Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[NH2:26][O:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CO>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][C:2]=3[F:1])[N:8]([CH3:11])[N:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 30 °C
Reaction time: 20 h
Yield: 72.5 %

Procedure:
To a solution of 1-(3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (50 mg, 0.155 mmol) in methanol (7 mL) was added 2-(aminooxy)ethanol hydrochloride (17.6 mg, 0.155 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at 30° C. for 20 h. The solvent was removed in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product which was purified by column chromatography to afford 43 mg (70%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.05 (d, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.53 (d, 1H), 4.75 (t, 1H), 4.43 (s, 1H), 4.23 (t, 2H), 3.97 (s, 3H), 3.68 (q, 2H), 2.28 (s, 3H). LCMS (method B): [MH]+=383, tR=2.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([OH:33])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:33][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@@H](O)Cc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](Cc2ccc(Cl)cc2)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
To a 15-mL round-bottomed flask equipped with a magnetic stir bar and containing (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}-piperazinyl)-2-hydroxy-propan-1-one (Step 3) (0.075 g, 0.15 mmol) in 2 mL THF at RT was added NaH (Aldrich) (0.007 g of 60% dispersion in oil, 0.17 mmol). Gas evolution was observed and after 5 min benzyl bromide (Aldrich) (20 ml, 0.17 mmol) was added. After stirring for 18 h, the mixture was quenched with aq. NaHCO3 and extracted with Et2O. The combined ether extracts were washed with H2O and brine, dried (Na2SO4) and concentrated onto silica gel. Purification by chromatography (30-55% EtOAc/hexanes) afforded (2S)-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]-phenyl}piperazinyl)-2-(phenyl-methoxy)propan-1-one as a colorless oil (0.065 g). MS (ESI, pos. ion) m/z 582 (M+1). Calc'd for C31H36ClN3O4S: 581.21.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([NH:24]O)=[NH:23]>O>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([NH:24][C:5](=[O:7])[CH3:6])=[NH:23]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(Cc1ccccc1-c1ccccc1Cl)NO
Solvent: O
Product: CC(=O)NC(=N)Cc1ccccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.88 %

Procedure:
To 10 mL acetic anhydride was added 2-(2′-chloro-biphenyl-2-yl)-N-hydroxy-acetamidine (16) (2 g, 7.692 mmol). The mixture was stirred for 6 h at room temperature. After completion of the reaction, water was added, the mixture was extracted with ethyl acetate, evaporated, dried and purified using a CombiFlash column using 25% ethyl acetate in hexane to get 2-(2′-chloro-biphenyl-2-yl)-N-acetyl-acetamidine (17) (2 g, 85.88%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.BrC1C=CC2OCCN3C(CN4CCCC4)=C(C(N)=O)N=C3C=2C=1.CNC.[CH3:50][C:51]([OH:55])([C:53]#[CH:54])[CH3:52]>>[CH3:20][N:19]([CH2:18][C:12]1[N:8]2[CH2:9][CH2:10][O:11][C:5]3[CH:4]=[CH:3][C:2]([C:54]#[C:53][C:51]([OH:55])([CH3:52])[CH3:50])=[CH:22][C:6]=3[C:7]2=[N:14][C:13]=1[C:15]([NH2:17])=[O:16])[CH3:21]
Reactant: C#CC(C)(C)O
Reactant: CN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: CNC
Agent: NC(=O)c1nc2n(c1CN1CCCC1)CCOc1ccc(Br)cc1-2
Product: CN(C)Cc1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(C)O)cc1-2
Yield: 34 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((dimethylamino)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing pyrrolidine with dimethylamine) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a grey solid (41 mg, 34%).
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3]C1>Cl.[C].[Pd]>[N:13]1[CH:14]=[CH:15][C:10]([CH:7]2[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: C1=C(c2ccncc2)CCC2(C1)OCCO2
Agent: [Pd]
Agent: Cl
Product: O=C1CCC(c2ccncc2)CC1
Yield: 83.7 %

Procedure:
4-(4-Pyridyl)cyclohex-3-enone ethyleneacetal (4 g) was dissolved in 70 ml of 0.5N hydrochloric acid. To the solution, there was added 400 mg of 10% palladium-carbon. Hydrogenation was carried out at room temperature under atmospheric pressure. After removing out the catalyst and adding an aqueous sodium hydroxide solution to alkalify, the reaction mixture was extracted with methylene chloride to obtain 2.7 g of 4-(4-pyridyl)cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.[Br-].[NH4+].CC(C)=[O:16]>>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:16])[CH2:1]1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Reactant: CC(C)=O
Agent: [Br-]
Agent: [NH4+]
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 239 %

Procedure:
5 g. of Acetonine and 12.4 g. of ammonium bromide were added to 30 g. of acetone and the mixture was maintained at room temperature for 38 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 239%.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:8]([O:21][CH2:22][CH3:23])[CH:7]=2.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[CH2:36][CH2:35]1>C(#N)C>[CH2:22]([O:21][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:34]3[CH2:39][CH2:38][CH:37]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[CH2:36][CH2:35]3)[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH3:20])(=[O:19])=[O:18])[CH3:23]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(C)(=O)=O
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CC#N
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(C)(=O)=O
Yield: 77.6 %

Procedure:
A suspension of methyl 3-(bromomethyl)-7-(ethyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.705 g, 3.12 mmol) and -(4-piperidinyl)morpholine (0.691 g, 4.06 mmol) in acetonitrile (30 mL) was stirred for 3 h. The solvent was removed under reduced pressure, and the residue was dissolved in DMSO and purified via HPLC (Biotage RP, 0-50% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and were extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo to afford methyl 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.54 g, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ8.40 (s, 1H), 7.98 (s, 1H), 7.87-7.94 (m, 2H), 7.76-7.81 (m, 2H), 4.40 (q, J=6.94 Hz, 2H), 4.01 (s, 3H), 3.61 (s, 2H), 3.53 (br. s., 4H), 3.42 (s, 3H), 2.62 (d, J=11.29 Hz, 2H), 2.38 (br. s., 4H), 1.93-2.05 (m, 1H), 1.81 (t, J=11.04 Hz, 2H), 1.62 (d, J=12.05 Hz, 2H), 1.47 (t, J=6.90 Hz, 3H), 1.18-1.30 (m, 2H); MS (m/z) 636.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=1.[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:3]=[C:4]([C:8]#[N:9])[N:5]([CH3:7])[CH:6]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: Cn1cc(Br)cc1C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1cc(Nc2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1C#N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Nitrogen is bubbled through a solution of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (2.82 g, 15.2 mmol) and 4-[(tert-butyldimethylsilyl)oxy]aniline (4.08 g, 18.3 mmol) in toluene (55 mL) for 5 minutes. Sodium tert-butylate (2.92 g, 30.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (556 mg, 0.6 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (255 mg, 0.6 mmol) are then added to the reaction mixture. The mixture is stirred for 1 hour at 80° C. under nitrogen. The suspension is then cooled to ambient temperature and filtered over Celite. The Celite cake is then rinsed with ethyl acetate. The filtrate is washed with water and then with brine. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The product is purified twice by chromatography over silica gel (AcOEt/heptane gradient), and then by trituration in heptane to obtain the expected product in the form of a solid.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.CCOCC.Cl.O.[CH3:17][CH2:18][CH2:19][CH2:20][CH2:21]C>>[CH:1]1([C:7](=[O:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(O)C1CC=CCC1
Reactant: CCCCCC
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCCC(=O)C1CC=CCC1
Temperature: 25 °C

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 18.9 g (0.15 mol) 3-cyclohexene-1-carboxylic acid, and 300 mL of ether. 132 mL of hexylithium (2.5 M solution in hexane, 0.33 mol) was slowly added to above mixture in ice bath over 40 min. After the above mixture was reacted at 0° C. for 30 minutes, the reaction mixture was warmed to room temperature. The mixture is slowly added into a vigorously stirred mixture of 27 mL (0.32 mol) of concentrated HCl and 400 mL of water. The organic phase is separated, and aqueous phase is extracted with 3×150 mL of ether, the combined organic solution is dried over sodium sulfate, and the solution is evaporated and distilled to give pure product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cnoc1-c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of methyl 3-[5-(4-bromophenyl)-4-isoxazolyl]propionate (4.06 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(4-bromophenyl)-4-isoxazolyl]propan-1-ol (3.58 g, yield 97%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 72–73° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(OCC)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1ccc2occc2c1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2occc2c1
Reaction time: 1 h

Procedure:
To a solution of 1-benzofuran-5-carbaldehyde (2.70 g, 18.5 mmol) in 50 mL THF under N2 was added phenylmagnesium bromide 3.0M solution in diethyl ether (7.39 mL, 22.2 mmol). The reaction was allowed to stir for 1 h, then was quenched with NH4Cl sat'd aq., extracted with diethyl ether, washed with brine, dried over anhyd. sodium sulfate, filtered, and concentrated in vacuo to a solid to give benzofuran-5-yl(phenyl)methanol which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.94 (d, J=2.0 Hz, 1H), δ 7.64 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.36-7.42 (m, 2H), 7.26-7.33 (m, 3H), 7.19 (t, J=7.3 Hz, 1H), 6.92 (d, J=1.5 Hz, 1H), 5.88 (d, J=4.0 Hz, 1H), 5.77-5.83 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[CH:8][CH:7]=2.[ClH:21].COC1C=NC2C(C=1)=CC(C(C)C(O)=O)=CC=2>>[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2
Reactant: COc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Agent: COc1cnc2ccc(C(C)C(=O)O)cc2c1
Agent: Cl
Product: COc1cnc2ccc(CC(=O)O)cc2c1

Procedure:
tert-Butyl 2-(3-methoxyquinolin-6-yl)acetate was saponified in a method similar to 2-(3-methoxyquinolin-6-yl)propanoic acid hydrochloride.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([NH:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:3][C@H:4]1[C:14]([O:16][CH3:17])=[O:15])=[O:8])([CH3:11])([CH3:12])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (2S,4R)-4-amino-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (6.04 g) in dichloromethane (60 ml) were added triethylamine (3.44 ml) and p-chlorobenzenesulfonyl chloride (6.26 g) in an ice bath. After being stirred at room temperature overnight, the solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (9.13 g) as a pale yellow crystal.
Reaction SMILES: C(O)=O.[C:4]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:4]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=C1CCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=CO
Product: OC1CCc2ccccc21
Temperature: 30 °C
Reaction time: 19 h

Procedure:
Formic acid (7.2 mL, 190.7 mmol) was added dropwise to a stirred solution of 1-indanone (5.09 g, 38.5 mmol), (S,S)-TsDPEN Ru (p-cymene) Cl (231 mg, 0.36 mmol) and triethylamine (26 mL, 186.5 mmol) in dichloromethane (50 mL) at 30° C. (internal) under a nitrogen atmosphere over a period of 30 minutes. The internal temperature reached 35° C. during the addition. After stirring for 19 hours at 30° C., 1H NMR analysis indicated a conversion of 80%. Additional (S,S)-TsDPEN Ru (p-cymene)Cl (47 mg, 0.07 mmol) was added to the reaction mixture followed by formic acid (3 mL, 79.5 mmol) dropwise over 30 minutes. After stirring for 21 hours at 35° C. (internal), 1H NMR analysis indicated complete conversion. The reaction was allowed to cool to room temperature before saturated aqueous sodium hydrogen carbonate solution (100 mL) was added. The two layers were separated then the aqueous layer was further extracted with dichloromethane (80 mL). The combined organic layers were washed with water (80 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The crude material was purified by passage trough a pad of silica using methyl tert-butyl ether as eluant to afford the S-enantiomer of the title compound as a red solid. (5.06 g, 98%). 1H NMR (400 MHz, d6-DMSO) δ ppm 7.37-7.34 (1H, m, Ar), 7.26-7.19 (3H, m, Ar), 5.23 (1H, d, J 6, OH), 5.06 (1H, dt, J 6 and 6, CH), 2.97-2.90 (1H, m, CHH), 2.77-2.69 (1H, m, CHH), 2.39-2.31 (1H, m, CHH) and 1.84-1.75 (1H, m, CHH). Analysis of this material by chiral GC indicated it to be 98% e.e.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>C1COCC1>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)Cc1ccsc1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccsc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To pure methyl 2-(thiophen-3-yl)acetate in THF cooled to −78° C. was added LiHMDS and the solution stirred at −78° C. for 30 min. Then N-(bromomethyl)phthalimide was added directly and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3(sat) extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-40% EtOAc/Hex) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E429).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([O:17][CH3:18])=[C:8]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:9]=1.C(Cl)Cl.C(OCC)(=O)C>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([O:17][CH3:18])=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:9]=1
Reactant: COc1c(N2CCC(=O)CC2)cc(Br)cc1C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1c(N2CCC(O)CC2)cc(Br)cc1C(C)(C)C
Yield: 64.4 %

Procedure:
NaBH4 (0.23 g, 6.1 mmol) was added to a mixed solution of. 1-[5-bromo-3-(tert-butyl)-2-methoxyphenyl]-4-piperidinone (2.0 g, 5.9 mmol) in methanol (12 ml)-methylene chloride (12 ml) while cooling on ice. After completion of the reaction, the mixture was diluted with water and extraction was performed with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.3 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>C(O)C>[CH2:11]([O:10][C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:9])[CH3:12]
Reactant: CC(C)CCN
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: CCO
Product: CCOC(=O)C1CCCCC1NCCC(C)C
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (3.0 mL, 17.8 mmol) in ethanol (30 mL) was added isoamylamine (2.1 mL, 17.9 mmol) at 25° C. The mixture was heated at reflux for 12 h. The reaction mixture was allowed to cool to 25° C. and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-30% ethyl acetate in hexanes) to afford the desired product, (2-(3-methylbutylamino)-cyclohexanecarboxylic acid ethyl ester (3.23 g, 13.5 mmol, 76%), as a yellowish oil. LC-MS (ESI) calcd for C14H25NO2 239.19, found 240.3 [M+H+].
Reaction SMILES: [O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]([CH:8]([C:10]1[N:15]=[N:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)nn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)nn1
Yield: 61.4 %

Procedure:
A suspension solution of methyl 6-(1-phenoxyethyl)pyridazine-3-carboxylate (0.1 g, 0.4 mmol) and lithium hydroxide (48 mg, 2 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was stirred at room temperature for 2 hours. The mixture solution was diluting with ethyl acetate (50 mL), and acidified with hydrochloric acid to PH<5. The organic layer was separated, dried over sodium sulfate, and concentrated to give 6-(1-phenoxyethyl)pyridazine-3-carboxylic acid (60 mg, 65%) which was used directly for the next step without purification.
Reaction SMILES: COC(=O)[C@@H](NC(=O)C1C=C(Cl)C=CC=1NCC(C)CC)CC1C=CC(Br)=CC=1.C(OC1C=CC=CC=1B(O)O)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C[O:54][C:55](=[O:94])[CH:56]([NH:78][C:79](=[O:93])[C:80]1[CH:85]=[C:84]([Cl:86])[CH:83]=[CH:82][C:81]=1[NH:87][CH2:88][CH:89]([CH3:92])[CH2:90][CH3:91])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[O:70][CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[CH:60][CH:59]=1>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>[CH2:71]([O:70][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=1[C:61]1[CH:62]=[CH:63][C:58]([CH2:57][C@H:56]([NH:78][C:79](=[O:93])[C:80]2[CH:85]=[C:84]([Cl:86])[CH:83]=[CH:82][C:81]=2[NH:87][CH2:88][CH:89]([CH3:92])[CH2:90][CH3:91])[C:55]([OH:94])=[O:54])=[CH:59][CH:60]=1)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: CCC(C)CNc1ccc(Cl)cc1C(=O)NC(Cc1ccc(-c2ccccc2OCc2ccccc2)cc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Product: CCC(C)CNc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2OCc2ccccc2)cc1)C(=O)O
Yield: 95.3 %

Procedure:
The methyl ester of the title compound was prepared by coupling of the 3-(4-bromo-phenyl)-(2S)-[5-chloro-2-(2-methyl-butylamino)-benzoylamino]-propionic acid methyl ester (1.24 mmol, 0.600 g) and 2-benzyloxyphenyl boronic acid (2.48 mmol, 0.567 g) with Pd (PPh3)4 (0.124 mmol, 0.143 g) as catalyst and Na2CO3 (3.732 mmol) as per Procedure D. The resulting 3-(2′-Benzyloxy-biphenyl-4-yl)-2-[5-chloro-2-(2-methyl-butylamino)-benzoylamino]-propionic acid methyl ester (0.430 g) was then hydrolyzed as per Procedure C to yield the title compound (0.400 g).