Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:35][CH2:34][C:33]4[N:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[7,8-dihydro[1,6]naphthyridin-6(5H)-ylcarbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 29) (281 mg, 0.58 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (245 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2].[C:18]1([C@@H:24]2[CH2:26][C@H:25]2[NH:27][C:28]2[S:29][CH2:30][C:31](=[O:33])[N:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:30]3/[C:31](=[O:33])[N:32]=[C:28]([NH:27][C@@H:25]4[CH2:26][C@H:24]4[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[S:29]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:16]#[N:17])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(C=O)cc12
Reactant: O=C1CSC(N[C@@H]2C[C@H]2c2ccccc2)=N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(N[C@@H]4C[C@H]4c4ccccc4)=NC3=O)cc12
Temperature: 150 °C
Yield: 26.5 %

Procedure:
To the suspension of 4-ethoxy-6-formyl-quinoline-3-carbonitrile (example 14e) (68 mg, 0.3 mmol) and 2-((1R,2S)-2-phenyl-cyclopropylamino)-thiazol-4-one (example 1f, 70 mg, 0.3 mmol) in toluene (2 mL) was added benzolic acid (3.5 mg, 0.03 mmol) and piperidine (35 uL, 0.03 mmol). The mixture was heated to 150° C. by microwave for 20 min. After cooling to room temperature, the solid was collected by filtration, washed with toluene and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-5% methanol in methylene chloride in 30 min) afforded 4-ethoxy-6-[4-oxo-2-((1R,2S)-2-phenyl-cyclopropylamino)-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (35 mg, 27%) as a light yellow solid: LC-MS m/e 441 (MH+).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([F:30])[F:29])[CH2:23][NH:22]1)=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1>CO>[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([F:30])[F:29])[CH2:23][N:22]1[CH2:1][CH2:2][OH:3])=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1
Reactant: CSC1OC(C(NC(=O)C2CC(CCC(F)F)CN2)C(C)C)C(O)C(O)C1O
Reactant: C1CO1
Solvent: CO
Product: CSC1OC(C(NC(=O)C2CC(CCC(F)F)CN2CCO)C(C)C)C(O)C(O)C1O
Temperature: 4 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Ethylene oxide (0.4 mL) was added to a solution of 4-(3,3-difluoro-propyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide, prepared as in Example 14 (29.7 mg, 0.07 mmol), in methanol (2 mL), at 0° C. The reaction mixture was stirred at 4° C. overnight. Additional ethylene oxide (0.4 mL) was added and stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (19.3 mg, 59%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6](Br)([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.[NH2:23][NH2:24]>O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:24][NH:23]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(C)(Br)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NN
Solvent: C1COCCO1
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 36.5 g of 3-bromo-3-(4'-fluoro-4-biphenylyl)-butyric acid ethyl ester [obtainable from 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and PBr3 ] and 7 g of hydrazine in 200 ml of dioxane is boiled for 2 hours and is evaporated. Working up gives 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH2:13]OS(C)(=O)=O)[C@@H:10]([OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O>[N:20]([CH2:13][C@@H:11]1[C@@H:10]([OH:19])[CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)=[N+:21]=[N-:22]
Reactant: CS(=O)(=O)OC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(Cc2ccccc2)C[C@@H]1O
Temperature: 120 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
(3R,4R)-1-Benzyl-3-hydroxy-4-methanesulfonyloxymethylpyrrolidine (835 mg), sodium azide (381 mg), and N,N-dimethylformamide (12 mL) were mixed with one another and the mixture was stirred at 120° C. for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure. To the resulting residue, water (10 mL) was added and the mixture was extracted with diethyl ether (2×30 mL). The diethyl ether extracts were combined and the combined extract was dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate: methanol=20:1) to give 576 mg of (3R,4R)-3-azidomethyl-1-benzyl-4-hydroxypyrrolidine as a pale brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH2:51])[CH2:45][CH2:46][CH3:47]>C(Cl)(Cl)Cl.O>[CH2:44]([N:48]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:49][CH2:50][NH:51][C:36]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([CH3:24])[C:18]=1[CH3:23])=[O:42])[CH2:45][CH2:46][CH3:47]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCN(CCN)CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-dibutyl-1,2-ethanediamine (81 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:24][O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([C:11]3[N:12]=[C:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[S:14][CH:15]=3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:31])=[CH:28][CH:27]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc([N+](=O)[O-])c(N)c2)cs1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc(-c3csc(NC(=O)OC(C)(C)C)n3)ccc2[N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 71.8 %

Procedure:
To a solution of compound 150 (390 mg, 1.28 mmol) in pyridine was added 4-methoxybenzoyl chloride (181 mg, 1.06 mmol) and 4-(N,N-dimethylamino)pyridine (13 mg, 0.11 mmol). The mixture was stirred for 16 h and partitioned between EtOAc and H2O. The organic layer was washed with brine and some compound was collected by filtration. The filtrate was dried over MgSO4, filtered and concentrated in vacuo and then crystallized from a mixture of EtOAc/Hexanes. The two crops were combined affording the title compound 151 (358 mg, 72% yield). 1H NMR: (400 MHz, CD3OD) δ(ppm): 11.73 (s, 1H), 10.71 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.83 (dd, J=8.6, 2.0 Hz, 1H), 7.10 (d, J=9.0 Hz, 2H), 3.85 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([O:22]CC4C=CC=CC=4)=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:30]=1)#[N:2].C(N(CCCC)CCCC)CCC>[Pd].C(O)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[C:8]([C:14]3[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[C:7]=2[CH:30]=1)#[N:2]
Reactant: CC1(C)C=C(c2ccc(C(=O)OCc3ccccc3)cn2)c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CCCCN(CCCC)CCCC
Solvent: O=CO
Product: CC1(C)C=C(c2ccc(C(=O)O)cn2)c2cc(C#N)ccc2O1
Yield: 35.8 %

Procedure:
5.06 g of benzyl 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylate were heated at 100° C. with 7.8 ml of tributylamine, 244 mg of 10% palladium-on-charcoal and 0.9 ml of formic acid. After 12 hours a further 7.8 ml of tributylamine and 10 ml of formic acid were added. After 24 hours a further 2 ml of tributylamine and 3 ml formic acid were added. After 26 hours a further 170 mg of 10% palladium-on-charcoal, 2 ml tributylamine and 3 ml of formic acid were added. After 28 hours the mixture was evaporated and filtered. The filtrate was evaporated and the residue obtained was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) and ethyl acetate for the elution. There were obtained 1.4 g of 6-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-3-pyridinecarboxylic acid which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>CN(C)C=O.[Cu]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: Brc1ccccc1
Reactant: Cc1ccc(O)cn1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methylpyridin-3-ol (25.2 g, 231 mmol) in N,N-dimethylformamide (100 ml) was added potassium tert-butoxide (25.9 g, 231 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was evaporated under reduced pressure and diluted with N,N-dimethylformamide (100 ml). A copper powder (3.7 g, 58 mmol) and bromobenzene (36.3 g, 231 mmol) were added, and the mixture was stirred at 120° C. overnight. Methanol was added to the reaction solution and insoluble material was filtered off using celite. The filtrate was diluted with water (500 ml) and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the objective substance (31 g, 72%).
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12][C:13]1[CH:18]=[C:17](C(OC)=O)[N:16]=[C:15]([C:23](OC)=[O:24])[CH:14]=1.O1CCN([Li])CC1.C(O[CH:38]([O:43]C(C)C)[O:39][CH:40]([CH3:42])[CH3:41])(C)C>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]([N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[O:24])[N:16]=[C:17]([C:38]([O:39][CH:40]([CH3:41])[CH3:42])=[O:43])[CH:18]=1
Reactant: CC(C)OC(OC(C)C)OC(C)C
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Reactant: C1COCCN1
Agent: [Li]CCCC
Agent: [Li]N1CCOCC1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cc(Cl)cc(C(=O)N2CCOCC2)n1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
n-butyllithium (1.92 mL, 2.5M in hexanes) was added dropwise to a −78° C. solution of morpholine (0.42 mL, 4.8 mmol) in anhydrous THF followed by slow warming to room temperature. The solution was transferred to an addition funnel via cannulation and then added dropwise to a solution of dimethyl 4-chloropyridine-2,6-dicarboxylate (1.0 g, 4.4 mmol, Intermediate 251) in anhydrous THF. A slight precipitate was observed during the addition. After stirring two hrs at room temperature an additional 0.5 equivalence of the morpholino-lithium reagent was added to the reaction and after an additional two hrs of stirring another 0.5 equivalence was added followed by stirring one hour to reach completion. The solvent was removed under reduced pressure and the residue was suspended in methylene chloride and the product was extracted with a sat. sodium bicarbonate solution (×3). The sodium bicarbonate portion was acidified with conc. HCl to pH 3 and then extracted with EtOAc (×10), followed by drying with MgSO4 and concentrating to a solid (0.8 g, 70%). MS (ES) MH+: 271 for C11H11ClN2O4. The solid was suspended in anhydrous toluene (75 mL) and to this was added triisopropylorthoformate (1.97 mL, 8.9 mmol) slowly followed by heating to reflux for 12 hours. After cooling to room temperature the solvent was removed under reduced pressure and the residue was suspended in 1N HCl. Basification to pH8 with saturated sodium bicarbonate followed by extraction with EtOAc (×3), drying with MgSO4 and removal of solvent yielded a tan solid. Purification by silica gel flash column (gradient elution to 3:1 EtOAc:CH2Cl2) yielded a white solid (0.23 g) MS (ES) MH+: 313 for C14H17ClN2O4; NMR: 1.33 (s, 3 H) 1.35 (s, 3 H) 3.41 (s, 2 H) 3.44 (d, 2 H) 3.58 (d, 2 H) 3.68 (s, 4 H) 5.17 (dt, 1 H) 8.01 (d, 1H) 8.13 (d, 1 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:21][C@@H:10]2[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:13][C@@H:9]2[CH2:8]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(O)C[C@H]2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H]2CC(OS(C)(=O)=O)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 mL, 2.33 mmol), was added dropwise to a solution of 1,1-dimethylethyl (3aR,6aS)-5-(hydroxy)-hexahydrocyclopenta [c] pyrrole-2(1H)-carboxylate (0.44 g, 1.94 mmol) and triethylamine (0.81 mL, 5.81 mmol) in 10 mL dichloromethane at 0° C. and the reaction mixture was stirred for 1 h at room temperature. The solvent was evaporated, the resulting crude mixture was diluted with 100 mL ethyl acetate and washed with water (30 mL), brine, 1M aqueous hydrochloric acid and brine again. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude 1,1-dimethylethyl (3aR,6aS)-5-{[(methylsulfonyl)oxy]}hexahydrocyclopenta[c]pyrrole -2(1H)-carboxylate was used without further purification. MS (EI) for C13H23NO5S: 306 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH3:16]>C(O)C>[CH2:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH2:15][CH3:16]
Reactant: CCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc(C(C)=O)cc1
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
To 272 g (2000 mmole) of 4'-hydroxyacetophenone dissolved in 800 ml of ethanol was added 249 g (2000 mmole) of 45% aqueous potassium hydroxide. After stirring for 5 minutes, 270 g (2200 mmole) of 1-bromopropane was added and the mixture was refluxed for 6 hours. After cooling, the precipitated potassium bromide was filtered off and washed with diethyl ether. The combined organic layers were concentrated in vacuo and then redissolved in 500 ml of diethyl ether. The resulting solution was washed with 1M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo yielding 270 g of the expected product, an oil, bp 110° C. at 1 torr.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([NH:25][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(2S)-(2-Amino-5-chloro-benzoylamino)-3-biphenyl-4-yl-propionic acid methyl ester was prepared following General Procedure A using 2-amino-5-chloro-benzoic acid (1.751 g, 98%, 10 mmol), (S)-2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride salt (2.95 g, 10 mmol), HBTU (4.55 g, 12 mmol) and DIEA (6.33 mL, 99%, 36 mmol) in DMF (60 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2, 1:1.5) gave solid (3.48 g, 8.45 mmol, 85% yield).
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[O:5][CH:6]=[CH:7][N:8]=1)C.[CH2:13]([N:16]([CH2:30][CH2:31][CH3:32])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27](I)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:14][CH3:15]>CN(C)C=O>[CH2:30]([N:16]([CH2:13][CH2:14][CH3:15])[C:17]([C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([C:4]2[O:5][CH:6]=[CH:7][N:8]=2)[CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH2:31][CH3:32]
Reactant: CC[Sn](CC)(CC)c1ncco1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncco2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
A stirred solution of 2-triethylstannyloxazole (Chem. Mater. 1994, 6, 1023) (1.5 g, 5.5 mmol) and methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (1.8 g, 4.6 mmol) in dimethylformamide (12 mL) was degassed under reduced pressure for 15 min and purged with argon. Palladium(0)tetrakis(triphenylphosphine) (158 mg, 0.14 mmol) was added and the reaction mixture was degassed under reduced pressure for 15 min and then purged with argon. The reaction mixture was heated at reflux for 2 d, cooled to room temperature, diluted with ethyl acetate, washed with water (3×50 mL), dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided methyl 3-[(dipropylamino)carbonyl]-5-(1,3-oxazol-2-yl)benzoate (423 mg): 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.76 (s, 1H), 7.28 (s, 1H), 3.97 (s, 3H), 3.49 (br s, 2H), 3.18 (br s, 2H), 1.72 (d, J=7 Hz, 2H), 1.55 (d, J=7 Hz, 2H), 1.00 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([C:34](OC)=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18].CCO>C1COCC1>[CH2:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:38])=[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([CH:34]=[O:35])[CH:27]=2)[CH:25]=1)[CH3:18]
Reactant: CCOc1ccc(F)c(-c2cc(OC)nc(C(=O)OC)c2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(-c2cc(C=O)nc(OC)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1M DIBAL in toluene (7.53 mL, 7.53 mmol) was added dropwise over 10 mins to a stirred solution of methyl 4-(5-ethoxy-2-fluoro-phenyl)-6-methoxy-pyridine-2-carboxylate (which may be prepared as described in Description 131) (1.15 g, 3.77 mmol) in dry THF (20 mL) at −75° C. The reaction was stirred at this temp for 2 h then EtOH (175 μL) was added to quench. After 1 min the reaction mixture was poured into saturated Rochelle salt solution (100 ml) and water (50 ml). The mixture was warmed to ambient temperature then extracted with EtOAc (3×50 ml). Filtration under suction through celite was necessary to clear the emulsion. The combined organic extracts were dried (MgSO4) and evaporated to 4-(5-ethoxy-2-fluoro-phenyl)-6-methoxy-pyridine-2-carbaldehyde (D132) a slightly coloured oil (970 mg);
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>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.O1CCOCC1.O>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:32]3[CH2:33][CH2:34][NH:29][CH2:30][CH:31]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Temperature: 90 °C

Procedure:
A mixture of 5-bromo-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (60.0 mg, 0.155 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (95.6 mg, 0.309 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol), potassium carbonate (64.1 mg, 0.464 mmol) and 4:1 dioxane/H2O (10 mL) was heated to 90° C. for 2 h. The solution was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in dioxane, and 4M HCl in dioxane (1 mL) was added. The solution was heated to 40° C. for 2 h. The material was loaded into an SCX cartridge, washed with MeOH (30 mL) and ejected with 2M NH3 in MeOH (10 mL). The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.88 (d, J=7.3 Hz, 3 H), 2.65-2.73 (m, 2 H), 3.45 (t, J=6.1 Hz, 2 H), 3.76-3.86 (m, 2 H), 5.28 (d, J=7.3 Hz, 1 H), 5.95 (dt, J=3.3, 1.7 Hz, 1 H), 7.19 (t, J=8.6 Hz, 1 H), 7.34 (d, J=2.3 Hz, 1 H), 7.36-7.50 (m, 2 H), 8.26 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 390.00 (100) [MH+]. HPLC: tR=2.48 min (ZQ3, polar—5 min).