Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[NH:18][CH:17]2[C:36](O)=[O:37])[CH:12]=[C:13]([F:15])[CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[CH2:42][O:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:44][C@H:43]([CH2:42][OH:41])[CH2:45][CH2:46][NH:47][C:36]([CH:17]1[CH:16]([C:11]2[CH:12]=[C:13]([F:15])[CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:19]([CH2:31][C:32]([CH3:35])([CH3:33])[CH3:34])[NH:18]1)=[O:37]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 34 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 83c (0.4 g, 0.69 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.3 g, 2.06 mmol), HATU (0.47 g, 1.24 mmol) and iPr2NEt (0.6 mL, 3.44 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.13 g, 35%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[N:16]=[C:17]([C:33]#[N:34])[C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=[O:14])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.O1CCCC1.[OH-].[Na+]>CO>[C:33]([C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:19]=2)[C:24]([OH:25])=[C:15]([C:13]([NH:12][C@@H:5]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][C:3]([OH:35])=[O:2])=[O:14])[N:16]=1)#[N:34]
Reactant: COC(=O)C[C@@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1nc(C(=O)N[C@H](CC(=O)O)c2cccnc2)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
3-(R)-[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-3-pyridin-3-yl-propionic acid methyl ester (25 mg, 0.0533 mmol) was dissolved in methanol (2 mL) and tetrahydrofuran (2 mL.) Sodium hydroxide solution (2 mL, 2M) was added and the reaction was permitted to stir overnight at room temperature. After 18 hours, the pH was adjusted to 4 and reaction lyophilized. The crude product was purified by HPLC to provide the title compound in 80% yield. LC-MS ESI+: 455 (M+1)+; ESI−: 453 (M−1)−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])[N:12]=1>CN(C=O)C.CCOC(C)=O>[O:7]([C:11]1[C:16]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:22]([F:23])([F:25])[F:24])[N:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Oc1ccccc1
Reaction time: 0.17 h
Yield: 18 %

Procedure:
Phenol (57 mg, 0.60 mmol) and sodium hydride (32 mg, 0.8 mmol) were added in DMF (15 mL). The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (70 mg, 0.27 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex EtOAc=1/1) to give the title product (15 mg).
Reaction SMILES: [N:1]([C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N+]=[N-].[H][H]>CO>[NH2:1][C@H:4]1[C:9]([F:11])([F:10])[CH2:8][CH2:7][CH2:6][C@H:5]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N=[N+]=[N-]
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of tert-butyl [(1R,6R)-2-azido-3,3-difluorocyclohexyl]carbamate 36 (0.94 g, 3.40 mmol) in methanol (20 mL) was degassed with nitrogen and treated with 10% PdJC (72 mg). The resulting heterogenous solution was exposed to a hydrogen atmosphere and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 0.78 g (91%) of tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate 37 as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 6.67 (1H, d, J=8.3 Hz), 3.55 (1H, bs), 3.07 (1H, bs), 2.03 (1H, m), 1.62 (3H, m), 1.45 (1H, m), 1.36 (12H, m).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:19][CH2:18]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[OH:3][CH:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])[CH2:21][CH2:22]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)[CH3:2]
Reactant: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)=O)oc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)O)oc23)CC1
Reaction time: 1 h

Procedure:
There was dissolved 4.3 g (0.01 mole) of 2-acetyl-7-{2-hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy}benzofuran in 50 ml of ethanol, and thereto 0.35 g of sodium borohydride was gradually added with cooling with ice. After stirring 1 hour, aceton was added to decompose the excess sodium borohydride and the solvent was distilled away under reduced pressure. The residue was extracted from ethyl acetate and the obtained extract was dried with magnesium after washing with water. Ethyl acetate was distilled away under reduced pressure and the obtained residue was crystallized from ethyl acetate.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17](=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:11][C:10]=1[O:39]CC1C=CC=CC=1)(C)(C)C.[H][H]>[OH-].[OH-].[Pd+2]>[C:31]([NH:30][CH:16]([C:17](=[O:29])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:47])=[O:5])=[C:10]([OH:39])[CH:11]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=C(NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Product: O=C(O)COc1ccc(CC(NC(=O)c2ccccc2)C(=O)NCCCCc2ccccc2)cc1O
Reaction time: 8 h

Procedure:
{4-[2-Benzoylamino-2-(4-phenyl-butylcarbamoyl)-vinyl]-2-benzyloxy-phenoxy}-acetic acid tert-butyl ester of Step C (80 mg, 0.13 mmol) is dissolved in ETOH (2 mL) and Pd(OH)2 (13 mg) on carbon is added. Hydrogen is applied and stirred overnight. The mixture is filtered through 0.45 μm Gelman Acrodisc and the filtrate is concentrated to oil. The oil is dissolved in TFA (2 mL). After 3 hours, the TFA is removed by evaporation. The crude material is purified by reverse phase chromatography (C18, CH3CN/H2O) to provide the title compound (compound 40), {4-[2-benzoylamino-2-(4-phenyl-butylcarbamoyl)-ethyl]-2-hydroxy-phenoxy}-acetic acid; 1H NMR (400 MHz, DMSO-d6): δ8.40 (d, 2H), 7.95 (t, 1H), 7.78 (d, 2H), 7.49 (m, 1H), 7.41 (m, 2H), 7.23 (m, 2H), 7.15 (m, 3H), 6.75 (s, 1H), 6.68 (d, 1H), 6.62 (d, 1H), 4.54 (m, 1H), 4.48 (s, 2H), 3.08 (m, 2H), 2.85 (m, 2H), 2.54 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H); MS (ES+) m/z 491 (M+1).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=2)=[O:19])=[CH:16][C:15]=1I>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:37])([F:36])[F:38])[CH:22]=2)=[O:19])=[CH:39][C:40]=1[C:12]#[C:11][C:8]1[N:7]=[N:6][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=1
Reactant: CN1CCN(Cc2ccc(NC(=O)c3ccc(Cl)c(I)c3)cc2C(F)(F)F)CC1
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: CC(C)Nc1ccc(C#Cc2cc(C(=O)Nc3ccc(CN4CCN(C)CC4)c(C(F)(F)F)c3)ccc2Cl)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 4-chloro-3-iodo-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp:133-134° C.; 1H NMR (300 MHz, CDCl3) δ: 9.62 (1 H, s), 8.11 (1 H, s), 8.05 (1 H, s), 8.01-8.03 (1 H, d, J=9.0 Hz), 7.86-7.88 (1 H, d, J=6.0 Hz), 7.60-7.63 (1 H, d, J=6.0 Hz), 7.44-7.47 (1 H, d, J=9.0 Hz), 7.33-7.36 (1 H, d, J=9.0 Hz), 6.63-6.66 (1 H, d, J=9.0 Hz), 3.99-4.07 (1 H, m), 3.67 (2 H, s), 2.84 (8 H, brs), 2.56 (3 H, s), 1.25-1.30 (6 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H30ClF3N6O: 571.2194. found: 571.2209.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:21][CH:20]=1)[C:13]([C:35]1[CH:40]=[CH:39][C:38]([O:41]CC3C=CC=CC=3)=[CH:37][CH:36]=1)=[C:12]2[CH3:49])C1C=CC=CC=1.C1CCC=CC=1>O1CCCC1.C(O)C.[Pd]>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([C:13]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)=[CH:21][CH:20]=3)[C:15]3[C:11]([C:12]=2[CH3:49])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)=[CH:36][CH:37]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1=CCCC=C1
Product: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indole No. 165 (2.35 g) in tetrahydrofuran (25 mL) and ethanol (25 mL) was added to 2.3 g of 10% palladium on carbon. Cyclohexadiene (10 mL) was added and the reaction allowed to stir at room temperature for 18 hours. The catalyst was filtered through celite and the reaction mixture was concentrated and chromatographed on silica gel using dichloromethane/methanol (4:1) to elute the product (0.8 g) as a white foam: Mp=125-130° C.; 1H NMR 9.68 (s, 1 H), 8.70 (s, 1 H), 7.15 (d, 2 H, J=8.6 Hz), 7.05 (d, 1 H, J=8.8 Hz), 6.85 (d, 2 H, J=8.6 Hz), 6.80 (d, 1 H, J=2.4 Hz), 6.74 (d, 4 H, J=2.6 Hz), 6.57 (dd, 1 H, J=8.6, 2.2 Hz), 5.09 (s, 2 H), 3.88 (t, 2 H, J=6.4 Hz), 3.60-3.15 (m, 2 H), 2.62-2.38 (m, 4 H), 2.09 (s, 3 H), 1.92-1.78 (m, 2 H), 1.55-1.43 (m, 4 H), 1.42-1.30 (m, 2 H); IR (KBr) 3400 (br), 2900, 1620, 1515 cm-1; MS eI m/z 470.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CN)CCCC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a cooled 0° C. solution of (1-cyano-cyclopentyl)-carbamic acid tert-butyl ester (430 mg, 2.04 mmol) in dry THF (4.3 ml) under an atmosphere of argon is added dropwise 1.0 M LiAlH4 (6.13 ml, 6.13 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 3.5 hours. The mixture is then re-cooled to 0° C. and cautiously quenched with water (0.4 ml): 15% NaOH (0.8 ml): water (1.2 ml) (1:2:3 eq). The resultant mixture is filtered through Celite® (filter material) to remove the inorganic solids and rinsed with MeOH. The filtrate is concentrated in vacuo, to yield a white solid, which is purified by chromatography on silica eluting with 30% MeOH in DCM to afford (1-Aminomethyl-cyclopentyl)-carbamic acid tert-butyl ester; [M+H]+ 215.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)[CH3:5])C.Cl.[NH:20]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1)[NH2:21].C(N(CC)CC)C.O>ClCCl.CO>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:7]2[N:20]([C:22]3[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:26][CH:27]=3)[N:21]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(C)=NC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cc2)cc1OC
Reaction time: 8 h
Yield: 73.5 %

Procedure:
N-(1-ethoxy-ethylidene)-3,4-dimethoxy-benzamide 536 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 4-hydrazinobenzenesulfonamide hydrochloride 515 mg (2.23 mmol) was added to the solution. Then, triethylamine 0.35 ml (2.51 mmol) was slowly added dropwise at room temperature for 10 minutes and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 4-[5-(3,4-dimethoxy-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-benzenesulfonamide (575 mg, yield: 72%) was obtained as a solid phase.
Reaction SMILES: [NH2-].[Na+].[C:3]1([CH2:13][C:14]#[N:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[N:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCOCC>[N:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:13]([C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)[C:14]#[N:15])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCCCCCN1CCCCC1
Reactant: N#CCc1cccc2ccccc12
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: N#CC(CCCCCCN1CCCCC1)c1cccc2ccccc12

Procedure:
3.9 g of sodium amide are added in small quantities to 16.7 g of 1-naphthyl-acetonitrile in solution in 200 ml of anhydrous ether. After 2 hours of heating to reflux, 20.5 g of 6-piperidino-1-chloro-hexane are added and heating is continued to reflux for another 5 hours. Then, using the conventional methods, 30 g of product are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Br)=[CH:49][C:48]=1[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>C1COCC1>[CH2:36]([O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:49][C:48]=1[O:55][C:56]([CH3:59])([CH3:58])[CH3:57])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)Oc1cc(CBr)ccc1OCCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCOCc2ccccc2)c(OC(C)(C)C)c1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
To a solution of 327 mg (0.91 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in 10 ml THF was added 2 ml (2 mmol) lithium bis(trimethylsilyl)amide solution in THF drop by drop at −78° C. The reaction mixture was stirred for 2 hours. 300 mg (0.76 mmol) 1-[2-(benzyloxy)ethoxy]-4-(bromomethyl)-2-tert-butoxybenzene in 2 ml THF were added at −78° C. The reaction mixture was stirred for 2 hours. 4.5 ml aqueous hydrogen chloride solution (2N) is added drop by drop. The solution was allowed to be warmed to room temperature. The solution was extracted repeatedly with dichloro methane. The combined organic phases were washed with water, dried with sodium sulfate and concentrated in vacuo. The crude product is purified twice by column chromatography (silica gel, hexane/ethylacetate gradient: 7:1→1:1). The desired product was obtained in 48.7% yield (358 mg, 0.45 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][CH3:11])=[C:6]([CH:8]=1)[NH2:7].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][CH2:10][CH3:11])=[C:6]([NH:7][C:21]([NH:20][C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[S:22])[CH:8]=1
Reactant: CCCc1ccc(C)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCCc1ccc(C)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 60 °C
Yield: 113.2 %

Procedure:
To 5-methyl-2-propylaniline (CA26) (1.38 g, 9.22 mmol) and benzoyl isothiocyanate (1.24 mL, 9.22 mmol) was added acetone (13 mL). The reaction was heated at 60° C. for 4 h. The reaction was cooled and concentrated. The resulting oil was dried in a vacuum oven overnight providing the title compound as a brown oil (3.26 g, 100%): 1H NMR (400 MHz, CDCl3) δ 12.20 (s, 1H), 9.15 (s, 1H), 7.92 (dt, J=8.5, 1.7 Hz, 2H), 7.71-7.60 (m, 1H), 7.55 (m, 3H), 7.18 (d, J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.1 Hz, 1H), 2.66-2.55 (m, 2H), 2.36 (s, 3H), 1.72-1.57 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 179.64, 166.90, 136.22, 135.72, 134.57, 133.74, 131.68, 129.79, 129.22, 128.64, 127.55, 127.24, 33.28, 23.58, 21.01, 13.98; ESIMS m/z 313 ([M+H]+).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CC([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.C(N)(C)(C)C>O1CCCC1>[CH2:1]([O:11][C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=2)=[CH:27][CH:26]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CC(C)(C)N
Solvent: C1CCOC1
Product: CCCCCCCCCCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.2 %

Procedure:
To a solution of n-decanol (1.6 g) and 4-methylcarbonyloxy-4'-carboxybiphenyl (2.6 g) in tetrahydrofuran (50 ml) were added dicyclohexylcarbodiimide (1.4 g) and dimethylaminopyridine (0.5 g), followed by stirring at room temperature for 24 hours. Thereto was added tert-butylamine and the mixture was refluxed at 70° C. for 2 hours and hydrolyzed. After the solvent was distilled off, dilute hydrochloric acid was added to make the solution neutral and the solution was extracted with diethyl ether. After the solvent was distilled off, the residue was washed with hexane and recrystallized from water/ethanol (1/9) solution to obtain the titled compound (about 2.3 g).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][C:14]([O-:16])=O)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([O:47][Si](C(C)(C)C)(C)C)[CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:55].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:47][C:44]1[CH:45]=[C:46]2[C:41]([CH:40]=[CH:39][CH:38]=[C:37]2[N:34]2[CH2:35][CH2:36][C@H:32]([NH:31][C:14](=[O:16])[CH2:13][C:11]3[N:10]=[CH:9][N:8]([C:7]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:12]=3)[C:33]2=[O:55])=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cccc(N3CC[C@H](N)C3=O)c2c1
Reactant: O=C([O-])Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)N[C@H]1CCN(c2cccc3ccc(O)cc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of lithium [1-(triphenylmethyl)-1H-imidazol-4-yl]acetate, as described above in Step B, (4.40 g, 11.6 mmol), (S)-3-amino-1-[7-(tert-butyldimethylsilyloxy)naphthalen-1-yl]-2-oxopyrrolidine hydrochloride, as described above in Step A (3.86 g, 9.84 mmol), HOBT (1.60 g, 11.8 mmol), EDC (2.30 g, 12.0 mmol), and N,N-diisopropylethylamine (6.00 mL, 34.4 mmol) was stirred in DMF (80 mL) at ambient temperature for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (50 mL) and CHCl3 (75 mL). The aqueous layer was extracted further with CHCl3 (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was dissolved in dry THF (75 mL) and TBAF (5 mL of a 1.0 M solution in TBF, 5 mmol) was added. The resulting mixture was stirred at ambient temperature for 30 min, then quenched with saturated aqueous NH4Cl (30 mL) and most of the TBF was removed under reduced pressure. The residual mixture was poured into saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with a gradient of CH2Cl2—2% to 4% MeOH to yield the titled product.
Reaction SMILES: [H-].[Na+].[C:3]([O:7]CC)(=O)[CH2:4][CH3:5].[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11].OS(O)(=O)=O>C1COCC1.CCO.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[C:13]1([C:10](=[O:12])[CH2:11][C:3](=[O:7])[CH2:4][CH3:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC
Reactant: CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
The title compound was prepared according to Popio, V. V. et al. Synthesis (March 1991), pp 195-197. To a stirred suspension of NaH (1.2 g, 50 mmol) and ethyl propionate (5.73 mL. 50 mmol) in 20 mL THF at 20° C. was added EtOH (2 drops), acetophenone (3.0 g, 25 mmol) in 20 mL of THF, and dibenzo-18-crown-6 (150 mg, 0.4 mmol) in 20 mL of THF. Stirred for 30 min, then at reflux for 1 hr. Cooled (0° C.), then added 25 mL of 10% H2SO4 solution and the aqueous was extracted with Et2O. The organics were washed with H2O, aqueous Na2CO3, and brine. The solution was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (1% to 10% EtOAc in hexanes) gave 4.0 g of Intermediate 16 as a thin oil. 1H NMR indicated an ˜10:1 mixture of tautomers favoring the enol form: 1H NMR (400 MHz, CDCl3, enol form) δ7.87 (m, 2H), 7.52-7.4 (m, 3H), 6.17 (s, 1H), 2.47 (q, 2H, J=7.5), 1.21 (t, 3H, J=7.5)