, and dried (Na2SO4) and evaporated to give the product as a tan solid (0.219 g, 0.540 mmol, 83%). 1H NMR (300 MHz, DMSO-d6) δ ppm 13.01 (br s, 1H), 8.65 (s, 1H), 8.06 (br s, 1H), 7.68 (d, 1H), 7.21 (m, 2H), 7.07 (d, 1H), 6.64 (d, 1H), 6.51 (dd, 1H), 6.35 (d, 1H), 4.92 (m, 1H), 3.71 (s, 3H), 2.22 (dd, 1H), 1.25-1.80 (m, 12H); MS (ESI+) m/z 407.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH:43]=2)=[CH:9]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:65]([OH:71])([C:67]([F:70])([F:69])[F:68])=[O:66]>C1COCC1>[F:68][C:67]([F:70])([F:69])[C:65]([OH:71])=[O:66].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:17]([NH:1][C:2]3[S:3][CH:4]=[CH:5][N:6]=3)(=[O:19])=[O:18])[CH:15]=2)[C:10]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:33]=2[C:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH:43]=2)=[CH:9]1
Reactant: Nc1nccs1
Reactant: Cn1cc(-c2ccc(C(F)(F)F)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc(C(F)(F)F)cc2C2=CCNCC2)c2ccc(S(=O)(=O)Nc3nccs3)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A flask containing a mixture of 2-aminothiazole (7.93 mg, 0.079 mmol), tert-butyl 4-(2-(1-methyl-6-((perfluorophenoxy)sulfonyl)-1H-indol-3-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (INTERMEDIATE O) (0.053 g, 0.075 mmol), and THF (0.503 ml) was cooled to 0° C. LHMDS (1.0M in THF) (0.151 ml, 0.151 mmol) was added dropwise and the reaction was stirred for 15 minutes at 0° C. An additional equivalent of aminothiazole was added, followed by 2 equivalents of LHMDS solution. The reaction was stirred for one hour at 0° C. The reaction was quenched with saturated ammonium chloride solution, diluted with DCM, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated. The material was dissolved in DCM and TFA (0.1 ml, 1.298 mmol) was added. The reaction was stirred at 50° C. overnight. The reaction was concentrated and the material was purified via column chromatography (RediSep Gold 12 g silica gel column (Teledyne Isco, Lincoln, Nebr., gradient elution 0 to 10% MeOH:DCM) to afford 1-methyl-3-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-1H-indole-6-sulfonamide 2,2,2-trifluoroacetate as a tan solid. m/z (ESI) 519.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.61 (br. s., 1 H), 8.70 (br. s., 2 H), 7.99 (s, 1 H), 7.81-7.67 (m, 5 H), 7.59-7.52 (m, 2 H), 7.24 (d, J=4.8 Hz, 1 H), 6.81 (d, J=4.5 Hz, 1 H), 5.89 (br. s., 1 H), 3.95 (s, 3 H), 3.71 (br. s., 2 H), 2.98 (br. s., 2 H), 2.11 (br. s., 3 H)
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([OH:8])=O)([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]=[C:17]=[S:18])[CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([N:16]2[C:6](=[O:8])[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:17]2=[S:18])[CH:15]=1
Reactant: CC(C)NCC(=O)O
Reactant: Cc1ccc(Cl)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Cl)cc1N1C(=O)CN(C(C)C)C1=S
Yield: 54.7 %

Procedure:
A mixture of the crude N-isopropyl glycine (21.2 g), 5-chloro-2-methylphenyl-isothiocyanate (18.3 g), triethyl amine (21.0 g) and chloroform (300 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 2N HCl (2×300 mL), then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (15.4 g) as a peach solid, m.p. 142°-144° C. Anal. Calcd. for. C13H15Cl N2O S: C, 55.21; H, 5.35; N, 9.91. Found: C, 55.07; H, 5.20; N, 9.82. Mass spectrum (+FAB, [M+H]+) m/z 283/285.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[F:1][C:2]1[C:3]([CH:14]=[O:15])=[CH:4][N:5]([S:39]([C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)(=[O:41])=[O:40])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1F
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: C1COCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Product: O=Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1F
Reaction time: 0.08 h
Yield: 48.8 %

Procedure:
To a solution of 4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (110 mg) in tetrahydrofuran (11 mL) was added sodium hydride (60% in oil, 43 mg) at room temperature and the mixture was stirred for 5 min. 15-Crown-5 (233 mg) was added dropwise, and the mixture was stirred for 5 min. Pyridine-3-sulfonyl chloride (141 mg) was added, and the mixture was further stirred for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 90 mg, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])N(OC)C)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[C:30]([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21](=[O:26])[CH3:30])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Reactant: O=C([O-])O
Agent: C[Mg+]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Temperature: 0 °C

Procedure:
To a solution of 4-[3-chloro-5-(methoxy-methyl-carbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester from step (b) above (1.0 g, 2.6 mmol) in anhydrous THF (20 mL) was added MeMgBr (2.6 mL, 3M solution in Et2O, 7.8 mmol, Aldrich) with stirring at 0° C. The reaction mixture was stirred at room temperature for 4 h and poured into satd. aq. NaHCO3 solution (20 mL). After the addition of EtOAc (50 mL), the mixture was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (70% EtOAc in hexane) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 340 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([Si:11]2(C3C=CC=CC=3)[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[C:20]([OH:24])=[C:19]([F:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:33][C@@H:34]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:35]O>>[CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([Si@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]3[CH:18]=[C:19]([F:25])[C:20]([O:24][CH2:35][C@H:34]([F:33])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:21]([F:23])[CH:22]=3)[CH2:15][CH2:16]2)[CH2:7][CH2:6]1
Reactant: CC(C)CC[C@H]1CC[C@H]([Si]2(c3ccccc3)CCC(c3cc(F)c(O)c(F)c3)CC2)CC1
Reactant: CCCCCCCC[C@H](F)CO
Product: CCCCCCCC[C@@H](F)COc1c(F)cc([C@H]2CC[Si@H]([C@H]3CC[C@H](CCC(C)C)CC3)CC2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(trans-4-(3-methylbutyl)cyclohexyl)-4-phenyl-4-silacyclohexyl)-2,6-difluorophenol and (S)-2-fluoro-1-decanol, thereby obtaining the intended compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1(N(C)CC)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O>[CH:20]1([CH2:4][N:3]([CH2:2][CH3:11])[C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: CCN(C)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC1CCCC1)c1nc2ccccc2cc1C=O
Temperature: 30 °C
Yield: 179.6 %

Procedure:
2-Chloroquinoline-3-carbaldehyde (0.27 grams, 1.40 mmol) and potassium carbonate (0.579 grams, 1.4 mmol) were added to a 25 mL two-necked round bottomed flask. To this flask was added 3 mL of N,N-dimethylformamide (DMF), followed by the drop-wise addition of a dimethylformamide solution of cyclopentyl methyl ethyl amine (0.214 grams, 1.69 mmol). The resulting mixture was refluxed for 2 hours and then cooled to 25-35° C., after which the mixture was poured onto crushed ice (10 mL), and extracted with ethyl acetate (3×50 mL). The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to provide the product as yellow oil (0.355 g, yield: 89%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cc(-c2cccs2)ccn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2cccs2)ccn1
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 2-iodo-4-thiophen-2-yl-pyridine (150 mg, 0.52 mmol) was dissolved in THF (3.2 mL). The light yellow solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.30 mL, 0.60 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.17 mL, 0.63 mmol) was slowly added. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and once with 5 mL brine then dried over sodium sulfate, filtered and concentrated to afford 4-thiophen-2-yl-2-(tributylstannanyl)pyridine a light brown oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C@H:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:38][OH:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:36][C@H:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:38][OH:39])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Intermediate 17 (0.25 g, 0.86 mmol), EDC (0.23 g, 1.2 mmol) and HOBT (0.139 g, 1.03 mmol) were suspended in DMF (5 ml) and the suspension was stirred at room temperature. After 25 min, (2R)-2-Amino-2-phenylethanol (0.13 g, 0.95 mmol, commercially available from Aldrich) was added, and the mixture was stirred at room temperature for 20 hours. Solvents were removed in vacuo and the residue was dissolved in DCM (50 ml) and washed successively with water (25 ml) and 5% sodium hydrogen carbonate solution (25 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was dissolved in dichloromethane (5 ml) and applied to a SPE cartridge (silica, 10 g), which was eluted with a gradient of ethyl acetate—petroleum ether (1:2, 1:1 and 1:0). Fractions containing the desired material were combined and concentrated in vacuo to afford Intermediate 42 as a white foam (0.318 g). LCMS showed MH+=410; TRET=2.55 min.
Reaction SMILES: [BrH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][O:6][C:4]1=[O:5]>Br.CC(O)=O>[BrH:1].[NH2:2][CH:3]([CH2:8][CH2:7][Br:1])[C:4]([OH:6])=[O:5]
Reactant: NC1CCOC1=O
Agent: Br
Solvent: CC(=O)O
Product: NC(CCBr)C(=O)O
Temperature: 100 °C
Yield: 64 %

Procedure:
A suspension of α-amino-γ-butyrolactone hydrobromide in 30% HBr in HOAc was heated at 100° C. in a sealed tube for 5 days. The mixture was concentrated to give a white solid that was washed with Et2O to provide 23.1 g (64%) of 2-amino-4-bromo-butyric acid hydrobromide.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:43])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=3)[C:20]([O:31][CH2:32][CH2:33][OH:34])=[C:19]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:48]CC1.O.S(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(#N)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CC(O)=O.CCOC(C)=O>[CH3:29][C:27]1[CH:28]=[C:23]([C:21]2[CH:22]=[C:17]([C:16](=[O:43])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=3)[C:20]=2[O:31][CH2:32][C:33]([OH:48])=[O:34])[CH:24]=[C:25]([CH3:30])[CH:26]=1
Reactant: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCCO)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: O=S([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3cc(C)cc(C)c3)c2OCC(=O)O)c1
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of N-8-phenyloctyl-3,5-bis-(3,5-dimethylphenyl)-4-(2-hydroxyethoxy)benzamide (850 mg, 1.47 mmol) in 15 mL of acetonitrile was added NMMO (415 mg, 3.05 mmol) and TPAP (52 mg, 0.149 mmol). The reaction was stirred for 2 hours then an additional 40 mg, 0.3 mmol NMMO and 52 mg, 0.149 mmol TPAP were added. The reaction was stirred overnight and an additional 40 mg, 0.3 mmol, NMMO was added. The reaction was stirred an additional two hours then water was added followed by the addition of sodium bisulfite/sodium dithionite. The aqueous mixture was stirred for 1 hour then it was extracted with EtOAc (3×). The combined extracts were dried with Na2SO4 and concentrated to give a black oil. This oil was subjected to flash chromatography (20% EtOAc: 80% Hexanes acidified with 1% CH3COOH) on HCOOH pretreated silica gel. There yielded 200 mg of the desired acid plus a fraction consisting of the desired acid and other impurities. This fraction was chromatographed again using the same solvent system to give 30 mg more of the acid for a total yield of 230 mg, 26.4% of the desired acid. 1H NMR (DMSO-d6) δ 1.27 (bs, 8H); 1.45–1.60 (m, 4H); 2.31 (s, 12H); 2.53 (t, J=7.58 Hz, 2H); 3.23 (quartet, J=6.37 Hz, 2H); 3.81 (s, 2H); 7.00–7.01 (m, 2H); 7.13–7.15 (m, 3H); 7.19–7.25 (m, 6H); 7.76 (s, 2H); 8.48 (t, J=6.00 Hz, 1H); 12.35 (bs, 1H); IR 3325, 2935, 2875, 1750, 1645, 1605, 1580, 1545, 1480, 1460, 1430, 1400, 1385, 1380, 1295, 1250, 1200, 1150, 850, and 700 cm−1; mass spectrum [(+)APCI], m/z 592 [M+H]+; Anal Calcd for C39H45NO4.C2H4O2.C4H8O2: C, 73.03; 7.63; H, 7.63; N, 1.89. Found: C, 73.32, H, 7.88; N, 2.04.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:11]2[CH:12]=[CH:13][CH:2]=[C:3]([CH:10]=2)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1N
Reactant: OB(O)c1cccc(Cl)c1
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: COCCOC
Solvent: O
Product: CON(C)C(=O)c1cccc(-c2cccc(Cl)c2)c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and was then heated at 85° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford 1-(4-amino-3 ′-chloro-biphenyl-3-yl)-ethanone as yellow solid (2 g, 47%): mp 89-90° C.; 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25-7.40 (i, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268([M+Na]+, 60%); Anal. Calc. For C14H12ClNO: C, 68.44, H, 4.92, N, 5.70. Found: C, 68.40, H, 4.89, N, 5.61.